Category: Diet

Research on glycogen storage disease

Research on glycogen storage disease

Research on glycogen storage disease clinical diseaase of glycogen dosease disease type Glycofen from severe hepatosplenomegaly to diwease insufficiency. Severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration, and neuronal Yoga for flexibility are features of the congenital form of the disease[- ]. Article CAS PubMed PubMed Central Google Scholar Hendrickx J, Coucke P, Hors-Cayla MC, Smit GP, Shin YS, Deutsch J, et al. In the perinatal fetal form, which can lead to hydrops fetalis and polyhydramnios, arthrogryposis develops due to akinesia[ ].

Research on glycogen storage disease -

A few cases of patients with a similar phenotype but without any mutation of SLC2A2 were reported, suggesting other genes involved in the pathogenesis of this condition, remaining unknown so far [ 58 ]. Remarkably, the mutations p.

These HNF4α mutations might decrease the SLC2A2 expression in both liver and kidney, resulting in nonfunctional GLUT2 and are responsive to therapy with diazoxide [ 59 , 60 ]. Fasting ketotic hypoglycemia is a hallmark of hepatic GSDs [ 26 , 61 ].

Patients with GSD type 0 and XI show also a typical post-prandial hyperglycemia [ 12 , 16 , 53 ]. In GSD type IV, hypoglycemia can appear late in the clinical course, but it can be also found in patients without signs of liver disease [ 26 ].

Ketotic hypoglycemia without hepatomegaly has also been recently described in GSD type VI and IX [ 6 ]. Futhermore, isolated ketonemia with normoglycemia has been described in patients with GSD types VI and IX [ 62 ].

GSD type XI exhibits a wide range of alterations in glucose homeostasis, including fasting hypoglycemia, hyperglycemia in the fed state, glucose intolerance up to diabetes mellitus in rare cases [ 53 ]. Elevated triglyceridemia and cholesterolemia are common findings in GSDs with liver involvement.

In these conditions, the dysregulation of glucose metabolism leads to fasting intolerance, enhancing secondary lipolysis and increased mitochondrial fatty acid oxidation [ 1 ]. In GDS type XI, the administration of statins may be required [ 63 ]. In the other forms, the dyslipidemia is generally moderate and an appropriate nutritional therapy is effective to reduce plasma lipid values [ 64 ].

As previously mentioned, the distinctive element of the glycogen synthase deficiency is the absence of hepatomegaly, since hepatic glycogen storage is impaired [ 9 , 12 ], although enlarged liver has been reported in some cases of GSD type 0 [ 13 , 16 ]. By contrast, hepatomegaly is the hallmark of the GSD type IV, VI, IX and XI with various degrees of severity, which may show an improvement after puberty in treated GSD type IX patients [ 64 , 65 ].

However, a progression of the liver disease may occur despite a reduction of the liver size [ 44 ]. In GSD type IV the accumulation of abnormal glycogen, less soluble than normal glycogen, causes a foreign body reaction with consequent osmotic swelling and cell death [ 50 ], leading to interstitial fibrosis evolving toward cirrhosis [ 24 ].

Liver fibrosis is outlined also in individuals with GSD types VI [ 38 , 66 ] and IX [ 4 , 51 ]. Furthermore, cirrhosis has recently been depicted in GSD type VI [ 38 ]. Among the GSD IX subtypes, the progression to liver cirrhosis had initially been described only in patients affected by PHKG2 mutations [ 49 ].

Nevertheless, Tsilianidis et al. More recently, early appearance of liver cirrhosis in a 2 years old child with homozygous mutations in PHKB has been reported [ 40 ].

Tumor degeneration is described in GSD type IV, VI and IX. Hepatocellular adenoma and carcinoma have been described in GSD type IV [ 67 ].

GSD type VI can be rarely complicated by focal nodular hyperplasia [ 68 ] and one case of hepatocellular carcinoma has been reported to date [ 69 ]. With regards to GSD type IX, hepatocellular adenomas have been reported in IXa and IXb subtypes [ 4 , 44 ].

Furthermore, the development of hepatocellular carcinoma associated to GSD type IXc has recently been described [ 70 ]. In GSD type XI, liver histology shows marked accumulation of glycogen in hepatocytes along with steatosis.

The degeneration to hepatic adenomas or carcinomas is rare [ 54 ]. The first case of hepatocellular carcinoma in a young boy affected by Fanconi-Bickel syndrome was described in by Pogoriler and colleagues [ 71 ]. Conversely, individuals affected by PHKA2 and PHKG2 mutations can display renal tubular acidosis and tubulopathy with secondary development of rickets in a patient with GSD type IXc.

The establishment of an adequate nutritional therapy improves tubular acidosis [ 37 ]. In addition, renal involvement represents a hallmark of GSD type XI, in which the renal epithelial cells are damaged by the accumulation of glycogen and monosaccharides; this alteration leads to proximal tubular dysfunction, documented by glycosuria and aminoaciduria.

Although this condition is related to a severe phenotype, rare cases of patients with mild renal dysfunction have been described [ 8 ].

Normal length and weight at birth are usually observed, suggesting that the metabolic disorders do not interfere with fetal growth [ 11 , 19 , 72 ], except for newborns with GSD type XI, which are typically low birth weight [ 53 ].

Patients diagnosed with GSD type 0 may show either normal or poor growth with a delayed bone age in early childhood [ 15 , 17 ]. A catch-up growth has been described after the introduction of adequate dietary therapy, comprising uncooked cornstarch [ 9 ].

Osteopenia is a possible complication [ 5 ]. Growth impairment is not a hallmark of GDS type IV and it may be present or not, depending on the causing mutation and the clinical subtype [ 24 ]. In contrast, short stature is a common feature in GSD types VI and IX, with a variability in the degree of improvement of parameters in treated patients reaching the adult age [ 36 ].

Most individuals affected by PhK deficiency achieve standard adult stature parameters, but they show a peculiar growth pattern, with an initial growth retardation in the first 2—3 years of age, followed by a gradual normalization of the linear growth [ 65 ].

Abnormal bone mineralization with and without osteopenia has been reported in GSDs types VI and IX [ 37 , 73 ]. Dietary deficiencies and chronic ketosis are speculated to be contributory factors [ 37 ]. Rickets has been reported in a case of GSD type IXc, due to renal tubulopathy with an inappropriate parathyroid response [ 37 ].

Severe growth impairment is described in Fanconi-Bickel syndrome. Patients affected by proximal renal tubular dysfunction of variable genetic causes show growth retardation ascribed to renal losses but the short stature observed in Fanconi-Bickel syndrome is more pronounced, suggesting other mechanisms not clearly understood [ 74 ].

Newborns are generally low birth weight, likely effect of the insulin deregulation starting in utero [ 53 ]. Furthermore, dwarfism is a striking feature in adult patients [ 1 ], with scarce response to nutritional therapy.

Remarkably, Pennisi and colleagues [ 63 ] reported a substantial improvement of height and weight by the administration of nocturnal enteral nutrition from the age of 1 year, in five patients. Four patients were supplemented with uncooked cornstarch in the enteral nutrition. Notably, untreated patients reached an adult height ranging from Among all GSDs, bone is mostly affected in GSD type XI, where hypophosphatemic rickets, frequent fractures and bone deformities are described as a result of the renal tubular dysfunction [ 76 ].

Limbs deformities and lumbar hyperlordosis may appear in patients with delayed diagnosis, as observed in developing countries [ 74 ]. Skeletal muscle and myocardial involvement is not observed in GSD type 0a [ 9 ].

Heart failure after orthotropic liver transplantation has been described in patients with the progressive liver form of GSD type IV with no previous history of cardiac involvement [ 27 , 28 ]. This could be due to a progression of disease, despite liver transplantation. Indeed, in patients dead after liver transplantation, amylopectin deposits have been observed in different organs and tissues myocardial fibers, skeletal muscle fibers, central and peripheral nervous system cells, macrophages at autopsy [ 77 ].

A good clinical response to liver transplantation may be explained by a mechanism of microchimerism, through which the donor cells transfer the deficient enzyme to the host cells, thus reducing amylopectin deposits [ 78 ].

Mild to severe myopathy and dilated cardiomyopathy are also described in the neuromuscular forms of GSD type IV [ 24 , 79 ].

Remarkably, cardiomyopathy has been reported as the sole presenting symptom of branching enzyme deficiency in one case [ 21 ]. Muscular cramps or fatigue after physical exercise have been recorded in a minority of reports of GSD type VI, usually related to undertreatment and protein deficiency [ 36 ].

Muscle weakness may or may not be observed in PhK deficiency with any genotype [ 48 , 49 ]. In a recent case series, asymptomatic left ventricular and septal hypertrophy was reported in a patient with GSD type VI, and interventricular septal hypertrophy was found in a patient with GSD type IXb.

The authors recommended echocardiogram every 1—2 years for patients with GSD type VI and IX after 5 years of age [ 44 ]. A systematic review of the literature did not reveal other individuals with GSD type VI or IX and cardiac problems [ 3 ]. Muscular involvement can be seen in the context of dyselectrolytemia in GSD type XI [ 52 ], revealed by exercise intolerance and rhabdomyolysis [ 33 ].

In these patients, hypoglycemia is often non symptomatic, as the loss of neuroglycopenic signs in recurrent hypoglycemia is notable [ 14 ]. The phenomenon, noted as hypoglycemia-associated autonomic failure, is due to a defective glucose counter-regulation with an attenuated sympathoadrenal and neural response leading to reduced neurogenic and cerebral symptoms [ 80 ].

Seizures are uncommon [ 5 ]. Mild developmental delay was also reported in GSD types VI, IX and XI [ 36 , 76 ]. With regards to GSD type IX, a recently published literature review with data analysis of patients outlined that a mild developmental delay was present in type IXc, with a frequency two times higher than other subtypes [ 4 ].

In the progressive hepatic GSD type IV the muscle tone is often normal at the time of diagnosis, but progression to generalized hypotonia may develop within the two years of life [ 20 ].

GSD type IV shows a complex involvement of neuromuscular system. The perinatal and congenital neuromuscular subtypes show severe congenital hypotonia and respiratory distress, which impose the differential diagnosis with spinal muscular atrophy and the inherited storage disorders with neuromuscular involvement eg Pompe disease, Zellweger disease [ 19 , 20 ].

Patients affected by the childhood neuromuscular subtype show skeletal myopathy and hypotonia and may experience motor developmental delay with possible death in early adulthood [ 24 ]. Furthermore, progressive spastic paraparesis, neurogenic bladder, and axonal neuropathy have been described in the adult polyglucosan body disease [ 33 ].

This is a rare condition due to the accumulation of polyglucosan bodies into the neuronal axons and processes of astrocytes and oligodendrocytes.

This process leads to a sensorimotor neuropathy, with involvement of both upper and lower motor neuron and onset around the fifth decade. The clinical presentation is very variable, characterized by symptoms of neurogenic bladder, legs weakness, gait disturbances, spasticity, cognitive dementia with different grades of severity.

Among the neurologic signs, spasticity, reduced ankle reflexes, extensor plantar response and sensory deficits of lower extremities are seen [ 81 ]. Mild hypotonia was reported in a few GSD type VI patients [ 36 ]. Hypotonia and motor delay can be rarely associated to PHKB and PHKG2 mutations [ 48 , 51 ].

With regards to PHKA2 mutations, Lau et al. Hypotonia and motor impairment were also recorded in GSD type XI [ 1 , 3 ]. A summary of the main clinical features of the GSDs is provided in Table 1.

A careful clinical history and examination together with laboratory findings may suggest the diagnosis. An OGTT can be realized when GSD types 0, VI and IX are suspected; in all forms elevated lactate will be recorded at min. Patients with GSD type 0 will show hyperglycemia within the first two hours, then hypoglycemia might be observed at a prolonged OGTT, likely due to hyperglycemia-induced hyperinsulinemia [ 12 ].

In the past, enzymatic activity in peripheral blood cells and cultured skin fibroblasts was performed.

The reduced activity of branching enzyme in leucocytes, erythrocytes and fibroblasts confirmed the diagnosis of GSD type IV, however normal activity in leukocytes could not exclude the neuromuscular forms [ 24 ]. In GSD type VI a reduced phosphorylase activity could be detected in erythrocytes and leukocytes [ 35 ].

The deficiency of phosphorylase kinase activity could be outlined in leucocytes, erythrocytes and fibroblasts, except for the forms associated to certain missense mutations of PHKA2 and PHKB [ 41 , 47 ]. In the case of normal enzymatic activity in peripheral blood cells, a liver biopsy for enzymatic assay in hepatocytes was assessed [ 47 ].

More recently, molecular analysis became the method of choice to confirm the diagnosis for each GSD type. However, these forms may have similar clinical and biochemical presentation. Thus, performing single gene analysis would result time consuming and expensive.

In the last decade, next generation sequencing technology as gene panel or clinical exome found a wide application for the diagnosis of inborn errors of metabolism for the genetic heterogeneity of these conditions, allowing to carry out large molecular characterization of patients within an useful timeframe and at a reasonable cost [ 18 ].

In these cases, histology and enzyme testing on a liver biopsy specimen may be required to confirm the diagnosis [ 37 ]. A strict dietary regimen high in proteins and low in simple carbohydrates, which includes frequent intake of complex carbohydrates such as maltodextrin and uncooked cornstarch, is fundamental to prevent hypoglycemia in ketotic GSDs [ 6 ].

Indeed, a metabolic imbalance results in overnight hypoglycemia and ketosis, that are associated to short stature, osteopenia, and neurologic complications [ 43 ]. GSDs types 0, VI and particularly type IX would benefit from a strict glycemia monitoring.

A minority of patients with mutations of PHKA2 and PHKG2 associated to a severe phenotype often require overnight feeding to maintain euglycemia [ 85 ]. Since gluconeogenesis is preserved, protein supplementation provides gluconeogenic precursors that can be used for repletion of Krebs cycle intermediates and endogenous glucose production in GSD types 0, IV, VI and IX.

By improving glucose homeostasis, hepatic glycogen accumulation and secondary complications might be restrained. High protein intake is especially needed in GSD type VI to improve muscle function [ 44 ]. In Ross and co-workers [ 85 ] described the efficacy of an extended-release cornstarch Glycosade in GSD types 0, III, VI and IX to achieve a longer time of euglycemia during the night, with stable values of other markers of metabolic control and hepatic function.

In the United States, the extended-release cornstarch preparation has been approved for nocturnal use in GSD patients above 5 years of age. However, the administration of Glycosade in patient between 2 and 5 years of age resulted safe and effective as well [ 86 ].

Adverse effects such as abdominal distension, diarrhea and flatulence have been reported, but to date they were not recorded in patients with GSD types 0, VI and IX [ 61 ]. Patients with GSD type 0 are treated with frequent feeds of hyperglucidic diet plus cornstarch and protein supplementation.

Patients with GSD type IV are managed with hyperglucidic diet plus cornstarch, nocturnal enteral feeding, protein enrichment with the aim to limit the accumulation of glycogen, to prevent catabolism and to improve growth and fasting tolerance.

The more severe forms are treated with liver transplantation [ 26 ]. For GSD type XI, Pennisi and co-workers [ 63 ] proposed the nocturnal enteral nutrition in younger children and in patients with a severe growth delay in order to prevent fasting hypoglycemia.

Frequent, small meals, restricted in glucose and galactose, and raw cornstarch administration at night are used to prevent metabolic acidosis, which may occur at times of surgery or other stresses. Hypercholesterolemia may require a medical treatment with statins after five years of age; bicarbonate supplementation may be required to balance the urinary bicarbonate loss [ 63 ].

According to the available data, universally accepted guidelines for the management of these types of GSDs have not been defined. Nevertheless, an appropriate follow-up should be provided, in order to establish a good metabolic control and monitor the possible complications.

Medical and nutritional evaluations and blood assessment, including complete liver and renal function, lipid profile, calcium-phosphate metabolism, serum electrolytes, blood gas analysis and urinalysis, should be fulfilled every 6 months on average; a higher frequency is recommended in younger patients and in those who have not achieved a metabolic balance.

A continuous glucose monitoring may be helpful to survey the glycemic fluctuations, especially in younger patients. Alpha-fetoprotein levels along with abdomen ultrasound can be used to screen for hepatocellular carcinoma, even though there are no validated surveillance protocols to date [ 37 ].

GSD type IV patients require a complete cardiac function evaluation, including electrocardiogram and echocardiography. For patients with GSD types VI and IX after 5 years of age a cardiac evaluation is recommended every 1—2 years [ 44 ]. Regarding the bone metabolism, a careful assessment of calcium and vitamin D intake and monitoring of OH vitamin D level is recommended.

Calcium, phosphate and vitamin D supplementations, along with annual DXA scan evaluation, are required to prevent osteopenia and fractures, particularly in GSD type XI, along with a surveillance of renal function [ 61 ]. Skeletal X-Rays are required in GSD type XI to evaluate rickets evolution [ 55 , 56 ].

GSDs type 0, IV, VI, IX and XI with liver involvement may have a similar clinical presentation. However, these diseases exhibit a phenotypic continuum, and even in the mildest forms, regular monitoring and dietary adjustments are necessary to restrain disease progression and complications.

Some cases may exhibit a clinical burden with severe organ complications. Building a proper knowledge among physicians about these rare conditions is crucial to improve prognosis and quality of life of patients, especially those affected by the most severe forms. Further studies are needed to outline the genotype—phenotype correlation and define personalized therapies and management.

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Ogawa A, Ogawa E, Yamamoto S, Fukuda T, Sugie H, Kohno Y. Case of glycogen storage disease type VI phosphorylase deficiency complicated by focal nodular hyperplasia. GSD6 is an autosomal recessive disorder, with very few documented cases, and with mutation in PYGL gene on chromosome 14q They are reported more in males, and considered most common of all GSD9.

Though, initially thought to be mild disease 38 ; severe presentations of liver cirrhosis are also reported. Symptomatic to prevent hypoglycemia with frequent meals and snacks, high protein diet, and complex carbohydrates. GSD9a has X-linked inheritance with mutations in the PHKA2 gene on chromosome Xp GSD9c results from impaired gamma unit of phosphorylase kinase enzyme function in liver and testis, with early childhood presentations of recurrent hypoglycemia, hepatomegaly progressing to liver cirrhosis and end stage liver disease; apart from motor delay, hepatosplenomegaly, renal tubular damage and muscle weakness Because the gamma subunit contains the catalytic site of the enzyme, GSD9C typically has a more severe phenotype.

In personal experience SK unpublished data , a teenager presented with seizure disorder, microcephaly, intellectual disability, short stature apart from clinical presentations noted above. Apart from clinical presentation noted above, elevated liver enzymes and lactate with severe fasting ketosis in setting of normal triglycerides creatine kinase CK and uric acid can be seen.

Measurement of enzyme activity in liver may help but diagnostic confirmation includes molecular analysis of PHKG2 gene Nutritional approaches to prevent recurrent hypoglycemia with high-protein and complex carbohydrates and symptomatic treatment and management for any hypoglycemia related complications may be helpful.

In personal experience SK unpublished data , teenage presentation of a GSD9c case with liver failure was treated successfully with liver transplantation and at 3-year post transplantation, showed improvement in cognitive abilities in late adolescence, to secure successful vocational training and employment, improved muscle strength, resolution of hepatosplenomegaly and seizures.

GSD9C is an autosomal recessive disorder caused by mutations of the PHKG2 gene which encodes the gamma subunit of phosphorylase kinase on chromosome 16p GSD3, also known as Cori Disease or Forbes disease results from glycogen debrancher enzyme GDE deficiency with impaired glycogen breakdown and abnormal glycogen accumulation, affecting liver, skeletal and cardiac muscles 35 , Muscular symptoms become apparent during and after adolescence though hypertrophic cardiomyopathy seen in younger childhood 43 , As noted above, characteristic findings include fasting hypoglycemia with ketosis, hyperlipidemia, elevated CK, an inverse relationship between a patients age and liver enzymes, lack of lactic acidosis and hyperuricemia 35 , 43 - A diagnosis can be made by mutation analysis of the AGL gene 46 or liver biopsy to detect the enzymatic defect.

Best approaches are nutritional with frequent meals, with high protein content and lesser amounts of UCCS than in GSD1 , or bedtime glycosade helps growth during adolescence Though there are suggestions that a modified Atkins diet improves myopathy symptoms GSD3 has autosomal recessive inheritance, with 58 different reported mutations in the AGL gene on chromosome 1p GSD4, also known as Andersen disease or Brancher deficiency, is a glycogenolysis defect with impaired and few α-1,6-glycosidic bonds along glycogen chain, resulting in abnormal glycogen with limited branch points limited dextran similar to amylopectin or polyglucosan Clinical presentation is variable and historically classified as two hepatic and four neuromuscular forms based upon age of onset and severity More recent studies suggest that GSD4 phenotypes should be considered a continuum of disease as opposed to discreet subtypes 49 , The classical hepatic GSD4 typically presents within 18 months of birth with patients having a failure to thrive, hepatosplenomegaly, and liver cirrhosis As the disease progresses, liver failure ultimately results, leading to death by the age of 5 unless a liver transplant is performed A non-progressive hepatic form with a similar presentation has also been described 52 , Neuromuscular variants range in onset from in utero presenting perinatally as fetal akinesia deformation sequence FADS to adulthood as adult polyglucosan body disease APBD with wide severity range from perinatal death to mild symptoms Commonly seen features of the neuromuscular variant of disease includes: hypotonia, muscle atrophy, myopathy, cardiomyopathy, central nervous system CNS , and peripheral nerve system PNS dysfunction Liver dysfunction with abnormal coagulation can be non-specific findings and amylopectin like material deposition can be seen in liver, heart, muscle, brain, spinal cord or reduced glycogen branching enzyme GBE activity seen in liver, muscle or leukocyte; but confirmation made by molecular analysis of GBE1 gene Unlike other liver GSDs, GSD4 has no specific treatment.

Early liver transplant is indicated in patients with the classical hepatic form but only in absence of cardiac or CNS disease GSD4 is rare and has autosomal recessive inheritance with mutations in the GBE1 gene on chromosome 3p GSD9B, also known as phosphorylase kinase deficiency of liver and muscle, have predominant hepatomegaly, short stature seen in early childhood and, sometimes in addition, muscle weakness and hypotonia Can be asymptomatic, but hypoglycemia and reduced enzyme activity can be seen.

Diagnosis is mainly confirmed by mutation analysis of the PHKB gene. Symptomatic with prevention of hypoglycemia with hi-protein and complex carbohydrate diet; though there is no specific treatment for muscle disease GSD9B is an autosomal recessive disorder caused by mutations of β subunit of PHKB gene on chromosome 16q GSD0b, also known as muscle glycogen synthase deficiency, is rare and seems to affect muscle mitochondrial structure and function apart from depleted glycogen Known symptoms include muscle fatigue, exercise intolerance, recurrent exertional syncope, hypertrophic cardiomyopathy, sudden cardiac death without cardiomyopathy 55 - Clinical suspicion with molecular analysis of GYS1 gene provides diagnostic confirmation.

Muscle biopsy can show depleted glycogen; oxidative fibers and abnormal mitochondria 55 - No specific treatment, preventive measures, supportive therapy with high protein complex carbohydrates diet may help.

GSD0b is an autosomal recessive disorder caused by mutations of GSY1 gene on chromosome 19q GSD2, also known as Pompe disease or acid maltase deficiency results from impaired lysosomal acid-α-glucosidase GAA function and accumulation of lysosomal glycogen in skeletal, respiratory and cardiac muscle and often considered as lysosomal storage disorder LSD than GSD.

A non-classical infantile form shows slower symptom progression, is less severe with no cardiomyopathy Late-onset Pompe disease childhood, juvenile, and adult forms is often used to describe patients who present after the first year of life with muscle weakness, and hypotonia Clinical suspicion as noted above with characteristic evidence of hypertrophic cardiomyopathy with EKG findings of shortened PR interval and high QRS complexes and elevated CK is seen in the infantile-onset form.

While, proximal myopathy with diaphragmatic weakness is seen in late-onset disease. Elevated blood aminotransferases and CK are common but diagnostic confirmation noted with deficient GAA enzyme activity in lymphocytes, fibroblasts, and muscle or molecular analysis of biallelic GAA gene GAA activity is usually absent in infantile-onset disease or decreased in late-onset disease.

Some genotype—phenotype correlations exist and determined by the type of the mutation 62 , Dried blood spot testing measuring GAA enzyme activity has helped GSD2 to be included in Newborn Screening Evaluation of the CRIM status is important, since CRIM negative status is associated with poor response to ERT and poor prognosis, if immunomodulation is not started early Results of newborn screening in Taiwan demonstrated significant long-term benefits from the early identification and treatment of patients with infantile Pompe disease before symptoms appeared making an argument for its inclusion in newborn screening panels in many states in the U.

and trialed in several countries 65 , Enzyme replacement therapy ERT using human recombinant acid α-glucosidase, the only approved treatment in the US and Europe since , is based on its ability to degrade accumulated lysosomal glycogen and improve cardiac and skeletal muscle function Though, a negative cross reacting immune material CRIM -negative status has high anti-rhGAA IgG antibodies development and resultant reduced ERT therapeutic effect with poor outcomes if not treated early with immunosuppression 65 , If early diagnosis of late-onset disease is made via newborn screening, the question of when to start treatment in an asymptomatic patient is debated.

Improvement in pulmonary function is seen in symptomatic patients with late-onset disease GSD2 is a pan-ethnic autosomal recessive disorder caused by mutations of the GAA gene on chromosome 17q The increasing list of GAA gene pathogenic mutations can be found at www.

The estimated prevalence is considered to be 1 in 5, GSD5, also known as McArdle disease results from deficient muscle phosphorylase activity and results in impaired glycogenolysis leading to exercise intolerance, muscle weakness and cramping alleviated by rest, and exercise induced rhabdomyolysis.

A common history of childhood onset exercise intolerance and a wide range of severity and age of onset reported with most serious complication being renal failure from myoglobinuria and rhabdomyolysis. Apart from clinical suspicion, elevated CK, myoglobinuria and renal dysfunction as common biochemical markers with additional non-invasive diagnostic confirmation with molecular analysis of PYGM gene is indicated.

Invasive muscle biopsy with negative muscle phosphorylase activity can help diagnosis too. Oral sucrose loading 30—40 minutes before exercise helps exercise tolerance as exogenous fuel source to help energy gap with lack of endogenous glucose from glycogenolysis and free fatty acids availability until ~10 minutes into exercising Regular exercise of moderate intensity helps maximize circulatory capacity and increase fuel delivery to muscles GSD5 is an autosomal recessive disorder caused by mutations of PYGM gene on chromosome 11q GSD7, also known as Tarui disease results from deficient muscle subunit of phosphofructokinase PFK enzyme as a rate limiting factor, with resultant impaired glycogenolysis and glycolysis.

The classical form is characterized by exercise intolerance, often with rhabdomyolysis , muscle cramps and pain.

In some cases jaundice accompanied by increased serum bilirubin, exercise related elevated CK levels, myoglobinuria and myogenic hyperuricemia may also be seen 72 , In addition, three other GSD7 subtypes are late-onset, infantile, and hemolytic.

Late-onset GSD7 typically presents in later life with muscle cramps and myalgias although patients may show increased muscular weakness and fatigability in childhood. Patients with severe infantile form of GSD7 present with hypotonia early after birth and often die within their first year of life.

Arthrogryposis and mental retardation may be present in cases who survived early death. The hemolytic form is characterized by non-spherocytic hemolytic anemia without muscle symptoms GSD7 though clinically similar to GSD5, is different with the absence of a second wind phenomenon and a detrimental, as opposed to beneficial, effect of glucose administration due to impaired fatty acid oxidation in GSD7 Presentations can include hyperbilirubinemia, increased reticulocytes due to the elevation of hemolysis from partial loss of PFK activity in erythrocytes, elevated CK, lactate dehydrogenase, and aspartate transaminase following acute exercise 4.

Non-invasive diagnostic confirmation includes molecular analysis of PFKM gene Muscle biopsy or forearm exercise test showing elevated ammonia but reduced lactate can confirm impaired glycolysis following anaerobic exercise can be supportive.

Symptomatic and preventive with avoiding strenuous exercise, high protein intake during exercise and avoiding exercise related simple sugars as sucrose intake.

GSD7 is an autosomal recessive disorder caused by mutations of the PFKM gene on chromosome 12q GSD9D, also known as muscle phosphorylase kinase deficiency or X-linked muscle glycogenosis results from impaired alpha subunit of the muscle phosphorylase kinase activity, associated with muscle weakness, atrophy, and exercise-induced pain and stiffness, with a variable age at onset, mainly seen in males, though can remain asymptomatic until intense exercise 39 , GSD9D is an X-linked recessive disorder caused by mutations of the PHKA1 gene which encodes the alpha subunit of muscle phosphorylase kinase on chromosome Xq GSD10 also known as PGAMM deficiency results from impaired muscle phosphoglycerate mutase-2 activity essential for conversion of 3-phosphoglycerate to 2-phosphoglycerate during glycolysis and resultant childhood or adolescence presentation of muscle cramping, rhabdomyolysis, and myoglobinuria precipitated by bursts of vigorous exercise Elevated CK, myoglobinuria can be confirmed non-invasively with molecular analysis of PGAM gene Enzymatic assay shows decreased muscle phosphoglycerate mutase-2 activity.

GSD10 is an autosomal recessive disorder caused by mutations of the PGAM2 gene on chromosome 7p Of the 15 cases reported in the medical literature, a founder exon1 null mutation noted in African Americans 76 , GSD11 78 also known as GSDXI results from impaired muscle M isoform of lactate dehydrogenase enzyme essential for interconversion of lactate and pyruvate in muscle glycolysis with resultant fatigue, exertional myoglobinuria and also uterine pain and stiffness during pregnancy and labor Biochemical findings of elevated CK, lactate and myoglobinuria can be confirmed with molecular analysis of LDHA gene.

LDH activity in red blood cells is low or absent. No specific treatment. In pregnant women with GSD11 planned cesarean section can avoid increased risk of dystocia during labor Lactate dehydrogenase A deficiency is an autosomal recessive disorder caused by mutations of the LDHA gene on chromosome 11p The H isoform of LDH is found in the heart and encoded by the lactate dehydrogenase B gene on chromosome 12p Hepatorenal glycogenosis or Fanconi-Bickel Syndrome, listed as MIM , previously also known as GSD XI, is an autosomal recessive disorder with mutations in SLC2A2 gene encoding GLUT2 transporter, affecting glycogen accumulation in liver and kidney, proximal renal tubular dysfunction and defective glucose and galactose utilization GSD12 also known as ALDOA deficiency, results from impaired fructose-1,6-bisphosphate aldolase A activity, essential for interconversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate in glycolysis, with resultant hereditary non-spherocytic hemolytic anemia and myopathy In contrast, overexpression of aldolase A is associated with multiple forms of cancer including squamous cell carcinoma of the lung, hepatocellular, and renal cancer suggestive that increased glycolysis promotes tumor growth in cells

Glycogen is a branched polymer Research on glycogen storage disease Researcj stored Research on glycogen storage disease in the Subcutaneous fat and body shape and muscle during times glycoegn Research on glycogen storage disease only to be broken ob and released as glucose during times of need. It appears as a densely branched snowflake shorage 3-D with Glyxogen in, a glycosyltransferase enzyme in the center. Glycogen in, initiates the formation of glycogen by glyccogen glucose residues from UDP Metabolic fat burning and subsequent linear prolongation up to ten glucose molecules making the core unit. To this core unit, subsequent attachment of glucose occurs by enzymes such as glycogen synthase, which adds the alpha 1,4 linkages, and glycogen debranching enzyme, which adds the alpha 1,6 branch points every 12—13 glucose residues to elongate and form a globular granule of 30, glucose units 12. The degradation of glycogen into usable glucose molecules result from combined actions of glycogen phosphorylase, glycogen debranching enzyme, and phosphoglucomutase. Glucose is stored as glycogen primarily in the cytoplasm of liver and muscle cellular tissue, and in small amounts in brain tissues. While glycogen in the liver acts as the main depot source that maintains blood glucose homeostasis, glycogen in skeletal muscles provides energy to muscles during high-intensity exertion.

because every child deserves Research on glycogen storage disease be Research on glycogen storage disease. Reseacrh Storage Glyogen Type 1 GSD1 is a Reesarch, genetic metabolic disorder that Ressearch when a specific glycoegn is either missing or not functioning properly.

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READ MORE. The Children's Fund for Glycogen Storage Disease Research is Research on glycogen storage disease Metabolism Boosting Herbs not-for-profit c RMR and long-term weight management foundation that Antioxidant-dense vegetables to make a difference in the diseasd of children and their Diabetes and stress management techniques affected by GSD1.

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Resewrch MORE. Ultragenyx Pharmaceuticals is establishing a Global Leadership Council to learn Rehydration for children about the needs and challenges of the Diseaae community.

If sisease would like to be considered, please click below to learn more. Running a marathon is not an easy task for anyone. Running a marathon with GSD is something else entirely. With hard work, determination, and lots of smarties, this past November, Jake Gordon completed the NYC Marathon.

Congrats Jake! Research is underway on an investigational mRNA treatment that could potentially correct the cause of GSD1a by teaching the body to break down glycogen. Click below to learn more about the Ba1ance Trial. info curegsd.

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Glycogen Storage Disease | Boston Children's Hospital The Research on glycogen storage disease subtypes ylycogen GSD IX include subtypes caused by dieease deficiency of phosphorylase kinase Research on glycogen storage disease, phosphorylase djsease γ Customizable resupply solutions δ, or muscle ob kinase. Low-dose storafe gene therapy Researc Pompe disease enhances therapeutic efficacy of ERT via immune tolerance induction. Neil WP, Hemmen TM. Glycogen storage diseases glycogenoses Pathophysiology and epidemiology Glycogen storage disease GSD is caused by a genetically determined metabolic block involving enzymes that regulate synthesis glycogenesis or glycogen breakdown glycogenolysis [ 13 ]. Glycogen storage disease type Ib: infectious complications and measures for prevention. What is glycogen storage disease? The α-subunit isoforms are inherited in an X-linked fashion, while the other isoforms have an autosomal recessive inheritance [ 40 ].

The frequency of G6PC mutations was similar to that reported previously for North American and European Caucasian populations. Notably, we detected two PHKB2 mutations that have not been described previously, suggesting the probability of inadequate identification and underdiagnosis of GSD IXa in Brazil.

The observations of MRI alterations in regions of high metabolism, such as the frontal lobes, temporal lobes, and basal ganglia, are consistent with the hypoglycemia-induced origin of the lesions.

Thus, the main neurological impact of glycogenosis is apparently related to inadequate metabolic control, especially that of hypoglycemia. The data presented in the study are deposited in the BioProject repository, accession number PRJNA and the new mutations detected were uploaded to the ClinVar database.

CAAE: Informed consent was also obtained for the publication of the images in Figures 1A—D. JM conceptualized the research, gathered and analyzed the data, and wrote the initial manuscript. DV helped with the data analyses and draft of the initial manuscript.

BT reviewed the neuroimaging scans. MC coordinated the study, and revised and conducted critical reviews of the manuscript for key intellectual content.

MS helped with the data analyses. All authors contributed to the article and approved the submitted version. This study was funded in part by the Coordenação de Aperfeiçoamento de Pessoal de Nivel Superior-Brazil CAPES conferred to JM and DV Finance Code The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The authors are grateful to the families and children who participated in the study. Kanungo S, Wells K, Tribett T, El-Gharbawy A.

Glycogen Metabolism and Glycogen Storage Disorders. Ann Transl Med —4. doi: PubMed Abstract CrossRef Full Text Google Scholar. Rich LR, Harris W, Brown AM.

The Role of Brain Glycogen in Supporting Physiological Function. Front Neurosci Wolfsdorf JI, Weinstein DA. Glycogen Storage Diseases. Rev Endocr Metab Disord 4 1 — Aydemir Y, Gürakan F, Saltık Temizel İN, Demir H, Oğuz KK, Yalnızoğlu D, et al.

Evaluation of Central Nervous System in Patients With Glycogen Storage Disease Type 1a. Turk J Pediatr —8. Beyzaei Z, Geramizadeh B, Karimzadeh S.

Diagnosis of Hepatic Glycogen Storage Disease Patients With Overlapping Clinical Symptoms by Massively Parallel Sequencing: A Systematic Review of Literature.

Orphanet J Rare Dis — Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GPA. Glycogen Storage Disease Type I: Diagnosis, Management, Clinical Course and Outcome. Results of the European Study on Glycogen Storage Disease Type I ESGSD I.

Eur J Pediatr Suppl — CrossRef Full Text Google Scholar. Ellingwood SS, Cheng A. Biochemical and Clinical Aspects of Glycogen Storage Diseases. J Endocrinol R— Bali GS, Chen YT, Austin S. Glycogen Storage Disease: Type I.

In: Adam MP, Ardinger HH, Pagon RA, editors. Seattle, Washington: University of Washington — Google Scholar. Beauchamp NJ, Dalton A, Ramaswami U, Niinikoski H, Mention K, Kenny P, et al. Glycogen Storage Disease Type IX: High Variability in Clinical Phenotype.

Mol Genet Metab — Herbert M, Goldstein JL, Rehder C, Austin S, Kishnani PS, Bali DS. Phosphorylase Kinase Deficiency Summary Genetic Counseling.

Achouitar S, Goldstein JL, Mohamed M, Austin S, Boyette K, Blanpain FM, et al. Common Mutation in the PHKA2 Gene With Variable Phenotype in Patients With Liver Phosphorylase B Kinase Deficiency. Mol Genet Metab —4. Neil WP, Hemmen TM.

Neurologic Manifestations of Hypoglycemia. In: Rigobelo E, editor. Diabetes - Damages and Treatments. Rijeka: InTech McNay EC, Williamson A, McCrimmon RJ, Sherwin RS.

Cognitive and Neural Hippocampal Effects of Long-Term Moderate Recurrent Hypoglycemia. Diabetes — Ho MS, Weller NJ, Ives FJ, Carne CL, Murray K, vanden Driesen RI, et al.

Prevalence of Structural Central Nervous System Abnormalities in Early-Onset Type 1 Diabetes Mellitus. J Pediatr — Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Genet Med — Froissart R, Piraud M, Boudjemline AM, Vianey-saban C, Petit F, Hubert-buron A, et al. Glucosephosphatase Deficiency. Orphanet J Rare Dis Rake JP, ten Berge AM, Visser G, Verlind E, Niezen-Koning KE, Buys CHCM, et al.

Glycogen Storage Disease Type Ia: Recent Experience With Mutation Analysis, a Summary of Mutations Reported in the Literature and a Newly Developed Diagnostic Flowchart.

Eur J Pediatr — Lei KJ, Chen YT, Chen H, Wong LJC, Liu JL, McConkie-Rosell A, et al. Genetic Basis of Glycogen Storage Disease Type 1a: Prevalent Mutations At the glucosephosphatase Locus.

Am J Hum Genet — PubMed Abstract Google Scholar. Chevalier-Porst F, Bozon D, Bonardot AM, Bruni N, Mithieux G, Mathieu M, et al. Mutation Analysis in 24 French Patients With Glycogen Storage Disease Type La. J Med Genet — Reis F de C, Caldas HC, Norato DYJ, Schwartz IVD, Giugliani R, Burin MG, et al.

Glycogen Storage Disease Type Ia: Molecular Study in Brazilian Patients. J Hum Genet —9. Carlin MP, Scherrer DZ, De Tommaso AMA, Bertuzzo CS, Steiner CE.

Determining Mutations in G6PC and SLC37A4 Genes in a Sample of Brazilian Patients With Glycogen Storage Disease Types Ia and Ib. Genet Mol Biol —6. During stress or short periods of fasting, glucagon signals the liver to break down glycogen stores into glucose glycogenolysis.

Glucose is then released into the circulation maintaining blood glucose homeostasis during the times of high energy demands or fasting. Skeletal muscles use glycogen in a similar manner, however, typically after several minutes of strenuous activity to keep up with its energy requirements.

Glucose and glycogen convert into one another via synthesis or degradation through various steps in the glycogen metabolism pathways as presented schematically in Figure 1. Mutations in genes encoding individual enzymes in the glycogen metabolism pathway lead to a class of diseases named glycogen storage disorders GSDs , whereas defects in glucose oxidation are identified as glycolysis defects.

Depending on the enzyme defect and its relative expression in the liver, kidney, skeletal muscle, or heart, the clinical manifestations of GSDs varies from one disorder to the other.

As a general rule, Liver GSDs commonly present with fasting hypoglycemia ± hepatomegaly. While muscle GSDs present in one of two different ways: exercise intolerance and rhabdomyolysis or fixed muscle weakness without rhabdomyolysis 3.

Often exercise intolerance and rhabdomyolysis is seen in dynamic disorders like McArdle GSD5 , and Tarui GSD7 diseases, while fixed muscle weakness without rhabdomyolysis is seen in cytoplasmic disorders associated with glycogenolysis defects as debrancher defect GSD3a or lysosomal glycogen breakdown defects as Pompe disease GSD2 4.

Genetic defects with clinical features and epidemiology of each disorder of the glycogen metabolism pathway are summarized in Table 1. We will review glycogenosis and GSDs involving the liver, muscle, brain and include the lysosomal storage of glycogen—Pompe disease.

GSD0a, is liver glycogen synthase enzyme deficiency with impaired ability to incorporate UDP-glucose onto glycogen strands and elongate it within the liver. Another consequence of glycogen synthase deficiency is excess of substrates of the glycolytic pathway due to a reduced flow into glycogenosis see Figure 1.

The net effect results in transient post- prandial hyperglycemia and hyperlactatemia 5 , 8. However, some affected individuals may be asymptomatic or go undiagnosed 6 , 9. GSD0a main clinical presentations include fasting Ketotic hypoglycemia without hepatomegaly, supported by a low pre-prandial blood glucose level associated with high blood and urine ketones and a high post-prandial blood glucose, lactate and alanine levels.

Ultimately diagnosis can be confirmed by non-invasive DNA analysis of the GYS2 gene or invasive enzymatic analysis from liver biopsy Current treatment for GSD0a includes avoiding fasting, and frequent meals that are high in protein, to promote gluconeogenesis and uncooked cornstarch UCCS as needed in the day and or at nighttime to prevent hypoglycemia 8 , With proper management, GSD0a has good prognosis.

GSD0a is an autosomal recessive disorder caused by a mutation in the GYS2 gene located at 12p There are less than 30 reported cases of GSD0a GSD1 is caused by defective glycogenolysis and gluconeogenesis and is subdivided into two types: GSD1a and GSD1b. GSD1a, also known as Von Gierke disease or Glucosephosphatase G6Pase deficiency results from impaired ability of the hydrolase subunit of G6Pase, also known as G6Pase-α to hydrolyze G6P, leading to impaired function of G6Pase in removing the phosphate group from glucosephosphate G6P , thus, impairing free glucose availability in the last step of gluconeogenesis see Figure 1 ; resulting in impaired glucose homeostasis and hypoglycemia.

G6Pase-α is necessary to convert fructose and galactose into glucose and is expressed in the liver, kidney, and intestines. Patients typically present by 6 months of age with fasting hypoglycemia or hepatomegaly, and are found to have protuberant abdomen, stunted growth, and doll-like facies 14 - Long term complication of from kidney glycogen accumulation include GSD nephropathy, chronic kidney disease, polycystic kidney and renal cancer, hyperuricemia associated with renal stones and renal tubular acidosis 16 , Poor disease management or disease progression can lead to short stature, osteoporosis, anemia, polycystic ovarian syndrome, and hepatic adenomas which may be associated with the risk of transforming into hepatocellular carcinoma 16 - Patients with GSD1a typically have hypoglycemia from impaired last step of gluconeogenesis as discussed above, hyperuricemia and hypertriglyceridemia from excess G6P resulting in increased flux through pentose phosphate pathway and lipogenesis respectively, lactic acidosis from excess G6P over working the glycolytic pathway GSD1a patients with hyperlipidemia seem to have increased fraction of apolipoprotein E apoE with suggested protective effect against atherosclerosis Initial clinical presentation of fasting hypoglycemia, lactic acidosis, hyperuricemia and hypertriglyceridemia can be confirmed by enzyme activity assay and or mutation analysis of both G6PC and SLC37A4 simultaneously due to the overlap of presentations seen in GSD1a and GSD1b 15 , Prenatal genetic diagnosis on chorionic villus sampling was reported in a family with known familial mutation The main aim of treatment in GSD1a is to maintain normoglycemia or avoid hypoglycemia.

ACMGG Consensus guidelines can be reviewed for further details on current guidelines on diagnosis and management of GSD1 Nutritional approaches with frequent feedings of formula, meals, snacks, and UCCS including use of nasogastric and gastrostomy tubes are the cornerstone to maintain glucose homeostasis throughout the day and night Glycosade, a modified form of cornstarch helps maintain normoglycemia overnight for a longer time in older children Simple sugars as fructose, sucrose and galactose are restricted because of their contribution to lactic acidosis A high-protein diet has been related to kidney damage and cannot be effectively converted into glucose because of the limited G6Pase activity Hyperuricemia can improve with metabolic control or allopurinol Hyperlipidemia may improve with metabolic control, but has historically been treated with fibrates, statins, niacin, fish oil, and medium-chain triglyceride milk Liver transplantation has been associated with favorable outcomes in severe disease Liver transplantation corrects glucose homeostasis, but does not prevent renal dysfunction 16 , However, based on the calculated liver disease score, GSD1a patients are typically low for liver transplant priority Multiple studies using animal models have showed the efficiency of gene therapy in correcting glucose homeostasis and improved metabolic profiles in an attempt to correct defective G6PC 27 may help establish gene therapy as a promising future approach.

GSD1a mode of inheritance is autosomal recessive; with mutations in the G6PC gene on chromosome 17p Within the Ashkenazi Jewish population, the suggested incidence of GSD1a is 1 in 20, No clear-cut genotype-phenotype correlation has been identified The G6PT enzyme is a transmembrane protein found within the endoplasmic reticulum and functions to move G6P into the endoplasmic reticulum.

G6Pase-α and G6PT together as the G6Pase complex maintains glucose homeostasis. G6PT is ubiquitously expressed with G6Pase complexes throughout the body, while G6Pase-α is localized to the liver, kidney, and intestines, leads myeloid cell energy homeostasis disruption and the resulting neutropenia.

Neutropenia can be severe, leading to recurrent infections and milder neutropenia with other features of GSD1b has been described with a homozygous mutation in G6PC gene 22 , Due to clinical presentation overlap seen in GSD1a and GSD1b, both G6PC and SLC37A4 should be analyzed for mutations simultaneously in patients with suspected GSD1 In addition to GSD1a treatment approaches, the only difference in GSD1b includes, addressing neutropenia and IBD with granulocyte colony-stimulating G-CSF to decreases the number and severity of infections and inflammation Liver transplantation in GSD1b will correct glucose homeostasis, but effects on neutropenia and bowel disease are variable and less clear GSD1b has autosomal recessive inheritance, with 92 different reported with 31 confirmed as pathogenic mutations in SLC37A4 gene on chromosome 11q23 33 , encoding glucosephosphate translocase G6PT enzyme GDE ; and no apparent genotype-phenotype relationship 15 , GSD6, also known as Hers disease or liver phosphorylase enzyme deficiency, is a glycogenolysis defect with impaired interconversion of unphosphorylated form into active phosphorylated form of liver phosphorylase enzyme, necessary to remove the terminal branch glycosyl unit of glycogen to form glucose 1 phosphate Varied clinical spectrum include mild to severe presentation of hepatomegaly, Ketotic hypoglycemia, with excessive glycogen accrual seen in liver biopsy Though, considered a milder disease, long term complications are not well studied Mainly is symptomatic, with frequent intake of complex carbohydrate, and high protein diet and avoiding fasting 10 , GSD6 is an autosomal recessive disorder, with very few documented cases, and with mutation in PYGL gene on chromosome 14q They are reported more in males, and considered most common of all GSD9.

Though, initially thought to be mild disease 38 ; severe presentations of liver cirrhosis are also reported. Symptomatic to prevent hypoglycemia with frequent meals and snacks, high protein diet, and complex carbohydrates.

GSD9a has X-linked inheritance with mutations in the PHKA2 gene on chromosome Xp GSD9c results from impaired gamma unit of phosphorylase kinase enzyme function in liver and testis, with early childhood presentations of recurrent hypoglycemia, hepatomegaly progressing to liver cirrhosis and end stage liver disease; apart from motor delay, hepatosplenomegaly, renal tubular damage and muscle weakness Because the gamma subunit contains the catalytic site of the enzyme, GSD9C typically has a more severe phenotype.

In personal experience SK unpublished data , a teenager presented with seizure disorder, microcephaly, intellectual disability, short stature apart from clinical presentations noted above.

Catch up on the latest GSD news and research from The Children's Fund. View our digital December Hopes and Dreams Newsletter below. Catching up with Jerrod Watts.

We recently sat down with Jerrod, the first GSD1a patient to receive Gene Therapy. Here is how he is doing today. Read the interview. GSD1a Leadership Council. Patient Spotlight. Read His Story. You will be compensated for your time.

If interested, please click on the image above for more information. DTX Trials. mRNA Trials Underway! The first patient in the world received Moderna mRNA trial infusion for GSD1a at UConn Health.

Read the Press Release. Investigational mRNA Treatment. Moderna Trials. Gene Therapy Update. Ultragenyx Therapeutics is now in Phase III clinical trials for GSD1a. The first participant recieved the infusion at Uconn Health in January Join Mailing List. Tell A Friend. Donate Now. Upcoming Events.

Glycogen Storage Disease and RussellD. Research on glycogen storage disease AISgorage DAAdam MPArdinger HH glycoben, Pagon RAet al. Wolf, G. Arch Dis Child. A high-protein diet is recommended in GSD III but not in GSD I where kidney damage is a concern. No clear-cut genotype-phenotype correlation has been identified and KarpatiG.

Research on glycogen storage disease -

Patients with GSD-Ib may require liver transplantation. Although hypoglycemia, lactic acidosis and dyslipidemia improve after liver transplantation, neutropenia generally continues to be present as it is primarily attributable to an intrinsic defect in the neutrophils[ - ].

Another characteristic clinical finding of GSD-Ib is the occurrence of Crohn disease-like colitis[ , ]. Accompanying findings and symptoms include fever, diarrhea, and perioral and anal ulcers.

Interestingly, the severity of the primary disorder does not appear to be correlated with the occurrence or severity of intestinal symptoms[ , ]. Manifestations of inflammatory bowel disease may improve with granulocyte colony-stimulating factor G-CSF treatment[ ]. Enteral nutrition with a polymeric formula enriched in the anti-inflammatory cytokine transforming growth factor-β is recommended as a first-line treatment of digestive complications in GSD-Ib[ ].

Inflammatory bowel disease may require treatment with anti-inflammatory and immunosuppressive medications[ ]. Successful treatment of inflammatory bowel disease with biologics including infliximab and adalimumab in GSD-Ib patients refractory to conventional treatment has been reported[ , ].

GSD-Ib is characterized by an increased risk for developing autoimmune disorders like thyroid autoimmunity and myasthenia gravis[ ]. GSD-Ib patients have a higher likelihood of developing thyroid autoimmunity and hypothyroidism, while GSD-Ia patients show little indication of thyroid pathologies[ , ].

Based on the slightly elevated levels of thyrotropin, even in patients with overt hypothyroidism, it could be postulated that there is concomitant damage occurring at the hypothalamus or pituitary gland[ ].

Recently, predisposition to autoimmunity in GSD-Ib patients was linked with a profound defect in conventional T cells and regulatory T cells caused by defective engagement of glycolysis in T cells due to G6PT deficiency[ ].

Although a rare outcome of GSD-Ib, patients may develop terminal kidney disease, which may necessitate kidney transplantation[ ]. Nutritional management of GSD-Ib is similar to that of GSD-Ia. Neutropenic patients with GSD-Ib should be treated with G-CSF.

G-CSF therapy may normalize the number of neutrophils and restore myeloid functions[ - ]. The implementation of a combined therapeutic approach including both dietary management and G-CSF treatment improves the prognosis of patients by significantly mitigating metabolic and myeloid abnormalities.

G-CSF administration is associated with not only an elevation of peripheral neutrophil counts, but also a reduction in the incidence of febrile episodes and infections, as well as improvement in enterocolitis in patients with GSD-Ib[ ].

In conjunction with other therapies aminosalicylates, mesalamine, and corticosteroids , G-CSF ameliorates inflammatory bowel disease symptoms[ ]. To prevent complications such as splenomegaly, hypersplenism, hepatomegaly, and bone pain, it is recommended that the lowest effective dose of G-CSF is used.

Caution must be exercised regarding the development of splenomegaly and myeloid malignancy[ , ]. Vitamin E has been reported to be effective in reducing the frequency of infections and improving neutropenia[ ].

Liver transplantation is the ultimate therapy for hepatic metabolic disease related to GSD-I. There is no possibility of the recurrence of GSD-I within the allograft. Recently, an unusual post-transplant finding of two siblings with persistent hyperuricemia requiring allopurinol treatment has been reported[ ].

Moreover, chronic renal failure is a well-known complication that may arise as a consequence of liver transplantation in individuals with GSD-Ia, and progression to renal failure within a few years of transplantation was reported[ ]. It is uncertain whether post-transplantation renal failure is related to disease progression, toxicity from immunosuppressants used after liver transplantation, a secondary reaction to poor metabolic control, or a combination of these factors.

Renal transplantation in GSD-I, on the other hand, corrects only renal abnormalities[ ]. Conflicting results have been reported in different studies regarding whether catch-up growth is achieved or not following liver transplantation in children with GSD-I[ , ]. Despite improved survival and growth, long-term complications of GSD-I like progressive renal failure and development of hepatic adenomas do not respond completely to dietary treatment.

Although liver transplantation corrects metabolic derangement and improves the quality of life of these patients, it is not without complications[ ]. These findings suggest that novel therapeutic approaches with higher success and lower complication rates are warranted.

A recent advance in the treatment of neutropenia and neutrophil dysfunction in individuals with GSD-Ib is repurposing empagliflozin, a sodium-glucose co-transporter-2 SGLT2 inhibitor that is approved to treat type 2 diabetes in adults, to improve neutrophil number and function.

A study conducted by Veiga-Da-Cunha et al [ ] revealed the crucial function of glucosephosphate transporter in neutrophils, which clarifies the pathophysiology of neutropenia in GSD-Ib patients. In addition to G6P, G6PT transports the G6P structural analog 1,5-anhydroglucitolphosphate 1,5AG6P.

Neutrophils lacking G6PT activity cannot transport 1,5AG6P from the cytosol into the endoplasmic reticulum, where it is normally dephosphorylated by G6PC3, a phosphatase in the membrane of the endoplasmic reticulum.

Cytosolic accumulation of 1,5AG6P inhibits glucose phosphorylation by hexokinases that catalyzes the first step of glycolysis. As glycolysis is the sole energy source for mature neutrophils, depletion of intracellular G6P leads to a deficit in energy production which in turn results in neutrophil dysfunction and subsequent apoptosis.

Empagliflozin inhibits renal SGLT2 leading to increased urinary excretion of 1,5AG. This leads to a reduction in the concentration of 1,5AG in the blood, thereby decreasing the cellular accumulation of toxic 1,5AG6P in neutrophils[ ].

Following the first report of successful repurposing of empagliflozin to treat neutropenia and neutrophil dysfunction in 4 patients with GSD-Ib, several case reports and case series have shown beneficial effects of this treatment approach on neutrophil number and function, inflammatory bowel disease, recurrent infections[ - ], oral and urogenital mucosal lesions, skin abscesses, anemia, wound healing, and dose reduction or even cessation of G-CSF therapy in GSD-Ib patients[ - ].

Despite a favorable safety profile in patients with GSD-Ib, there is a risk of hypoglycemia with SGLT2 inhibitors. A low dose at treatment initiation with careful titration to optimal dosing is recommended[ ].

Growing evidence suggests that empagliflozin is a candidate for first-line treatment of neutropenia and neutrophil dysfunction related symptoms in GSD-Ib patients.

Another promising novel therapeutic strategy is gene therapy by using recombinant adeno-associated virus vectors. The use of a viral vector to administer G6Pase and hepatocyte transplantation are being investigated as potential treatments for GSD-I.

Various animal models have shown an increase in hepatic G6Pase and G6PT activity, as well as improvements in metabolic parameters[ - ]. Multiple approaches have been explored for the integration of the G6Pase transgene into the host genome[ , ].

The successful correction of metabolic imbalances in animal models through gene therapy shows promising potential for future applications of gene therapy in humans.

Glycogen debrancher enzyme has two independent catalytic activities; alpha-glucanotransferase and amylo-1,6-glucosidase, with the two catalytic sites being separated on the same polypeptide. Both catalytic activities are required for complete debranching enzyme activity[ ].

Deficient activity of these catalytic sites results in accumulation of glycogen with short outer chains, previously defined as limit-dextrins. Deficiency in glycogen debranching enzyme due to biallelic pathogenic variants in the AGL gene results in the harmful accumulation of abnormal glycogen in hepatocytes.

The AGL gene was mapped to the chromosomal locus 1p21, and its nucleotide sequence was determined, revealing the existence of multiple tissue-specific isoforms[ , ]. GSD-III is inherited in an autosomal recessive manner. Certain populations have an increased prevalence due to a founder effect.

The highest known GSD-III prevalence occurs in Inuit population in Nunavik about , c. There is currently limited evidence supporting a correlation between disease severity and pathogenic variants in the AGL gene, except for specific exon 3 variants c.

It was suggested that in muscle isoforms of the AGL gene, alternative exon or translation initiation may not require exon 3, thereby resulting in normal enzyme activity in the muscle tissues of patients with GSD-IIIb who harbor an exon 3 deletion[ , ].

Recent evidence suggests that the presence of frameshift, nonsense, and splice site variants may lead to severe phenotypes. Differences in tissue expression of the deficient enzyme is responsible for the phenotypic variability observed in GSD-III patients[ ].

GSD-III is characterized by heterogeneous involvement of the liver, skeletal muscle, and cardiac muscle, leading to variable clinical presentations. Various subtypes are defined by the extent of tissue involvement.

Two major subtypes of GSD-III have been identified. In a limited number of cases, it has been demonstrated that there is a selective loss of either glucosidase activity resulting in muscle involvement, referred to as GSD-IIIc or transferase activity resulting in both muscle and liver involvement, referred to as GSD-IIId [ , ].

Hepatomegaly, ketotic hypoglycemia, growth retardation and dyslipidemia hypertriglyceridemia are the dominant features of hepatic involvement in infancy and childhood. As gluconeogenesis is intact in GSD-III, fasting hypoglycemia tends to be milder than that seen in GSD-I.

During infancy, serum hepatic transaminases are markedly elevated. Uric acid and lactate concentrations are relatively normal[ ]. Symptoms and laboratory findings related with liver involvement often improve with age and usually disappear after puberty[ , ].

However, liver disease can also be progressive resulting in liver fibrosis, cirrhosis, hepatic failure, and end-stage liver disease[ , ]. Hepatic fibrosis may occur as early as 1 year of age[ ].

Overt liver cirrhosis is not common and occurs rarely[ , ]. Hepatocellular carcinoma can develop as a long-term complication of liver cirrhosis, rather than transformation of an adenoma to carcinoma, as seen in GSD-I[ , ]. Children with failure to thrive often catch-up in height in adulthood with optimized, individualized dietary management.

Muscle symptoms associated with GSD-III can manifest concurrently with liver disease or long after hepatic disorders or even after the resolution of hepatic symptoms during childhood.

Nonetheless, a normal CK level does not entirely exclude the possibility of an underlying muscular disease[ , ]. The median age of onset of CK elevation was reported to be 10 years[ ]. Although muscle involvement becomes clinically more obvious later in life, mild muscle weakness on physical examination, motor developmental delay delayed sitting, delayed standing upright, delayed onset of walking , exercise intolerance, and hypotonia were reported in the majority of pediatric patients with GSD-III[ - ].

Muscle weakness and wasting may slowly progress and become severe by the third or fourth decade of life[ , ]. In a subset of adult patients with GSD-III, muscle symptoms can present in the absence of any clinical or previous evidence of liver dysfunction[ , ].

Muscle weakness, although minimal during childhood, is slowly progressive in nature and may become the predominant feature with significant permanent muscle weakness in adults with type IIIa disease[ ]. Although myopathy generally progresses slowly and is not severely debilitating, some patients may have severe muscle involvement leading to loss of ambulation[ ].

Myopathy can be proximal, distal, or more generalized. Exercise intolerance with muscle fatigue, cramps and pain are evident in more than half of patients[ , , ]. Bulbar or respiratory dysfunctions are rarely seen in GSD-III patients while no clinical involvement of facial or ocular muscles has been described in the literature[ ].

Cardiac involvement in GSD-III is variable. Cardiac involvement is present in most patients, with varying degrees of severity ranging from ventricular hypertrophy detected on electrocardiography to clinically apparent cardiomegaly[ ].

Mogahed et al [ ] reported that cardiac muscle involvement is less common and mostly subclinical in the pediatric age group. Sudden death has occasionally been reported[ ]. Patients with GSD-III may exhibit facial abnormalities such as indistinct philtral pillars, bow-shaped lips with a thin vermillion border, a depressed nasal bridge and a broad upturned nasal tip, and deep-set eyes, particularly in younger patients[ ].

Some individuals with GSD-III may have an increased risk of developing osteoporosis with reduced bone mineral density which, in part, may be due to suboptimal nutrition, the effects of metabolic abnormalities and muscle weakness[ 41 , , ]. Bone fractures due to osteopenia and osteoporosis were reported in patients with GSD-III[ ].

Polycystic ovary disease has been reported in women with GSD-III with no significant effect on fertility[ ]. Type 2 diabetes may occur during the course of the disease in adulthood[ ]. Michon et al [ ] reported global cognitive impairment in adult GSD-III patients as an underlying cause of psychological and attention deficits seen in this patient group.

Liver histology shows uniform distension of hepatocytes secondary to glycogen accumulation. There is often septal formation, periportal and reticular fibrosis, fine microsteatosis, and less frequently, micronodular cirrhosis without inflammation or interface hepatitis.

Skeletal muscle shows subsarcolemmal glycogen accumulation[ 12 ]. The diagnosis of GSD-III is made by identification of biallelic AGL pathogenic variants on molecular genetic testing. If the diagnosis cannot be established by genetic analysis, demonstrating enzyme deficiency in peripheral leukocytes or erythrocytes, cultured skin fibroblasts or in the liver or muscle tissue samples is necessary.

A practice guideline was published by the American College of Medical Genetics and Genomics in providing recommendations on the diagnosis and management of the complications of GSD-III[ ]. The mainstay of GSD-III treatment is dietary intervention, which aims to maintain normal blood glucose levels while balancing macronutrient and total caloric intake.

This is achieved by the avoidance of fasting, frequent meals enriched in complex carbohydrates and use of UCCS. Continuous enteral feeding may be needed in some cases. Sucrose, fructose, and lactose are not contraindicated unlike GSD-I. UCCS can be used as early as the first year of life to prevent hypoglycemia.

As an alternative, Glycosade ® , an extended-release cornstarch, can also be used[ 87 ]. Caution must be exercised to avoid overtreating with cornstarch or carbohydrates, which may lead to excessive storage of glycogen in the liver and weight gain.

In patients with myopathy, along with managing hypoglycemia, a high-protein diet is recommended as it prevents muscle protein breakdown during glucose deprivation, thereby preserving skeletal and cardiac muscle[ ].

A ketogenic diet alone or in combination with high protein and ketone bodies was also shown to ameliorate cardiomyopathy[ , ]. It has been shown that a high-fat, low-calorie and high-protein diet can reduce cardiomyopathy in individuals with GSD-III[ , ].

The beneficial effects on cardiac or skeletal muscle function of these ketogenic or high-fat diets are possibly related to the increased ketone bodies or fats as fuel sources, or reduced glycogen accumulation through decreased carbohydrate intake.

Whether long-term muscular, cardiac, or even liver complications can be prevented by these dietary approaches warrants further studies[ ]. Liver transplantation corrects all liver related biochemical abnormalities but does not correct myopathy or cardiomyopathy[ , , ].

Detailed information about surveillance recommendations on hepatic, metabolic, musculoskeletal, cardiac, nutritional, and endocrine aspects of the disease can be found elsewhere[ ]. Gene therapy and gene-based therapeutic approaches are in development.

Branching of the chains is essential to pack a very large number of glycosyl units into a relatively soluble spherical molecule. Without GBE, abnormal glycogen with fewer branching points and longer outer chains resembling an amylopectin-like structure polyglucosan accumulates in various tissues including hepatocytes and myocytes[ ].

The mapping of the GBE1 gene to chromosome 3p Notably, mutations in the same gene are also responsible for adult polyglucosan body disease. GSD-IV accounts for only 0.

This rare disorder has a prevalence of to [ ]. GSD-IV exhibits significant clinical heterogeneity and phenotypic variability, partly due to variations in tissue involvement, which may be influenced by the presence of tissue-specific isozymes[ , ].

The liver is the primary organ affected, with the classical hepatic form appearing normal at birth but progressing rapidly to cirrhosis in early life, leading to liver failure and death between 3 to 5 years of age[ ]. Besides the complications of progressive cirrhosis including portal hypertension, ascites and esophageal varices, the development of hepatocellular carcinoma was also reported[ ].

In rare cases, the hepatic disease in GSD-IV may not progress or progress slowly[ ]. Patients with the non-progressive hepatic form may present with hepatosplenomegaly and mildly elevated liver transaminases, and experience normal growth.

Liver size and transaminase levels may return to normal[ ]. Patients with the non-progressive hepatic form usually survive into adulthood. GSD-IV can present with multiple system involvement, with the enzyme deficiency in both liver and muscle[ ].

This form of the disease can manifest as peripheral myopathy with or without cardiomyopathy, neuropathy, and liver cirrhosis. Onset of the disease can be from the neonatal period to adulthood[ ]. The neuromuscular presentation can be divided into four groups based on age at onset[ ].

In the perinatal fetal form, which can lead to hydrops fetalis and polyhydramnios, arthrogryposis develops due to akinesia[ ]. Detection of cervical cystic hygroma during pregnancy may indicate the disease[ ].

Prenatal diagnosis can be performed by determining enzyme activity in cultured amniocytes or chorionic villi samples. Genetic studies can complement uncertain enzyme activity studies, such as equivocal results in prenatal fetal samples and in patients with higher levels of residual enzyme activity that overlap heterozygote levels[ ].

Mortality is unavoidable in the neonatal period. Liver cirrhosis or liver failure has not been reported. Severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration, and neuronal involvement are features of the congenital form of the disease[ , - ].

Liver disease is not severe, and the child dies in early infancy due to other reasons. The childhood neuromuscular form may start at any age with either myopathy or cardiomyopathy[ , ]. Presenting symptoms mainly include exercise intolerance, exertional dyspnea, and congestive heart failure in advanced stages.

The disease can be confined to muscular tissue and serum CK level can be within the normal range. In the adult form, there is isolated myopathy or a multisystemic disease called adult polyglucosan body disease.

Onset of symptoms can occur at any age during adulthood, usually after the age of 50, and may exhibit a resemblance to muscular dystrophies. Symptomatology includes progressive gait difficulty and proximal muscle weakness, which is more pronounced in the arms as compared to the legs.

Both upper and lower motor neurons are affected in the disorder. The disease may manifest as pyramidal tetraparesis, peripheral neuropathy, early onset of neurogenic bladder, extrapyramidal symptoms, seizures, and cognitive dysfunction leading to dementia[ ]. The diagnosis can be established by enzyme activity assay in erythrocytes[ ].

Amylopectin-like inclusions are detected through ultrastructural examination of the central nervous system and skeletal muscle. These inclusions are intensely PAS-positive and diastase-resistant, both in neurons and muscular fibers[ ].

Magnetic resonance imaging shows white matter abnormalities[ ]. Liver biopsy can be diagnostic in patients with hepatic involvement[ ]. The histopathological evaluation of the liver reveals abnormal hepatocellular glycogen deposits in the form of PAS-positive, diastase-resistant inclusions.

Ultrastructural examination with electron microscopy reveals accumulation of fibrillar aggregations that are typical of amylopectin. Typically, enzyme deficiency can be documented through diagnostic assays performed on hepatocytes, leukocytes, erythrocytes, and fibroblasts.

However, patients with cardioskeletal myopathy may exhibit normal leukocyte enzyme activity[ ]. The diagnosis of GSD-IV can be confirmed through histopathological examination, detection of enzyme deficiency, and mutation analysis of the GBE1 gene.

Genetic confirmation is recommended whenever possible in patients with suspected GSD-IV to provide more data for genotype-phenotype correlations in this extremely rare disease.

The genotype-phenotype correlation remains unclear for GSD-IV and the same genetic defect may cause different clinical presentations in unrelated patients[ ]. Mutation analysis can also provide crucial diagnostic information in cases with equivocal results of biochemical analyses[ ].

Mutations with significant preservation of enzyme activity may be related with milder e. Hypoglycemia has traditionally been considered a late manifestation and generally develops due to hepatocellular dysfunction caused by progressive cirrhosis. At this stage of the disease, the biochemical profile of the patients is representative of what is observed in other causes of liver cirrhosis.

No specific dietary and pharmacological treatments are available for GSD-IV. There is a lack of established guidelines based on either evidence or expert consensus for the dietary management of GSD-IV.

Improvement in clinical, anthropometric, and laboratory parameters was reported with a high-protein and low-carbohydrate diet[ , ]. Derks et al [ ] recently reported improved clinical and biochemical outcomes after dietary interventions including a late evening meal, continuous nocturnal intragastric drip feeding, restriction of mono- and disaccharides, the addition of UCCS, and protein enrichment in patients with GSD-IV.

Individual dietary plans should also aim to avoid hyperglycemia to minimize glycogen accumulation in the liver. At present, there is no effective therapeutic approach other than liver transplantation for GSD-IV patients who are affected by progressive liver disease.

However, anecdotal reports indicate that liver transplantation may not alter the extrahepatic progression of GSD-IV[ ].

The presence of extrahepatic involvement, especially amylopectin storage in the myocardium, may lead to fatal complications following liver transplantation[ - ]. Careful assessment of cardiac function even in the absence of clinical decompensation or consideration of combined liver-heart transplantation is warranted for patients with GSD-IV[ ].

Liver transplantation may provide beneficial effects not only for patients with liver disease but also for those affected by muscular involvement in GSD-IV[ , , ]. This may be explained by systemic microchimerism donor cells presenting in various tissues of the liver recipient after liver allotransplantation and amelioration of pancellular enzyme deficiencies resulting in a decrease in amylopectin in other organ systems[ 12 ].

It has been suggested that the donor cells can transfer enzyme to the native enzyme-deficient cells[ ]. In recent years, animal studies have been conducted to prevent glycogen and polyglucosan body accumulation in GSD-IV patients, and GYS inhibitor guaiacol and DG11 are promising in this regard[ , ].

The molecular target of DG11 is the lysosomal membrane protein lysosome-associated membrane protein 1 LAMP1 , which enhances autolysosomal degradation of glycogen and lysosomal acidification. In the adult polyglucosan body disease mouse model, DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve[ ].

GSD-VI was first reported by Hers[ ] in three patients with hepatomegaly, mild hypoglycemia, an increased glycogen content and deficient activity of glycogen phosphorylase in the liver in GSD-VI is a rare autosomal recessive genetic disease caused by deficiency of hepatic glycogen phosphorylase.

At least three human glycogen phosphorylases exist including muscle, liver, and brain isoforms[ ]. In response to hypoglycemia, liver glycogen phosphorylase catalyzes the cleavage of glucosyl units from glycogen which results in the release of glucosephosphate.

The glucosephosphate is subsequently converted to glucosephosphate. The PYGL gene is currently the only known genetic locus associated with the development of GSD-VI and was mapped to chromosome 14qq22 in [ ]. Incidence of the disease is estimated to be and believed to be underestimated due to nonspecific and variable phenotypes, and a paucity of cases confirmed by genetic testing[ ].

GSD-VI is more prevalent among the Mennonite community, with a prevalence of 1 in , representing the only known population at higher risk for the disease[ ]. GSD-VI is a disorder with broad clinical heterogeneity[ ]. Infants with liver phosphorylase deficiency mainly present with hepatomegaly and growth retardation.

The condition typically has a benign course, and symptoms tend to improve as the child grows[ ]. Hepatomegaly usually normalizes by the second decade of life[ ]. The child shows mild to moderate ketotic hypoglycemia related to prolonged fasting, illness, or stressful conditions[ ].

As gluconeogenesis is intact in GSD-VI, hypoglycemia is usually mild. Despite gross hepatomegaly, the patient may be largely asymptomatic without hypoglycemia. However, there is a range of clinical severity in GSD-VI, with some patients experiencing severe and potentially life-threatening hypoglycemia.

There is generally mild ketosis, growth retardation, abdominal distension due to marked hepatomegaly and mildly elevated levels of serum transaminases, triglycerides, and cholesterol. However, in patients with high residual enzyme activity, biochemical investigations may be normal[ , ].

Hypertriglyceridemia may persist despite treatment[ ]. A few patients showing mild muscular hypotonia, muscle weakness or developmental impairment were observed, but otherwise, no neurological symptoms were reported in the literature[ ].

Sleep difficulties and overnight irritability are common[ ]. In contrast to GSD-I, serum levels of lactic acid and uric acid are generally within the normal range[ 15 ]. However, in a recent clinical study including 56 GSD-VI patients, hyperuricemia was reported as a complication in adolescent and adult patients with GSD-VI, which indicates the need for long-term monitoring of uric acid in older GSD-VI patients[ ].

CK concentration is usually normal. In some patients, severe and recurrent hypoglycemia, pronounced hepatomegaly, and postprandial lactic acidosis have been reported[ ]. Recently, children with GSD-VI have been reported to present with only ketotic hypoglycemia as the sole manifestation of the disease, without the characteristic hepatomegaly[ ].

Mild cardiopathy has also been described for GSD-VI[ ]. The clinical picture of GSD-VI virtually overlaps with phosphorylase kinase PHK deficiency GSD-IX and the differential diagnosis includes other forms of GSDs associated with hepatomegaly and hypoglycemia, especially GSD-I and GSD-III[ ]. It is not possible to distinguish between GSD-VI and GSD-IX based on clinical or laboratory findings alone[ ].

Mutation analysis is the suggested method for the diagnosis of GSD-VI. A liver biopsy is not recommended to establish the diagnosis to avoid an invasive procedure.

Excessive glycogen accumulation with structurally normal glycogen in the liver biopsy is consistent with GSD-VI. Fibrosis, mild steatosis, lobular inflammatory activity and periportal copper binding protein staining have also been reported in GSD-VI patients.

Although it is possible to document glycogen phosphorylase deficiency in frozen liver biopsy tissue or blood cells including leukocytes and erythrocytes, normal in vitro residual enzyme activity may be seen and prevents establishment of a definitive diagnosis by an enzyme assay alone in some patients[ , ].

In GSD-VI, nutrition therapy aims to improve metabolic control and prevent primary manifestations such as hypoglycemia, ketosis, and hepatomegaly, as well as secondary complications including delayed puberty, short stature, and cirrhosis.

The aim of the therapeutic approach is to achieve euglycemia and normoketosis by administration of the appropriate doses of cornstarch. An extended-release corn starch derived from waxy maize, marketed as Glycosade ® , has been found to have a positive impact in delaying overnight hypoglycemia in children over 5 years of age and adults[ 87 ].

Some individuals with GSD-VI may not require any treatment. GSD-VI usually has a benign disease course. However, focal nodular hyperplasia, fibrosis, cirrhosis, and a degeneration to hepatocellular carcinoma have been reported in some patients[ - ].

Cirrhosis has been reported in patients as young as preschool age, even within the second year of life[ ]. Based on these findings, aggressive treatment of GSD-VI has recently been suggested to maintain optimal metabolic control and prevent long-term complications[ ].

Long-term monitoring of hepatic function is also recommended[ ]. Glucagon and epinephrine play a critical role in the regulation of glycogenolysis by activation of adenylate cyclase which leads to an increase in the cytosolic concentration of cyclic adenosine monophosphate cAMP.

The increased level of cAMP activates cAMP-dependent protein kinase which activates PHK. PHK is a heterotetramer composed of 4 different subunits α, β, γ, and δ.

Each subunit is encoded by different genes that are located on different chromosomes and differentially expressed in a variety of tissues[ ]. α and β subunits have regulatory functions, the γ subunit contains the catalytic site, and δ is a calmodulin protein[ ]. PHK has a wide tissue distribution with multiple tissue-specific isoforms.

The α subunit has two isoforms, a muscle isoform, and a liver isoform, which are encoded by two different genes PHKA1 and PHKA2 , respectively on the X chromosome[ ]. The genetic loci of other subunits are mapped to autosomal chromosomes. The γ subunit also has muscle and liver isoforms, each of which is encoded by a distinct gene PHKG1 and PHKG2 , respectively.

There is only one gene encoding the β-subunit PHKB. However, PHKB is expressed in both muscle and liver[ , ].

Liver PHK deficiency liver GSD-IX can be classified according to the involved gene, the X-linked form GSD-IXa, X-linked glycogenosis and autosomal recessive forms GSD-IXb and GSD-IXc. GSD-IXa PHKA2 -related GSD-IX is caused by pathogenic variants in the PHKA2 gene on X chromosome.

GSD-IXb PHKB -related GSD-IX and GSD-IXc PHKG2 -related GSD-IX are inherited in an autosomal recessive manner and caused by mutations in PHKB and PHKG2 genes, respectively Table 1. GSD-IXa is further classified into subtypes XLG-I formerly GSD-VIII with no enzyme activity in liver or erythrocytes, and XLG-II with no enzyme activity in liver, but normal activity in erythrocytes[ , ].

GSD-IX is one of the most common forms of GSDs. The frequency of liver PHK deficiency was estimated to be [ 15 ]. On the X chromosome, there are two enzyme loci; one for the alpha subunit of muscle PHK, and one for the alpha subunit of liver PHK. In , the liver PHK gene was located to Xp GSD-IXa is more common in males due to the X-linked inheritance pattern.

Female carriers may become symptomatic due to X chromosome inactivation[ ]. Hepatomegaly, growth retardation, delayed motor development, mild hypotonia, significantly elevated serum transaminase levels, hyperlipidemia, fasting hyperketosis, and hypoglycemia are the main symptoms and findings[ - ].

Rarely described clinical features include splenomegaly, liver cirrhosis, doll-like facies, osteoporosis, neurologic involvement, high serum lactate levels, metabolic acidosis, and renal tubular acidosis[ ]. With increasing age, there is a gradual resolution of both clinical symptoms and laboratory abnormalities.

Although puberty may be delayed, eventual attainment of normal height and complete sexual development is still possible[ ]. Most adult patients are asymptomatic[ ]. Unusual presentations including asymptomatic hepatomegaly and isolated ketotic hypoglycemia without hepatomegaly have been reported in affected male children underscoring the importance of screening for GSD-IXa in male patients who are suspected of having GSD with atypical features[ , ].

More severe phenotypes including severe recurrent hypoglycemia and liver cirrhosis have also been reported[ , , ]. Recent findings suggest that GSD-IXa is not a benign condition as is often reported in the literature and patients may have fibrosis even at the time of diagnosis[ ].

GSD-IXc is caused by autosomal recessive mutations in the PHKG2 gene. The genetic locus of the liver form was located to 16p The presence of PHKG2 mutations has been linked to more severe clinical and biochemical abnormalities, such as an elevated risk for liver fibrosis and cirrhosis[ - ].

Liver cirrhosis can develop in infancy[ ]. Cirrhosis related esophageal varices and splenomegaly, liver adenomas, renal tubulopathy and significant hypocalcemia were other reported clinical findings[ ]. Patients with this condition commonly present with severe hypoglycemia requiring overnight feeding, show very low PHK activity in the liver, and exhibit highly elevated serum transaminase levels.

A wide range of clinical symptoms can be observed, including hypoglycemia during fasting, hepatomegaly, elevated levels of transaminases, hepatic fibrosis, cirrhosis, muscle weakness, hypotonia, delayed motor development, growth retardation, and fatigue[ ].

The genetic cause of GSD-IXb is attributed to mutations in the PHKB gene, which is located on 16qq13 and encodes the beta subunit of PHK[ ]. The main features of the disease include marked hepatomegaly, increased glycogen content in both liver and muscle, and the development of hypoglycemic symptoms after physical activity or several hours of fasting[ ].

Patients with liver fibrosis, adenoma-like mass, mild cardiopathy and interventricular septal hypertrophy were reported[ ]. The muscle symptoms are generally mild or absent, affecting virtually only the liver.

Distinction between GSD-IXb and individuals with pathogenic variants in PHKA2 or PHKG2 cannot be carried out based on clinical findings alone. Genetic analysis is the preferred first-line diagnostic test in suspected patients.

An approach using next-generation sequencing panels is advised due to the involvement of multiple genes. Liver biopsy can be a valuable diagnostic tool for confirming the diagnosis in cases where there are variants of unknown significance.

Histopathological assessment of liver involvement is superior to biochemical parameters[ ]. It is important to keep in mind that PHK enzyme activity can be normal in blood cells and even in liver tissue of affected patients.

On the other hand, a reduction in PHK enzyme activity can also occur secondary to other metabolic defects such as pathogenic variants in GLUT2 in Fanconi-Bickel syndrome FBS , PRKAG2 cardiomyopathy syndrome, or mitochondrial complex 1 deficiency[ ].

In patients with GSD-IX, close monitoring of long-term liver and cardiac complications is recommended[ ]. Aggressive structured dietary treatment with UCCS and relatively high protein intake was associated with considerable improvement in growth velocity, energy, biochemical abnormalities, hepatomegaly, and overall well-being of patients with GSD-IX.

Radiographic features of fibrosis were also reported to be improved with early and aggressive dietary management[ ]. General nutritional recommendations for GSD-IX are similar to those for GSD-VI and have recently been published[ ]. The primary defect in FBS is deficiency of glucose transporter 2 GLUT2 , a monosaccharide carrier that is responsible for the transport of both glucose and galactose across the membranes in hepatocytes, pancreatic β-cells, enterocytes, and renal tubular cells.

Utilization of both glucose and galactose is impaired in FBS[ ]. Hepatorenal glycogen accumulation and proximal renal tubular dysfunction are the characteristic features of this rare disease[ , ]. FBS follows an autosomal recessive inheritance pattern. The responsible gene, GLUT2 gene solute carrier family 2 member 2, SLC2A2 , was localized to 3q Infants with FBS typically present between the ages of 3 to 10 mo.

In addition to hepatorenal glycogen accumulation and proximal renal tubular dysfunction, FBS is characterized by fasting hypoglycemia, postprandial hyperglycemia and hypergalactosemia, rickets and marked growth retardation.

Patients have entirely normal mental development. In older patients, dwarfism is the most notable finding. Puberty is significantly delayed, with other remarkable observations including a distended abdomen caused by hepatomegaly, deposition of fat on the abdomen and shoulders, and a moon-shaped face[ ].

Some patients may not exhibit hepatomegaly during the early stages of the disease[ , ]. Hyperlipidemia and hypercholesterolemia are prominent and may cause acute pancreatitis.

The development of generalized osteopenia occurs early and may result in fractures. Hypophosphatemic rickets and osteoporosis are characteristics of the disease that emerge later in life[ ]. Tubular nephropathy is characterized by excessive glucosuria, moderate hyperphosphaturia along with persistent hypophosphatemia, hyperuricemia, hyperaminoaciduria, and intermittent albuminuria, collectively referred to as renal Fanconi syndrome[ , ].

Hypercalciuria is also evident. Due to increased renal losses, there is a frequent tendency towards hyponatremia and hypokalemia. Polyuria may develop due to high urinary osmotic load[ ]. Progression to renal failure is not the case. Nephrocalcinosis was also reported in one third of the patients in a recent retrospective study[ ].

There may be mild metabolic hyperchloremic acidosis with normal anion gap due to renal loss of bicarbonate[ ]. Cataracts, a frequently documented consequence of hypergalactosemia, are only present in a small number of patients[ ].

Laboratory findings include fasting hypoglycemia and ketonuria, hyperglycemia and hypergala ctosemia in the postabsorptive state, hypercholesterolemia, hyperlipidemia, moderately elevated alkaline phosphatase, mildly elevated transaminases, normal hepatic synthetic function, hypophosphatemia, hyperaminoaciduria, glucosuria, galactosuria, proteinuria, normal activity of enzymes involved in galactose and glycogen metabolism, normal fructose metabolism, and normal endocrinologic results[ ].

FBS patients develop different patterns of dysglycemia, ranging from fasting hypoglycemia, postprandial hyperglycemia, glucose intolerance, to transient neonatal diabetes to gestational diabetes and frank diabetes mellitus[ ].

The exact molecular mechanisms underlying the occurrence of dysglycemia in individuals with FBS are not yet fully understood. Impaired renal glucose reabsorption, as well as the accumulation of glucose within the hepatocytes, which stimulates glycogen synthesis and inhibits gluconeogenesis and glycogenolysis, result in fasting ketotic hypoglycemia and hepatic glycogen deposition.

Postprandial findings of hyperglycemia and hypergalactosemia are caused by impaired hepatic uptake and diminished insulin response[ ]. Glycated hemoglobin A1c is usually within the normal range due to recurrent hypoglycemia episodes[ ].

Accumulation of glycogen and free glucose in renal tubular cells leads to general impairment in proximal renal tubular function. Histological evaluation of liver biopsy indicates an excessive buildup of glycogen along with steatosis. Due to the presence of galactose intolerance, newborn screening for galactosemia can sometimes identify patients with FBS[ ].

The diagnosis is ultimately confirmed by genetic analysis of SLC2A2 gene. The management of symptoms involves measures to stabilize glucose homeostasis and compensate for the renal loss of water and various solutes. Patients typically require replacement of water, electrolytes, and vitamin D, while also restricting galactose intake and adhering to a diabetes mellitus-like diet.

Frequent small meals with adequate caloric intake and administration of UCCS are important components of symptomatic treatment. In cases of renal tubular acidosis, it may be required to administer alkali to maintain acid-base balance. Catch-up growth was reported to be induced by UCCS[ ].

Continuous nocturnal gastric drip feeding may be indicated in some cases with growth failure[ ]. With these measures, the prognosis is good. However, a recent retrospective study reported poor outcome despite adequate metabolic management emphasizing the importance of early genetic diagnosis and facilitating prompt nutritional interventions[ ].

Pompe disease is a typical example of a lysosomal storage disease. The clinical manifestations of Pompe disease are variable, predominantly due to the varying amounts of residual acid alpha-glucosidase GAA activity linked with distinct mutations in the causative gene GAA.

GAA gene is mapped to chromosome 17q Enzyme deficiency results in intra-lysosomal storage of glycogen especially in skeletal and cardiac muscles.

There is no genotype-phenotype correlation, but DD genotype in the angiotensin converting enzyme gene and XX genotype in the alpha actinin 3 gene are significantly associated with an earlier age of onset of the disease[ ]. There are mainly two types of GSD-II according to age of onset: Infantile-onset and late-onset Pompe disease.

Patients with disease onset before the age of 12 mo without cardiomyopathy and all patients with disease onset after 12 mo of age are included in the late-onset form[ ]. The combined frequency of infantile onset and late onset GSD-II varies between and depending on ethnicity and geographic region.

In the infantile-onset form, cardiomyopathy and muscular hypotonia are the cardinal features and patients die around 1 year of age. Patients also have feeding difficulties, macroglossia, failure to thrive, hearing impairment and respiratory distress due to muscle weakness.

The liver is rarely enlarged unless there is heart failure. Hypoglycemia and acidosis do not occur[ ]. In the late-onset form, involvement of skeletal muscles dominates the clinical picture, and cardiac involvement is generally clinically insignificant depending on the age of onset.

Glycogen accumulation in vascular smooth muscle may cause the formation and subsequent rupture of an aneurysm[ ]. Both severe infantile and asymptomatic adult forms of the disease were observed in two generations of the same family[ ].

Although women with GSD-II do not have an increased risk of pregnancy or delivery complications, pregnancy may worsen muscle weakness and respiratory complications[ ].

As a rule, there is an inverse correlation between the age at disease onset and the severity of clinical manifestations with the level of residual enzyme activity[ ].

Laboratory testing reveals nonspecific elevations in CK, aldolase, aminotransferases, and lactate dehydrogenase. Elevated urinary tetrasaccharide is highly sensitive but not specific.

To establish the final diagnosis, the measurement of enzyme activity in skin fibroblasts or muscle tissue or the demonstration of the responsible mutation is required[ ].

Although it is not curative, ERT has changed the course of Pompe disease since its first use in [ ]. Alglucosidase alfa, a lysosomal glycogen-specific recombinant enzyme, was approved by the European Medicines Agency EMA in in the European Union and by the Food and Drug Administration FDA in in the United States.

pdf ; accessed on November 5, Based on data from later studies, treatment initiation was shifted to the neonatal period. A new formulation of GAA enzyme, avalglucosidase alfa, improves the delivery of the enzyme to target cells and has 15 times higher cellular uptake when compared with alglucosidase alfa.

The FDA and EMA approved avalglucosidase in and in , respectively, for the treatment of patients who are one year of age and older with late-onset Pompe disease[ ].

Ongoing studies show that avalglucosidase is generally well tolerated in patients with infantile-onset Pompe disease[ ]. Criteria for starting and stopping ERT in adult patients with GSD-II are similar in different countries.

While a confirmed diagnosis and being symptomatic are general criteria for starting ERT, patient wish, severe infusion associated reactions, noncompliance with treatment, and lack of effect are criteria for stopping ERT[ ].

Another way to increase the effectiveness of ERT is to use antibodies as an intracellular delivery vehicle. The 3E10 anti-nuclear antibody, that penetrates cells and localizes to the cell nucleus, has been used for this purpose. VAL is a fusion protein consisting of 3E10 antibody and GAA complex.

The presence of 3E10 increases the delivery of GAA to both lysosomal and extra-lysosomal storage of glycogen within cells[ ]. The earlier ERT is started, the better its effectiveness. Therefore, it is recommended that ERT is started before irreversible clinical symptoms begin.

This concept has led to the development of screening programs for Pompe disease[ ]. Recently, it has been shown that in utero alglucosidase alfa treatment, which was started at 24 wk 5 d of gestation and given 6 times at 2-wk intervals through the umbilical vein, was successful[ ].

Although antibodies against the enzyme may develop, a recent study showed that the development of antibodies did not affect the clinical course[ ]. Whether additional treatments such as oral supplementation of L-alanine is beneficial is being investigated[ ]. As an alternative to ERT, studies on gene therapy have also commenced[ ].

Although Danon disease was previously classified as a variant of GSD-II with normal alpha-glucosidase activity, it is still controversial whether it is a real GSD. A lysosomal structural protein, LAMP2, is deficient in Danon disease.

LAMP2 is involved in autophagosome maturation. Disruption of autophagy leads to accumulation of glycogen granules and autophagic vacuoles[ ]. It is an X-linked Xq24 dominant hereditary disease affecting both skeletal and cardiac muscles, and characterized by skeletal and cardiac myopathy, proximal muscle weakness and intellectual disability.

Female patients have a milder disease predominantly involving cardiac muscle[ ]. There is currently no treatment for Danon disease. There are ongoing studies evaluating the efficacy and safety of gene therapy[ ].

Another glycogen storage cardiomyopathy results from PRKAG2 the gene encoding gamma-2 non-catalytic subunit of adenosine monophosphate-activated protein kinase mutations on chromosome 7q The disease is characterized by left ventricular hypertrophy due to altered glycogen metabolism and glycogen storage in cardiac muscle, similar to Danon disease[ - ].

It is inherited in an autosomal dominant pattern. PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation[ ].

Mutations in the gamma-2 non-catalytic subunit of AMP-activated protein kinase may cause lethal congenital storage disease of the heart, and death in the first year of life[ ]. It is important to differentiate the clinical picture related to PRKAG2 mutations from Danon disease, as management and prognosis are different.

GSD-V is caused by mutations in PYGM gene which is the gene encoding the muscle isoform of glycogen phosphorylase. The PYGM gene is located on 11q The clinical manifestations generally occur during early adulthood with physical activity intolerance and muscle cramps characterized by muscle fatigue and pain, contracture, tachypnea, tachycardia, ptosis, and retinal dystrophy.

Exercise induced rhabdomyolysis can cause transient myoglobinuria, leading to acute renal failure. Hyperuricemia, gout development and thyroid dysfunction are not uncommon[ ]. Many patients are diagnosed with an incidental finding of abnormal serum CK levels[ ].

Echaniz-Laguna et al [ ] studied a family of 13 affected members with adult-onset muscle weakness, and reported a phenotype caused by a dominant myophosphorylase gene mutation p.

The first signs of the disease occurred after 40 years of age with proximal leg weakness, followed by proximal arm weakness.

In contrast to McArdle disease, the patients did not have exercise intolerance, second wind phenomenon, markedly increased CK levels, or rhabdomyolysis.

The authors concluded that specific PYGM mutations can cause either dominant or recessive GSDs[ ]. The responsible gene is located on chromosome 12q Exercise induced muscle cramps and myoglobinuria are the main characteristics of GSD-VII.

Neurological examination does not reveal any abnormalities at rest. Muscle weakness and stiffness invariably occur in muscle groups that are subjected to intense or prolonged exertion. The ischemic exercise test is characterized by the absence of an increase in venous lactate level.

Myoglobinuria may develop following exercise. Nausea and vomiting, icterus, elevated CK, hyperuricemia and reticulosis may also be observed[ ].

In contrast to GSD-V, glucose intake prior to exercise worsens exercise capacity due to blocked use of both muscle glycogen and blood glucose[ ]. The gene is located on chromosome Xq In most patients, clinical findings appear in adulthood and are characterized by muscle weakness and muscle cramps during exercise.

Elevated serum CK level and myopathic findings on electromyography may guide the diagnosis[ ]. The last steps of glycogenolysis are abnormal. The disease is inherited in an autosomal recessive manner and characterized by exercise induced muscle cramps, myalgia, rhabdomyolysis and myoglobinuria.

Serum CK level is increased between episodes[ ]. GSD-XI was first described by Kanno et al [ ] in and characterized by easy fatigue, increase in serum CK, myoglobin, lactate, and pyruvate levels immediately after ischemic work.

The gene locus is on chromosome 11p It is an autosomal recessive disorder, and the gene is located on chromosome 16p GSD-XIII was first described by Comi et al [ ] in in a year-old man with severe deficiency of muscle enolase activity.

The patient had recurrent exercise induced myalgia without cramps. Serum CK concentration was elevated while serum lactate level was normal following ischemic forearm exercise. The related gene is located on chromosome 17p Similar to Danon disease and PRKAG2 variants, glycogenin deficiency may cause left ventricular arrhythmogenic cardiomyopathy.

Patients present with chest pain, progressive weakness, and vague presyncope spells[ ]. There have been significant changes and improvements in the classification, diagnosis, and treatment of GSDs in recent years.

We are now more aware that many GSDs, which were previously identified as childhood diseases, may present first in adulthood. P-Reviewer: El-Shabrawi MH, Egypt; Rathnaswami A, India; Yao G, China S-Editor: Wang JJ L-Editor: Webster JR P-Editor: Zhao S.

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Citation of this article. Gümüş E, Özen H. Glycogen storage diseases: An update. World J Gastroenterol ; 29 25 : [PMID: DOI: Corresponding Author of This Article.

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Publication Name. Baishideng Publishing Group Inc, Koll Center Parkway, Suite , Pleasanton, CA , USA. Review Open Access. Copyright ©The Author s Published by Baishideng Publishing Group Inc. All rights reserved. World J Gastroenterol. Jul 7, ; 29 25 : Published online Jul 7, doi: Ersin Gümüş , Hasan Özen.

ORCID number: Ersin Gümüş ; Hasan Özen Author contributions : Both authors contributed all parts of the study. Conflict-of-interest statement : All the authors report no relevant conflicts of interest for this article.

Open-Access : This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial CC BY-NC 4.

Received: December 28, Peer-review started : December 28, First decision : February 1, Revised: February 15, Accepted: April 30, Article in press : April 30, Published online: July 7, Key Words: Glycogen storage disease , Liver , Muscle , Hypoglycemia.

Citation: Gümüş E, Özen H. Open in New Tab Full Size Figure Download Figure. Figure 1 Simplified pathway of glycogen synthesis and degradation in hepatocytes. Glucose and glycogen convert into one another via synthesis or degradation glycogenolysis through various steps.

The liver plays a central role in maintaining normoglycemia. During the fasting state, the liver maintains glucose homeostasis via a metabolic shift from synthesizing glycogen to endogenous glucose production by glycogenolysis and gluconeogenesis. Specific enzyme or transporter defects in these pathways are associated with clinical and biochemical manifestations including hepatomegaly, hypoglycemia, hyperlipidemia, hypertriglyceridemia, hyperlactatemia, and hyperuricemia.

GSD: Glycogen storage disease; UDP-Glucose: Uridine diphosphate glucose; GlucoseP: Glucose 1-phosphate; GlucoseP: Glucosephosphate; Acetyl-CoA: Acetyl coenzyme A; TCA: Tricarboxylic acid. Table 1 Overview of glycogen storage diseases. Postprandial hyperglycemia, glycosuria, and hyperlactatemia.

Electrocardiographic preexcitation and conduction system disease. Non-progressive hepatic form. Neuromuscular presentation perinatal, congenital, childhood and adult forms.

Myopathy, cardiomyopathy, neuropathy, CNS involvement, APBD. TEXTBOOKS Chen YT, Bali DS. Prenatal Diagnosis of Disorders of Carbohydrate Metabolism. In: Milunsky A, Milunsky J, eds. Genetic disorders and the fetus — diagnosis, prevention, and treatment. West Sussex, UK: Wiley-Blackwell; Chen Y.

Glycogen storage disease and other inherited disorders of carbohydrate metabolism. In: Kasper DL, Braunwald E, Fauci A, et al. New York, NY: McGraw-Hill; Weinstein DA, Koeberl DD, Wolfsdorf JI. Type I Glycogen Storage Disease. In: NORD Guide to Rare Disorders.

Philadelphia, PA: Lippincott, Williams and Wilkins; JOURNAL ARTICLES Chou JY, Jun HS, Mansfield BC. J Inherit Metab Dis. doi: Epub Oct 7. PubMed PMID: Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, Chung WK, Dagli AI, Dale D, Koeberl D, Somers MJ, Wechsler SB, Weinstein DA, Wolfsdorf JI, Watson MS; American College of Medical Genetics and Genomics.

Genet Med. Austin SL, El-Gharbawy AH, Kasturi VG, James A, Kishnani PS. Menorrhagia in patients with type I glycogen storage disease. Obstet Gynecol ;— Dagli AI, Lee PJ, Correia CE, et al. Pregnancy in glycogen storage disease type Ib: gestational care and report of first successful deliveries.

Chou JY, Mansfield BC. Mutations in the glucosephosphatase-alpha G6PC gene that cause type Ia glycogen storage disease. Hum Mutat. Franco LM, Krishnamurthy V, Bali D, et al. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.

Lewis R, Scrutton M, Lee P, Standen GR, Murphy DJ. Antenatal and Intrapartum care of a pregnant woman with glycogen storage disease type 1a. Eur J Obstet Gynecol Reprod Biol. Ekstein J, Rubin BY, Anderson, et al. Mutation frequencies for glycogen storage disease in the Ashkenazi Jewish Population.

Am J Med Genet A. Melis D, Parenti G, Della Casa R, et al. Brain Damage in glycogen storage disease type I. J Pediatr.

Rake JP, Visser G, Labrune, et al. Guidelines for management of glycogen storage disease type I-European study on glycogen storage disease type I ESGSD I. Eur J Pediatr. Rake JP Visser G, Labrune P, et al. Glycogen storage disease type I: diagnosis, management, clinical course and outcome.

Results of the European study on glycogen storage disease type I EGGSD I. Eur J Pediat. Chou JY, Matern D, Mansfield, et al. Type I glycogen Storage diseases: disorders of the glucosePhosphatase complex.

Curr Mol Med. Schwahn B, Rauch F, Wendel U, Schonau E. Low bone mass in glycogen storage disease type 1 is associated with reduced muscle force and poor metabolic control.

Visser G, Rake JP, Labrune P, et al. Consensus guidelines for management of glycogen storage disease type 1b. Results of the European study on glycogen storage disease type I. Weinstein DA and Wolfsdorf JI.

Effect of continuous gucose therapy with uncooked cornstarch on the long-term clinical course of type 1a glycogen storage disease. Eur J Pediatr ; Janecke AR, Mayatepek E, and Utermann G.

Molecular genetics of type I glycogen storage disease. Mol Genet Metab. Viser G, Rake JP, Fernandes, et al. Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type 1b: results of the European study on glycogen storage disease type I.

Chen YT, Bazarre CH, Lee MM, et al. Type I glycogen storage disease: nine years of management with corn starch. INTERNET Bali DS, Chen YT, Austin S, et al.

Glycogen Storage Disease Type I. In: Adam MP, Ardinger HH, Pagon RA, et al. GeneReviews® [Internet]. Seattle WA : University of Washington, Seattle; NORD strives to open new assistance programs as funding allows. NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder. Rare Disease Database.

Glycogen Storage Disease Type I Print. Acknowledgment NORD gratefully acknowledges Deeksha Bali, PhD, Professor, Division of Medical genetics, Department of Pediatrics, Duke Health; Co-Director, Biochemical Genetics Laboratories, Duke University Health System, and Yuan-Tsong Chen, MD, PhD, Professor, Division of Medical Genetics, Department of Pediatrics, Duke Medicine; Distinguished Research Fellow, Academia Sinica Institute of Biomedical Sciences, Taiwan for assistance in the preparation of this report.

Disease Overview Glycogen storage diseases are a group of disorders in which stored glycogen cannot be metabolized into glucose to supply energy and to maintain steady blood glucose levels for the body. Detailed evaluations may be useful for a differential diagnosis: Forbes or Cori disease GSD-III is one of several glycogen storage disorders that are inherited as autosomal recessive traits.

Genetic counseling is recommended for affected individuals and their families. For information about clinical trials being conducted at the National Institutes of Health NIH in Bethesda, MD, contact the NIH Patient Recruitment Office: Tollfree: TTY: Email: prpl cc.

Additional Assistance Programs MedicAlert Assistance Program NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations. Rare Caregiver Respite Program This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Association for Glycogen Storage Disease AGSD. Email: info agsdus. Related Rare Diseases: Adult Polyglucosan Body Disease , Danon Disease , Pompe Disease , Metabolic Support UK. Email: contact metabolicsupportuk.

Related Rare Diseases: Glucose-Galactose Malabsorption , Sandhoff Disease , Aromatic L-Amino Acid Decarboxylase Deficiency , Phone: Email: NDDIC info.

Association for Glycogen Storage Disease UK Ltd. Phone: Email: info agsd. Related Rare Diseases: Adult Polyglucosan Body Disease , Pompe Disease , Glycogen Storage Disease Type VI , Phone: Email: info curegsd.

The disase estimated GSD incidence is 1 case per live births. Diseaxe are over Research on glycogen storage disease types of GSD including the subtypes. Vlycogen heterogeneous group of rare diseases represents inborn Research on glycogen storage disease of carbohydrate Best-selling slimming pills and are classified based on the deficient enzyme and affected tissues. GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues. Although GSDs share similar clinical features to some extent, there is a wide spectrum of clinical phenotypes. Currently, the goal of treatment is to maintain glucose homeostasis by dietary management and the use of uncooked cornstarch.


Glycogen Storage Disorders : Carbohydrates metabolism

Author: Voodoojinn

2 thoughts on “Research on glycogen storage disease

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