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Glycogen storage disease type I Microchapters |
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Differentiating Glycogen storage disease type I from other Diseases |
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Directions to Hospitals Treating 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]
Pathophysiology
Pathophysiology
- GSD type 1 results due to defects in either hydrolysis or transport of glucose-6-phosphate
- GSD type 1a is due to the deficiency of enzyme glucose-6-phosphatase (G6Pase).
- GDS type 1b is due to defect in glucose-6-phosphate translocase (T1 deficiency).
- G6Pase is primarily expressed in expressed primarily in the gluconeogenic the liver and kidney. It is also expressed to a lesser extent in the intestine and pancreas.
- 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.
Hepatomegaly and liver disorders
- 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:
- Hepatocellular adenoma (most common)
- HCC
- 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.
Renal disorders
- Patients with GSD type 1 have renal manifestations early in childhood.
- Glycogen deposits in kidneys leading to nephromegaly, which is usually detected by imaging techniques.
- There is a progressive decrease in urinary citrate excretion as the age increases. Hypocitraturia along with hypercalciuria leads to nephrolithiasis and nephrocalcinosis.[1][2][3]
- 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.
Hematologic Disorders
Anemia
- Anemia in GSD type 1 is due to an array of factors including:[4][5]
- 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 hepacidin in GSD type 1 leads to refractory iron deficiency anemia.[6]
- 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
- Bleeding diathesis in GSD type 1 secondary to metabolic abnormalities and include:[7][8][9]
- Acquired platelet dysfunction with prolonged bleeding times
- Decreased platelet adhesiveness
- Abnormal aggregation of platelets
Neutropenia and neutrophil dysfunction
- Neutropenia and neutrophil dysfunction is specific fo GSD type 1b.[10]
- 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:[11]
- Enhanced endoplasmic reticulum stress
- Oxidative stress
- Apoptosis of neutrophils
- Patients with GSD type 1b associated with neutropenia are at increased risk of:
- Infections
- Gingivitis
- Mouth ulcers
- Upper respiratory infections
- Deep abscesses
- Enterocolitis
- Also, there is dysfunction of monocytes leads to:[12]
- Granuloma formation
- Chronic inflammatory responses
Genetics
- 80% Cases of GSD 1 are of GSD type 1a.[13]
- G6Pase gene is located on chromosome locus 17q21.
- Glucose-6-phosphate translocase is located on chromosome locus 11q23.
- GSD type 1 follows an autosomal recessive pattern.
References
- ↑ Weinstein DA, Somers MJ, Wolfsdorf JI (2001). "Decreased urinary citrate excretion in type 1a glycogen storage disease". J Pediatr. 138 (3): 378–82. doi:10.1067/mpd.2001.111322. PMID 11241046.
- ↑ Lee PJ, Dalton RN, Shah V, Hindmarsh PC, Leonard JV (1995). "Glomerular and tubular function in glycogen storage disease". Pediatr Nephrol. 9 (6): 705–10. PMID 8747109.
- ↑ Restaino I, Kaplan BS, Stanley C, Baker L (1993). "Nephrolithiasis, hypocitraturia, and a distal renal tubular acidification defect in type 1 glycogen storage disease". J Pediatr. 122 (3): 392–6. PMID 8441093.
- ↑ Kishnani, Priya S.; Austin, Stephanie L.; Abdenur, Jose E.; Arn, Pamela; Bali, Deeksha S.; Boney, Anne; Chung, Wendy K.; Dagli, Aditi I.; Dale, David; Koeberl, Dwight; Somers, Michael J.; Burns Wechsler, Stephanie; Weinstein, David A.; Wolfsdorf, Joseph I.; Watson, Michael S. (2014). "Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics". Genetics in Medicine. doi:10.1038/gim.2014.128. ISSN 1098-3600.
- ↑ Wang DQ, Carreras CT, Fiske LM, Austin S, Boree D, Kishnani PS; et al. (2012). "Characterization and pathogenesis of anemia in glycogen storage disease type Ia and Ib". Genet Med. 14 (9): 795–9. doi:10.1038/gim.2012.41. PMC 3808879. PMID 22678084.
- ↑ Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC (2002). "Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease". Blood. 100 (10): 3776–81. doi:10.1182/blood-2002-04-1260. PMID 12393428.
- ↑ Czapek EE, Deykin D, Salzman EW (1973). "Platelet dysfunction in glycogen storage disease type I." Blood. 41 (2): 235–47. PMID 4350560.
- ↑ Corby DG, Putnam CW, Greene HL (1974). "Impaired platelet function in glucose-6-phosphatase deficiency". J Pediatr. 85 (1): 71–6. PMID 4212074.
- ↑ Hutton RA, Macnab AJ, Rivers RP (1976). "Defect of platelet function associated with chronic hypoglycaemia". Arch Dis Child. 51 (1): 49–55. PMC 1545862. PMID 942229.
- ↑ Visser G, Rake JP, Labrune P, Leonard JV, Moses S, Ullrich K; et al. (2002). "Granulocyte colony-stimulating factor in glycogen storage disease type 1b. Results of the European Study on Glycogen Storage Disease Type 1". Eur J Pediatr. 161 Suppl 1: S83–7. doi:10.1007/s00431-002-1010-0. PMID 12373578.
- ↑ Chou JY, Jun HS, Mansfield BC (2010). "Neutropenia in type Ib glycogen storage disease". Curr Opin Hematol. 17 (1): 36–42. doi:10.1097/MOH.0b013e328331df85. PMC 3099242. PMID 19741523.
- ↑ Kilpatrick L, Garty BZ, Lundquist KF, Hunter K, Stanley CA, Baker L; et al. (1990). "Impaired metabolic function and signaling defects in phagocytic cells in glycogen storage disease type 1b". J Clin Invest. 86 (1): 196–202. doi:10.1172/JCI114684. PMC 296707. PMID 2164043.
- ↑ Mansfield BC (1999). "Molecular Genetics of Type 1 Glycogen Storage Diseases". Trends Endocrinol Metab. 10 (3): 104–113. PMID 10322403.