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Glycogen storage disease due to glucose-6-phosphatase deficiency type IA(GSD1A)

MedGen UID:
415885
Concept ID:
C2919796
Disease or Syndrome
Synonyms: Glucose-6-phosphatase deficiency; Glucose-6-phosphatase deficiency glycogen storage disease; Glycogen storage disease type 1A; Glycogen Storage Disease Type Ia; Glycogenosis type 1; GSD Ia; GSD1A; Hepatorenal form of glycogen storage disease; Hepatorenal glycogenosis; Von Gierke disease
SNOMED CT: Glycogen storage disease type Ia (444707001)
 
Gene (location): G6PC1 (17q21.31)
 
Monarch Initiative: MONDO:0009287
OMIM®: 232200
Orphanet: ORPHA79258

Disease characteristics

Excerpted from the GeneReview: Glycogen Storage Disease Type I
Glycogen storage disease type I (GSD I) is characterized by accumulation of glycogen and fat in the liver and kidneys resulting in hepatomegaly and nephromegaly. Severely affected infants present in the neonatal period with severe hypoglycemia due to fasting intolerance. More commonly, untreated infants present at age three to four months with hepatomegaly, severe hypoglycemia with or without seizures, lactic acidosis, hyperuricemia, and hypertriglyceridemia. Affected children typically have doll-like faces with full cheeks, relatively thin extremities, short stature, and a protuberant abdomen. Xanthoma and diarrhea may be present. Impaired platelet function and development of reduced or dysfunctional von Willebrand factor can lead to a bleeding tendency with frequent epistaxis and menorrhagia in females. Individuals with untreated GSD Ib are more likely to develop impaired neutrophil and monocyte function as well as chronic neutropenia resulting in recurrent bacterial infections, gingivitis, periodontitis, and genital and intestinal ulcers. Long-term complications of untreated GSD I include short stature, osteoporosis, delayed puberty, renal disease (including proximal and distal renal tubular acidosis, renal stones, and kidney failure), gout, systemic hypertension, pulmonary hypertension, hepatic adenomas with potential for malignancy, pancreatitis, and polycystic ovaries. Seizures and cognitive impairment may occur in individuals with prolonged periods of hypoglycemia. Normal growth and puberty are expected in treated children. Most affected individuals live into adulthood. [from GeneReviews]
Authors:
Deeksha S Bali  |  Areeg El-Gharbawy  |  Stephanie Austin, et. al.   view full author information

Additional descriptions

From OMIM
Glycogen storage disease type I, also known as von Gierke disease, typically manifests during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of glycogen. Affected individuals exhibit growth retardation, delayed puberty, lactic acidemia, hyperlipidemia, hyperuricemia, and in adults a high incidence of hepatic adenomas (summary by Lei et al., 1993).  http://www.omim.org/entry/232200
From MedlinePlus Genetics
Glycogen storage disease type I (also known as GSDI or von Gierke disease) is an inherited disorder caused by the buildup of a complex sugar called glycogen in the body's cells. The accumulation of glycogen in certain organs and tissues, especially the liver, kidneys, and small intestines, impairs their ability to function normally.

Signs and symptoms of this condition typically appear around the age of 3 or 4 months, when babies start to sleep through the night and do not eat as frequently as newborns. Affected infants may have low blood sugar (hypoglycemia), which can lead to seizures. They can also have a buildup of lactic acid in the body (lactic acidosis), high blood levels of a waste product called uric acid (hyperuricemia), and excess amounts of fats in the blood (hyperlipidemia). As they get older, children with GSDI have thin arms and legs and short stature. An enlarged liver may give the appearance of a protruding abdomen. The kidneys may also be enlarged. Affected individuals may also have diarrhea and deposits of cholesterol in the skin (xanthomas).

People with GSDI may experience delayed puberty. Beginning in young to mid-adulthood, affected individuals may have thinning of the bones (osteoporosis), a form of arthritis resulting from uric acid crystals in the joints (gout), kidney disease, and high blood pressure in the blood vessels that supply the lungs (pulmonary hypertension). Females with this condition may also have abnormal development of the ovaries (polycystic ovaries). In affected teens and adults, tumors called adenomas may form in the liver. Adenomas are usually noncancerous (benign), but occasionally these tumors can become cancerous (malignant).

Researchers have described two types of GSDI, which differ in their signs and symptoms and genetic cause. These types are known as glycogen storage disease type Ia (GSDIa) and glycogen storage disease type Ib (GSDIb). Two other forms of GSDI have been described, and they were originally named types Ic and Id. However, these types are now known to be variations of GSDIb; for this reason, GSDIb is sometimes called GSD type I non-a.

Many people with GSDIb have a shortage of white blood cells (neutropenia), which can make them prone to recurrent bacterial infections. Neutropenia is usually apparent by age 1. Many affected individuals also have inflammation of the intestinal walls (inflammatory bowel disease). People with GSDIb may have oral problems including cavities, inflammation of the gums (gingivitis), chronic gum (periodontal) disease, abnormal tooth development, and open sores (ulcers) in the mouth. The neutropenia and oral problems are specific to people with GSDIb and are typically not seen in people with GSDIa.  https://medlineplus.gov/genetics/condition/glycogen-storage-disease-type-i

Clinical features

From HPO
Focal segmental glomerulosclerosis
MedGen UID:
4904
Concept ID:
C0017668
Disease or Syndrome
Segmental accumulation of scar tissue in individual (but not all) glomeruli.
Proteinuria
MedGen UID:
10976
Concept ID:
C0033687
Finding
Increased levels of protein in the urine.
Nephrolithiasis
MedGen UID:
98227
Concept ID:
C0392525
Disease or Syndrome
The presence of calculi (stones) in the kidneys.
Enlarged kidney
MedGen UID:
108156
Concept ID:
C0542518
Finding
An abnormal increase in the size of the kidney.
Decreased glomerular filtration rate
MedGen UID:
163428
Concept ID:
C0853068
Finding
An abnormal reduction in the volume of fluid filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Intermittent diarrhea
MedGen UID:
66782
Concept ID:
C0239181
Sign or Symptom
Repeated episodes of diarrhea separated by periods without diarrhea.
Protuberant abdomen
MedGen UID:
340750
Concept ID:
C1854928
Finding
A thrusting or bulging out of the abdomen.
Hepatocellular carcinoma
MedGen UID:
389187
Concept ID:
C2239176
Neoplastic Process
Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002).
Abnormal bleeding
MedGen UID:
264316
Concept ID:
C1458140
Pathologic Function
An abnormal susceptibility to bleeding, often referred to as a bleeding diathesis. A bleeding diathesis may be related to vascular, platelet and coagulation defects.
Gout
MedGen UID:
42280
Concept ID:
C0018099
Disease or Syndrome
Recurrent attacks of acute inflammatory arthritis of a joint or set of joints caused by elevated levels of uric acid in the blood which crystallize and are deposited in joints, tendons, and surrounding tissues.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Decreased muscle mass
MedGen UID:
373256
Concept ID:
C1837108
Finding
Pancreatitis
MedGen UID:
14586
Concept ID:
C0030305
Disease or Syndrome
The presence of inflammation in the pancreas.
Lactic acidosis
MedGen UID:
1717
Concept ID:
C0001125
Disease or Syndrome
An abnormal buildup of lactic acid in the body, leading to acidification of the blood and other bodily fluids.
Hyperlipidemia
MedGen UID:
5692
Concept ID:
C0020473
Disease or Syndrome
An elevated lipid concentration in the blood.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Fasting hypoglycemia
MedGen UID:
75765
Concept ID:
C0271708
Disease or Syndrome
HYPOGLYCEMIA expressed in the postabsorptive state, after prolonged FASTING, or an overnight fast.
Hyperuricemia
MedGen UID:
149260
Concept ID:
C0740394
Disease or Syndrome
An abnormally high level of uric acid in the blood.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Doll-like facies
MedGen UID:
383894
Concept ID:
C1856361
Finding
A characteristic facial appearance with a round facial form, full cheeks, a short nose, and a relatively small chin.
Xanthomatosis
MedGen UID:
21939
Concept ID:
C0043325
Disease or Syndrome
The presence of multiple xanthomas (xanthomata) in the skin. Xanthomas are yellowish, firm, lipid-laden nodules in the skin.
Xanthelasma
MedGen UID:
56357
Concept ID:
C0155210
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.
Delayed puberty
MedGen UID:
46203
Concept ID:
C0034012
Pathologic Function
Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty.
Lipemia retinalis
MedGen UID:
137918
Concept ID:
C0339477
Disease or Syndrome
A creamy appearance of the retinal blood vessels that occurs when the concentration of lipids in the blood are extremely increased, with pale pink to milky white retinal vessels and altered pale reflexes from choroidal vasculature.

Professional guidelines

PubMed

Ito K, Tajima G, Kamisato C, Tsumura M, Iwamoto M, Sekiguchi Y, Numata Y, Watanabe K, Yabe Y, Kanki S, Fujieda Y, Goto K, Sogawa Y, Oitate M, Nagase H, Tsuji S, Nishizawa T, Kakuta M, Masuda T, Onishi Y, Koizumi M, Nakamura H, Okada S, Matsuo M, Takaishi K
J Clin Invest 2023 Dec 1;133(23) doi: 10.1172/JCI163464. PMID: 37788110Free PMC Article
Derks TGJ, Rodriguez-Buritica DF, Ahmad A, de Boer F, Couce ML, Grünert SC, Labrune P, López Maldonado N, Fischinger Moura de Souza C, Riba-Wolman R, Rossi A, Saavedra H, Gupta RN, Valayannopoulos V, Mitchell J
Nutrients 2021 Oct 27;13(11) doi: 10.3390/nu13113828. PMID: 34836082Free PMC Article
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 2014 Nov;16(11):e1. doi: 10.1038/gim.2014.128. PMID: 25356975

Recent clinical studies

Etiology

Fukuda T, Ito T, Hamazaki T, Inui A, Ishige M, Kagawa R, Sakai N, Watanabe Y, Kobayashi H, Wasaki Y, Taura J, Imamura Y, Tsukiuda T, Nakamura K
J Inherit Metab Dis 2023 Jul;46(4):618-633. Epub 2023 Jun 14 doi: 10.1002/jimd.12610. PMID: 37114839
Derks TGJ, Rodriguez-Buritica DF, Ahmad A, de Boer F, Couce ML, Grünert SC, Labrune P, López Maldonado N, Fischinger Moura de Souza C, Riba-Wolman R, Rossi A, Saavedra H, Gupta RN, Valayannopoulos V, Mitchell J
Nutrients 2021 Oct 27;13(11) doi: 10.3390/nu13113828. PMID: 34836082Free PMC Article
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 2014 Nov;16(11):e1. doi: 10.1038/gim.2014.128. PMID: 25356975
Ferrecchia IA, Guenette G, Potocik EA, Weinstein DA
J Perinat Neonatal Nurs 2014 Jan-Mar;28(1):26-31. doi: 10.1097/JPN.0000000000000017. PMID: 24476649
Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F, Hubert-Buron A, Eberschweiler PT, Gajdos V, Labrune P
Orphanet J Rare Dis 2011 May 20;6:27. doi: 10.1186/1750-1172-6-27. PMID: 21599942Free PMC Article

Diagnosis

de Marchi R, Nalin T, Sperb-Ludwig F, Pinheiro FC, Schwartz IVD, Steiner CE
Genes (Basel) 2023 Dec 15;14(12) doi: 10.3390/genes14122219. PMID: 38137041Free PMC Article
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Front Endocrinol (Lausanne) 2021;12:685272. Epub 2021 May 21 doi: 10.3389/fendo.2021.685272. PMID: 34093448Free PMC Article
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 2014 Nov;16(11):e1. doi: 10.1038/gim.2014.128. PMID: 25356975
Ferrecchia IA, Guenette G, Potocik EA, Weinstein DA
J Perinat Neonatal Nurs 2014 Jan-Mar;28(1):26-31. doi: 10.1097/JPN.0000000000000017. PMID: 24476649
Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F, Hubert-Buron A, Eberschweiler PT, Gajdos V, Labrune P
Orphanet J Rare Dis 2011 May 20;6:27. doi: 10.1186/1750-1172-6-27. PMID: 21599942Free PMC Article

Therapy

Rossi A, Venema A, Haarsma P, Feldbrugge L, Burghard R, Rodriguez-Buritica D, Parenti G, Oosterveer MH, Derks TGJ
J Clin Endocrinol Metab 2022 Aug 18;107(9):e3612-e3623. doi: 10.1210/clinem/dgac411. PMID: 35786777Free PMC Article
Derks TGJ, Rodriguez-Buritica DF, Ahmad A, de Boer F, Couce ML, Grünert SC, Labrune P, López Maldonado N, Fischinger Moura de Souza C, Riba-Wolman R, Rossi A, Saavedra H, Gupta RN, Valayannopoulos V, Mitchell J
Nutrients 2021 Oct 27;13(11) doi: 10.3390/nu13113828. PMID: 34836082Free PMC Article
Zhang L, Cho JH, Arnaoutova I, Mansfield BC, Chou JY
J Inherit Metab Dis 2019 May;42(3):470-479. Epub 2019 Feb 22 doi: 10.1002/jimd.12069. PMID: 30714174Free PMC Article
Chou JY, Jun HS, Mansfield BC
J Inherit Metab Dis 2015 May;38(3):511-9. Epub 2014 Oct 7 doi: 10.1007/s10545-014-9772-x. PMID: 25288127
Chou JY, Mansfield BC
Expert Opin Biol Ther 2011 Aug;11(8):1011-24. Epub 2011 Apr 20 doi: 10.1517/14712598.2011.578067. PMID: 21504389Free PMC Article

Prognosis

Derks TGJ, Rodriguez-Buritica DF, Ahmad A, de Boer F, Couce ML, Grünert SC, Labrune P, López Maldonado N, Fischinger Moura de Souza C, Riba-Wolman R, Rossi A, Saavedra H, Gupta RN, Valayannopoulos V, Mitchell J
Nutrients 2021 Oct 27;13(11) doi: 10.3390/nu13113828. PMID: 34836082Free PMC Article
Muzetti JH, do Valle DA, Santos MLSF, Telles BA, Cordeiro ML
Front Endocrinol (Lausanne) 2021;12:685272. Epub 2021 May 21 doi: 10.3389/fendo.2021.685272. PMID: 34093448Free PMC Article
Dambska M, Labrador EB, Kuo CL, Weinstein DA
Pediatr Diabetes 2017 Aug;18(5):327-331. Epub 2017 Jun 1 doi: 10.1111/pedi.12540. PMID: 28568353
Ferrecchia IA, Guenette G, Potocik EA, Weinstein DA
J Perinat Neonatal Nurs 2014 Jan-Mar;28(1):26-31. doi: 10.1097/JPN.0000000000000017. PMID: 24476649
Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F, Hubert-Buron A, Eberschweiler PT, Gajdos V, Labrune P
Orphanet J Rare Dis 2011 May 20;6:27. doi: 10.1186/1750-1172-6-27. PMID: 21599942Free PMC Article

Clinical prediction guides

Muzetti JH, do Valle DA, Santos MLSF, Telles BA, Cordeiro ML
Front Endocrinol (Lausanne) 2021;12:685272. Epub 2021 May 21 doi: 10.3389/fendo.2021.685272. PMID: 34093448Free PMC Article
Kaiser N, Gautschi M, Bosanska L, Meienberg F, Baumgartner MR, Spinas GA, Hochuli M
Mol Genet Metab 2019 Apr;126(4):355-361. Epub 2019 Feb 28 doi: 10.1016/j.ymgme.2019.02.008. PMID: 30846352
Kasapkara CS, Tümer L, Okur I, Eminoğlu T, Ezgü FS, Hasanoğlu A
Turk J Pediatr 2012 Jan-Feb;54(1):35-7. PMID: 22397040
Specht A, Fiske L, Erger K, Cossette T, Verstegen J, Campbell-Thompson M, Struck MB, Lee YM, Chou JY, Byrne BJ, Correia CE, Mah CS, Weinstein DA, Conlon TJ
J Biomed Biotechnol 2011;2011:646257. Epub 2011 Jan 3 doi: 10.1155/2011/646257. PMID: 21318173Free PMC Article
Ekstein J, Rubin BY, Anderson SL, Weinstein DA, Bach G, Abeliovich D, Webb M, Risch N
Am J Med Genet A 2004 Aug 30;129A(2):162-4. doi: 10.1002/ajmg.a.30232. PMID: 15316959

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