Glycogen storage disease type I

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Glycogen storage disease type 1 also known as Von Gierke’s disease is an enzymopathy. The most common defect is deficiency of glucose-6-phosphatase enzyme. Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis. The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia. Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly. Glycogen storage disease type 1 is an autosomal recessive disorder. Glycogen storage disease type 1a is caused by the deficiency of the glucose-6-phosphatase enzyme. Glycogen storage disease type 1b is caused by a defect in the microsomal glucose-6-phosphate transporter. The incidence of glycogen storage disease type 1 (GSD 1) is approximately 1 per 100,000 individuals worldwide. Glycogen storage disease type 1 (GSD 1) presents first as an average age of 6 months (1 – 12 months). If left untreated, glycogen storage disease type 1 develop complications including protruding abdomen due to marked hepatomegaly (storage of glycogen and fat), short stature, truncal obesity, rounded doll-like face, and wasted muscles. Glycogen storage disease type 1 is diagnosed by identification of proband by either molecular genetic testing or enzyme activity assay. Molecular genetic testing shows biallelic pathogenic variants in G6PC for patients with GSD type 1a and biallelic pathogenic variants in SLC37A4 for patients with GSD type 1b. Liver transplantation is the final treatment for patients with metabolic disease associated associated with GSD type 1. The medical management of GSD type 1 is divided into nutritional therapy and medical management of systemic complications. The primary concern in infants and young children with GSD type 1 is hypoglycemia. There is resolution of metabolic derangements (correction of hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia) after liver transplantation in patients with GSD type 1. Effective measures for primary prevention of glycogen storage disease type 1 include genetic counseling, prenatal diagnosis, and screening. Effective measures for secondary prevention of glycogen storage disease type 1 (GSD type 1) include blood glucose (BG) monitoring, prevent overtreatment, growth tracking as well as several system wise recommendations including general medical care, gastrointestinal or nutritional, hepatic and hepatic transplantation, nephrology, hematology, cardiovascular, surgery/anesthesia, and gynecological/obstetrical recommendations.

Glucose-6-phosphatase deficiency in glycogen storage disease (GSD 1) is identified as first specific enzymopathy in a hereditary disorder. In 1952, Gerty T. Cori and Carl F. Cori were the first to discover the association between deficiency of glucose-6-phosphatase and glycogen storage disease type I (GSD 1). In 1952, Gerty T. Cori and Carl F. Cori were the first to discover the association between deficiency of glucose-6-phosphatase and glycogen storage disease type Ia (GSD-1a). In 1978, Narisawa et al. suggested that a defect in the microsomal transport system of glucose-6-phosphate (T1 deficiency) may cause a new variant known as glycogen storage disease type Ib (GSD-1b). In 1982, the first liver transplantation for GSD type 1 was performed.

Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit consist of calcium binding protein and three transport proteins (T1, T2, and T3). The movement of glucose-6-phosphate, phosphate, and glucose into and out of the enzyme is facilitated by T1, T2, and T3 respectively. Glycogen storage disease type 1 (GSD1) is divided on the basis of defect/deficiency of either enzyme or transporter into four types including glycogen storage disease type 1a, type 1b, type 1c, and 1d.

Glycogen storage disease type 1 (GSD 1) results due to defects in either hydrolysis or transport of glucose-6-phosphate. Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis. The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia. Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly. Glycogen also deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques. Hematologic disorders in GSD type 1 include anemia, bleeding diathesis, and neutropenia. Neutropenia and neutrophil dysfunction is specific of GSD type 1b. Abnormal expression of hepcidin in GSD type 1 leads to refractory iron deficiency anemia. GSD type 1 follows an autosomal recessive pattern. On gross pathology analysis, the features of glycogen storage disease type 1 include hepatomegaly. Hepatomegaly decreases as age increases. On microscopic histopathological analysis, the features of glycogen storage disease type 1 include distended liver cells by glycogen and fat, PAS positive and diastase sensitive glycogen distributed uniformly within the cytoplasm, and numerous large lipid vacuoles.

Glycogen storage disease type 1 is an autosomal recessive disorder. Glycogen storage disease type 1a is caused by the deficiency of the glucose-6-phosphatase enzyme. The gene for the glucose-6-phosphatase enzyme is located on chromosome 17q21. Glycogen storage disease type 1b is caused by a defect in the microsomal glucose-6-phosphate transporter. The gene for the microsomal glucose-6-phosphate transporter is located on chromosome 11q23.

The incidence of glycogen storage disease type 1 (GSD 1) is approximately 1 per 100,000 individuals worldwide. The prevalence of glycogen storage disease type 1 is approximately 5 per 100,000 individuals in Ashkenazi Jewish population. Glycogen storage disease type 1 is usually first diagnosed among infants.

The most potent risk factor in the development of glycogen storage disease type 1 is a sibling with glycogen storage disease type 1.

Glycogen storage disease type 1 is an autosomal recessive disease so carrier screening of at-risk relatives may be done. Screening requires prior identification of G6PC or SLC37A4 pathogenic variants in the family.

Glycogen storage disease type 1 (GSD 1) presents first as an average age of 6 months (1 – 12 months). If left untreated, glycogen storage disease type 1 develop complications including protruding abdomen due to marked hepatomegaly (storage of glycogen and fat), short stature, truncal obesity, rounded doll-like face, and wasted muscles. Common complications of glycogen storage disease type I include bleeding diathesis, chronic renal failure, hepatic adenoma, anemia, and inflammatory bowel disease (specifically in GSD type 1b).

Glycogen storage disease type 1 is diagnosed by identification of proband by either molecular genetic testing or enzyme activity assay. Molecular genetic testing shows biallelic pathogenic variants in G6PC for patients with GSD type 1a and biallelic pathogenic variants in SLC37A4 for patients with GSD type 1b. Enzyme activity assay performed are glucose-6-phosphatase (G6Pase) catalytic activity and glucose-6-phosphate exchanger SLC37A4 (transporter) activity.

The presentation of GSD type 1 may vary depending on the age of the patients. Glycogen storage disease type 1 commonly presents in infancy period (particularly age 3 – 6 months) with protruded abdomen due to hepatomegaly. Neonates presents rarely with hypoglycemia and lactic acidosis.

Physical examination of patients with glycogen storage disease type 1 is usually remarkable for protruding abdomen due to marked hepatomegaly, short stature, doll-like facial appearance, truncal obesity, and wasted muscles.

Laboratory findings consistent with the diagnosis of glycogen storage disease include hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia.

There is no ECG finding associated with glycogen storage disease type 1.

There is no X-ray finding associated with glycogen storage disease type 1.

Abdominal computed tomography or magnetic resonance imaging with contrast is performed to screen for hepatocellular carcinoma and should be repeated every 6 – 12 months or earlier on the basis of laboratory and clinical findings.

Recurrent hypoglycemia causes brain damage in patients with glycogen storage disease type 1. MRI findings in glycogen storage disease type 1 due to brain damage include dilatation of occipital horns and/or hyperintensity of subcortical white matter in the occipital lobes. Abdominal magnetic resonance imaging or computed tomography with contrast is performed to screen for hepatocellular carcinoma and repeated every 6 – 12 months or earlier on the basis of laboratory and clinical findings.

Ultrasound may be helpful in the diagnosis of glycogen storage disease type 1. Findings on an ultrasound suggestive of glycogen storage disease type 1 include hepatomegaly, increased hepatic echogenicity, and enlarged kidneys. Abdominal ultrasound should be performed at baseline and every 12-24 months to detect transformation of hepatocellular adenoma to hepatocellular carcinoma.

Dual energy X-ray absorptiometry (DXA) may be helpful in the diagnosis of osteoporosis and/or osteopenia due to poor metabolic control in patients with glycogen storage disease type 1. Findings on an dual energy X-ray absorptiometry suggestive of osteoporosis and/or osteopenia in patients with glycogen storage disease type 1 include low bone mineral density (BMD).

Other studies used for diasnosis of glycogen storage disease type 1 include identification of proband by either molecular genetic testing or enzyme activity assay. Molecular genetic testing shows biallelic pathogenic variants in G6PC for patients with GSD type 1a and biallelic pathogenic variants in SLC37A4 for patients with GSD type 1b. Enzyme activity assay performed are glucose-6-phosphatase (G6Pase) catalytic activity and glucose-6-phosphate exchanger SLC37A4 (transporter) activity.

The medical management of GSD type 1 is divided into nutritional therapy and medical management of systemic complications. The primary concern in infants and young children with GSD type 1 is hypoglycemia. Small frequent feeds high in complex carbohydrates (preferably those high in fiber) are distributed evenly throughout 24 hours for the prevention of hypoglycemia. Sucrose (fructose and glucose) and lactose (galactose and glucose) may be limited or avoided. Solis food is introduced at the time of 4 – 6 months. Infant cereals are started followed by vegetables and then by meat. Preferred treatment for young child is cornstarch (CS) which may be used alone or by mixing it with sucrose-free, fructose-free, lactose-free infant formula, sugar-free soy milk, sugar-free drinks, and/or water. Other treatment strategy are directed towards management of hypocitraturia, hypercalcemia, proteinuria, platelet dysfunction, and neutropenia.

Liver transplantation is the final treatment for patients with metabolic disease associated associated with GSD type 1. Indications for liver transplantation include patients with multifocal lesions, growing lesions that do not regress with improved dietary regimens, and patients who do not have evidence of distant metastatic disease. There is resolution of metabolic derangements (correction of hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia) after liver transplantation in patients with GSD type 1 after Liver transplantation.

Effective measures for primary prevention of glycogen storage disease type 1 include genetic counseling, prenatal diagnosis, and screening.

Effective measures for secondary prevention of glycogen storage disease type 1 (GSD type 1) include blood glucose (BG) monitoring, prevent overtreatment, growth tracking as well as several system wise recommendations including general medical care, gastrointestinal or nutritional, hepatic and hepatic transplantation, nephrology, hematology, cardiovascular, surgery/anesthesia, and gynecological/obstetrical recommendations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Glucose-6-phosphatase deficiency in glycogen storage disease (GSD 1) is identified as first specific enzymopathy in a hereditary disorder. In 1952, Gerty T. Cori and Carl F. Cori were the first to discover the association between deficiency of glucose-6-phosphatase and glycogen storage disease type I (GSD 1). In 1952, Gerty, T. Cori, and Carl F. Cori were the first to discover the association between deficiency of glucose-6-phosphatase and glycogen storage disease type Ia (GSD-1a). In 1978, Narisawa et al. suggested that a defect in the microsomal transport system of glucose-6-phosphate (T1 deficiency) may cause a new variant known as glycogen storage disease type Ib (GSD-1b). In 1982, the first liver transplantation for GSD type 1 was performed.

• In 1929, Von Gierke was the first to describe glycogen storage disease in a 8 year old girl.^[1]
• In 1952, Gerty T. Cori and Carl F. Cori were the first to discover the association between deficiency of glucose-6-phosphatase and glycogen storage disease type Ia (GSD-1a).^[2]
• In 1978, Narisawa et al. suggested that a defect in microsomal transport system of glucose-6-phosphate (T1 deficiency) may cause a new variant known as glycogen storage disease type Ib (GSD-1b).^[3]
• In 1983, Nordlie et al. suggested that T2 deficiency may cause another new variant known as glycogen storage disease type Ic (GSD-1c).^[4]
• In 1986, Roe et al. were the first to describe inflammatory bowel disease in glycogen storage disease type Ib.^[5]
• In 1993, Brody et al. located the gene encoding the catalytic unit of the glucose-6-phosphatase complex on chromosome 17q21.^[6]
• In the same year, Lei et al. identified the mutations causing glycogen storage disease type 1a by cloning human glucose-6-phosphatase gene.^[7]
• In 1998, Annabi et al. located the gene responsible for glycogen storage disease type Ib through linkage analysis to chromosome 11q23.^[8]

• In 1982, the first liver transplantation for GSD type 1 was performed.^[9]

• Glucose-6-phosphatase deficiency in GSD-1 is identified as first specific enzymopathy in a hereditary disorder.^[10]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit consist of calcium binding protein and three transport proteins (T1, T2, and T3). The movement of glucose-6-phosphate, phosphate, and glucose into and out of the enzyme is facilitated by T1, T2, and T3 respectively. Glycogen storage disease type 1 (GSD1) is divided on the basis of defect/deficiency of either enzyme or transporter into four types including glycogen storage disease type 1a, type 1b, type 1c, and 1d.

Glucose-6-phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit consist of calcium binding protein and three transport proteins (T1, T2, and T3). The movement of glucose-6-phosphate, phosphate, and glucose into and out of the enzyme is facilitated by T1, T2, and T3 respectively.^[1]

Glycogen storage disease type 1 (GSD1) is divided on the basis of defect/deficiency of either enzyme or transporter into four types:^[2][3][4]

Type of GDS 1	Type of defect	Molecular mechanism
Glycogen storage disease type 1a	Enzyme deficiency	Deficiency of glucose-6-phosphatase
Glycogen storage disease type 1b	Glucose-6-phosphate translocase deficiency (T1 deficiency)	Deficiency of liver microsomal transport of glucose-6-phosphate
Glycogen storage disease type 1c	Phosphate/pyrophosphate translocase deficiency (T2 deficiency)	Deficiency of liver microsomal transport of phosphate
Glycogen storage disease type 1d	Glucose deficiency translocase (T3 deficiency)	Deficiency of liver microsomal transport of glucose

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Glycogen storage disease type 1 (GSD 1) results due to defects in either hydrolysis or transport of glucose-6-phosphate. Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis. The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia. Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly. Glycogen also deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques. Hematologic disorders in GSD type 1 include anemia, bleeding diathesis, and neutropenia. Neutropenia and neutrophil dysfunction is specific of GSD type 1b. Abnormal expression of hepcidin in GSD type 1 leads to refractory iron deficiency anemia. GSD type 1 follows an autosomal recessive pattern. On gross pathology analysis, the features of glycogen storage disease type 1 include hepatomegaly. Hepatomegaly decreases as age increases. On microscopic histopathological analysis, the features of glycogen storage disease type 1 include distended liver cells by glycogen and fat, PAS positive and diastase sensitive glycogen distributed uniformly within the cytoplasm, and numerous large lipid vacuoles.

• Glycogen storage disease type 1 (GSD 1) results due to defects in either hydrolysis or transport of glucose-6-phosphate.^[1][2]
• GSD type 1a is due to the deficiency of enzyme glucose-6-phosphatase (G6Pase).^[3]
• GDS type 1b is due to defect in glucose-6-phosphate translocase (T1 deficiency).^[4][5]

• G6Pase is primarily expressed in gluconeogenesis in the liver and kidney. It is also expressed to a lesser extent in the intestine and pancreas.^[6][7]
• Glucose-6-phosphatase catalyzes the conversion of glucose-6-phosphate to glucose during glycogenolysis and gluconeogenesis.
• This defects hinders the conversion of glucose-6-phosphate to glucose in organs.
• This leads to accumulation of glycogen in organs including liver, kidney, and intestine.
• The inability of glucose-6-phosphate to leave cells leads to severe fasting hypoglycemia.
• This also results in the development of various secondary metabolic and biochemical abnormalities including hyperlactacidemia, hyperuricemia, and hyperlipidemia.

• Hyperuricemia in glycogen storage disease type 1 is due to:^{[8][9][10][11][12][13][14][15]}
  • Decrease uric acid excretion: High serum lactate and ketoacid levels cause a decrease in renal clearance of uric acid.
  • Uric acid overproduction

• Impairment of glycogenolysis leads to the accumulation of fat and glycogen deposition resulting in characteristic hepatomegaly.
• Hepatomegaly is more pronounced when the child is young and decreases as the age progresses. The hepatomegaly leads to protrusion of the abdomen.
• Patients with GSD type 1 may develop hepatic lesions including:^{[6][16][17][18][19][20]}
  • Hepatocellular adenoma (most common)
  • Hepatocellular carcinoma
  • Hepatoblastoma
  • Focal fatty infiltration
  • Focal fatty sparing
  • Focal nodular hyperplasia
  • Peliosis hepatis
• The prevalence of hepatocellular adenoma increases as the age progress. 70 – 80 % Patients have at least one lesion of hepatocellular adenoma by the time they reach the age of 25 years.

• Patients with GSD type 1 have renal manifestations early in childhood.^[21]
• Glycogen deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques.^[22][23]
• There is a progressive decrease in urinary citrate excretion as the age increases. Hypocitraturia along with hypercalciuria leads to nephrolithiasis and nephrocalcinosis.^[24][25][26]
• Glycogen storage and metabolic disturbances in patients with GSD type 1 leads to progressive glomerular injury and finally end-stage renal disease requiring renal transplantation.

• Anemia in GSD type 1 is due to an array of factors including:^[2][27]
  • The restricted nature of the diet
  • Chronic lactic acidosis
  • Renal disorders
  • Bleeding diathesis
  • Chronic nature of the illness
  • Suboptimal metabolic control
  • Hepatic adenomas
  • Inflammatory bowel disease (specifically in GSD type 1b)
• Abnormal expression of hepcidin in GSD type 1 leads to refractory iron deficiency anemia.^[28]
• In GSD type 1b associated with inflammatory bowel disease is believed to be due to Interleukin-6. Increased expression of Interleukin-6 due to inflammation leads to upregulation of hepcidin leading to anemia.

• Bleeding diathesis in GSD type 1 secondary to metabolic abnormalities and include:^[29][30][31]
• Acquired platelet dysfunction with prolonged bleeding times
• Decreased platelet adhesiveness
• Abnormal aggregation of platelets

• Neutropenia and neutrophil dysfunction is specific of GSD type 1b.^[32]
• Neutropenia and neutrophil dysfunction in glycogen storage disease type Ib is thought to be due to loss of glucose-6-phosphate translocase activity leading to:^[33]
  • Enhanced endoplasmic reticulum stress
  • Oxidative stress
  • Apoptosis of neutrophils
• Patients with GSD type 1b associated with neutropenia are at increased risk of:^[34][35]
  • Infections
  • Gingivitis
  • Mouth ulcers
  • Upper respiratory infections
  • Deep abscesses
  • Enterocolitis
• Also, there is dysfunction of monocytes leads to:^[36]
  • Granuloma formation
  • Chronic inflammatory responses

• 80% Cases of GSD 1 are of GSD type 1a.^[37]
• G6PC gene mutation is responsible for Glucose-1-phosphatase deficiency in GSD type 1a and is located on chromosome locus 17q21.^[3]
• SLC37A4 gene mutation is responsible for Glucose-6-phosphate translocase defect in GSD type 1b and is located on chromosome locus 11q23.^[38][5]
• GSD type 1 follows an autosomal recessive pattern.

On gross pathology analysis, the features of glycogen storage disease type 1 include hepatomegaly. Hepatomegaly decreases as age increases.^[2]

• On microscopic histopathological analysis, the features of glycogen storage disease type 1 include:^[39][40][41]
  • Distended liver cells by glycogen and fat
  • PAS positive and diastase sensitive glycogen distributed uniformly within the cytoplasm
  • Normal or mildly increased glycogen as compared with that seen in other liver GSDs (especially GSDIII and GSDIX)
  • Large and numerous lipid vacuoles
  • No fibrosis and cirrhosis is present

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Glycogen storage disease type 1 is an autosomal recessive disorder. Glycogen storage disease type 1a is caused by the deficiency of the glucose-6-phosphatase enzyme.G6PC gene mutation responsible for the glucose-6-phosphatase enzyme deficiency is located on chromosome 17q21. Glycogen storage disease type 1b is caused by a defect in the microsomal glucose-6-phosphate transporter. SLC37A4 gene mutation responsible for the microsomal glucose-6-phosphate transporter is located on chromosome 11q23.

• Glycogen storage disease type 1 is an autosomal recessive disorder.^[1][2][3]
• Glycogen storage disease type 1a is caused by the deficiency of the glucose-6-phosphatase enzyme. G6PC gene mutation responsible for the glucose-6-phosphatase enzyme deficiency is located on chromosome 17q21.
• Glycogen storage disease type 1b is caused by a defect in the microsomal glucose-6-phosphate transporter. SLC37A4 gene mutation responsible for the microsomal glucose-6-phosphate transporter is located on chromosome 11q23.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

The differential diagnosis list includes glycogenoses types III and VI, fructose 1,6-bisphosphatase deficiency, and a few other conditions, but none are likely to produce all of the features of GSD I.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

The incidence of glycogen storage disease type 1 (GSD 1) is approximately 1 per 100,000 individuals worldwide. The prevalence of glycogen storage disease type 1 is approximately 5 per 100,000 individuals in Ashkenazi Jewish population. Glycogen storage disease type 1 is usually first diagnosed among infants.

• The incidence of glycogen storage disease type 1 (GSD 1) is approximately 1 per 100,000 individuals worldwide.^[1][2]
• Around 80% Cases of GSD 1 are of GSD type 1a.

• The prevalence of glycogen storage disease type 1 is approximately 5 per 100,000 individuals in Ashkenazi Jewish population.^[3][4]

• Glycogen storage disease type 1 is usually first diagnosed among infants.^[3]

• Glycogen storage disease type 1 usually affects individuals of the Ashkenazi Jewish population.^[3][5]

• Glycogen storage disease type 1 affects men and women equally.^[6]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

The most potent risk factor in the development of glycogen storage disease type 1 is a sibling with glycogen storage disease type 1.

The most potent risk factor in the development of glycogen storage disease type 1 is a sibling with glycogen storage disease type 1.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Glycogen storage disease type 1 is an autosomal recessive disease so carrier screening of at-risk relatives may be done. Screening requires prior identification of G6PC or SLC37A4 pathogenic variants in the family.

• Glycogen storage disease type 1 is an autosomal recessive disease.^[1]
• Carrier screening of at-risk relatives may be done.
• Screening requires prior identification of G6PC or SLC37A4 pathogenic variants in the family.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Glycogen storage disease type 1 (GSD 1) presents first as an average age of 6 months (1 – 12 months). If left untreated, glycogen storage disease type 1 develop complications including protruding abdomen due to marked hepatomegaly (storage of glycogen and fat), short stature, truncal obesity, rounded doll-like face, and wasted muscles. Common complications of glycogen storage disease type I include bleeding diathesis, chronic renal failure, hepatic adenoma, anemia, and inflammatory bowel disease (specifically in GSD type 1b).

• Glycogen storage disease type 1 (GSD 1) presents first as an average age of 6 months (1 – 12 months).^[1]
• If left untreated, glycogen storage disease type 1 develop complications including protruding abdomen due to marked hepatomegaly (storage of glycogen and fat), short stature, truncal obesity, rounded doll-like face, and wasted muscles.
• Untreated patients usually have a cushingoid appearance due to short stature with a round face and full cheeks.^[2]
• Hepatomegaly improves as the age progresses.

Common complications of glycogen storage disease type I include:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]}

• Bleeding diathesis
  • Epistaxis
  • Easy bruising
  • Excessive bleeding during surgical procedures
  • Menorrhagia
• Chronic renal failure requiring renal transplant
• Delayed puberty
• Gout arthritis due to hyperuricemia
• Hepatic adenoma with potential for malignant transformation into hepatocellular carcinoma
• Hypertriglyceridemia leading to
  • Acute pancreatitis
  • Cholelithiasis
• Inflammatory bowel disease (particularly GSD type 1b)
• Nephrolithiasis and nephrocalcinosis due to hyperuricemia
• Nephromegaly
• Osteopenia leading to pathologic fractures
• Osteoporosis
• Polycystic ovaries
• Pulmonary hypertension
• Refractory anemia (especially in patients with hepatic adenoma)
• Rickets
• Splenomegaly (particularly in GSD type 1b)
• Systemic hypertension
• Thyroid autoimmunity and hypothyroidism (particularly in GSD type 1b)

• If left untreated, patients with GSD I develops complications and dies in infancy or childhood of overwhelming hypoglycemia and acidosis.^[1][2]
• Surviving individuals have stunted physical growth and delayed puberty due to chronically low insulin levels.
• Mental retardation as a result of severe and recurrent hypoglycemia is considered preventable with appropriate treatment.

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