Von Gierke Disease
Introduction
Von Gierke disease or Glycogen Storage Disease Type 1 (GSD-1) belongs to a group of rare metabolic disorders with a reported incidence of 1 case per 100,000 births per year. The clinical condition results from deficiency of key enzymes in the glycolytic pathway resulting in an increase in intermediate metabolites and accumulation of glycogen in the affected tissues. It is a genetic disorder with a natural history of severe developmental abnormalities and long term complications. This paper provides an overview of GSD-1 based on studies published in peer reviewed journals with a focus on its genetic determinants, clinical picture, available therapeutic modalities and its debilitating complications. The mode of inheritance is also discussed along with the role of genetic testing as a means of primary prevention.
Studies in the last 2 decades have helped resolve considerable ambiguity surrounding the causation of Glycogen storage diseases (Veiga-da-Cunha, Gerin, and Schaftingen, 314-318) (Moses, S2-9) (Jun, Brian, Mansfield, Janice and Chou, 676-688). The following two main subtypes of Von Gierke disease are now well recognized both in terms of genetic involvement and certain variability in the clinical picture. Type Ia is due to deficient Glucose 6-phosphatase (G6Pase) enzyme and accounts for about 80% of all GSD-1 cases; while type Ib is due to deficient glucose-6-phosphate translocase enzyme (G6PT)
Physiology of Glycogen metabolism
Both subtypes are autosomal recessive disorders with phenotypic G6Pase deficiency. G6Pase enzyme is a part of a complex system comprising of several membranous proteins, a catalytic subunit (G6PC) and transporter proteins for glucose-6-phosphate, inorganic phosphate and glucose (Marcolongo, Fulceri, Gamberucci, Czegle, Banhegyi, Benedetti, 2608-18). Of these 2 membrane proteins play a central role in achieving glucose hemostasis. G6PT translocates glucose-6-phosphate (G6P) from cytoplasm to the lumen of the endoplasmic reticulum and G6Pase in turn catalyzes hydrolytic conversion of G6P to glucose and phosphate.
The specific cause is mutations in the genes G6PC (17q21) and SLC37A4 (11q23) encoding the phosphatase of the G6Pase and G6PT respectively. (Froissart, Piraud, Boudjemline, Vianey-Saban, Petit, Hubert-Buron, Eberschweiler, Gajdos, and Labrune, 27) The G6PC gene family has three isoforms (G6PC, G6PC2, and G6PC3) which despite having only partial similarity in respective amino acid sequences, are virtually indistinguishable in terms of their location at the catalytic sites (Chou, 25-44).
Studies on GSD Ia patients have shown abnormal Single Strand Conformational polymorphism (SSPC) patterns in G6Pase gene. Rake JP et al reported mutations on both alleles of the G6Pase gene. In addition to glycemic control, G6PCs also regulates the cross-membranous dynamics of glucose metabolism. Moreover, their signal role in monitoring both intracellular glucose and intraluminal glucose-6-phosphate in the endoplasmic reticulum has been widely postulated. (Rake, Annelies, Gepke, Verlind, Klary, Buys, Smit, and Hans Scheffer, 322-330), (Rake, Gepke, Philippe, Leonard, Ullrich, and Smit – Suppl. 20-34)
The condition is inherited as an autosomal recessive trait. Both parents of an affected child are heterozygotes. There is a 1 in 4 chance of disease recurrence in each successive pregnancy. With the ability to exactly identify mutations in these patient, genetic techniques may be used to pin point out potential heterozygotes in the family. Certain population groups have a higher annual incidence of GSD-1, e.g., Ekstein J et al reported an annual incidence of 1 in 20,000 in Ashkenazi Jew population. (Ekstein, Rubin, Anderson, Weinstein, Bach, Abeliovich, Webb, and Risch, 162-164)
Clinical signs and symptoms
Both subtypes can lead to severe growth retardation (delayed puberty, short stature), hypoglycemia, enlargement of kidneys and liver, elevated serum levels of lipids, uric acid and lactic acid. GSD-1b patients additionally have poor cellular immunity owing to both quantitative and qualitative reduction in functionality of White Blood Cells and Monocytes. By virtue of this deranged cellular immunity, these patients are prone to recurrent bouts of opportunistic infections and inflammation of gastrointestinal mucosa. Correlation between individual mutations and reduced cellular immunity has so far been elusive thus incriminating other genes in the pathogenesis of impaired cellular immunity. This explains the variable clinical spectrum in these patients.
GSD-1 usually manifests itself in the neonatal period, the most common presentation being protruding abdomen caused by rapid liver enlargement. ‘Doll like facies’ and thin limbs make up the classical triad of Von Gierke disease. Hepatomegaly presenting at the time of birth has also been documented. Rapid onset post-parandial hypoglycemia presenting as seizures (within 120 minutes of feeding) is a common phenomenon in these patients. Other typical findings include muscle weakness, reduced bone mass, renal stones and pancreatitis. Anaemia is a frequent accompaniment as is hyperlipidaemia, platelet dysfunction, and consequent bleeding diathesis (menorhagia, skin discoloration, epistaxis) and polycyctic ovary. Recent association with hypothyroidism has also been reported. (Austin, El-Gharbawy, Kasturi, James, Kishnani, 1246-54)
Long term sequelae
The disease is associated with crippling long term complications which, however, can be alleviated and even prevented with sustained and optimal metabolic control.
Hepatocellular adenoma: The propensity for this complication is comparable in both sexes.
Usually this is detected between 20-39 years with frequencies being reported between 16 and 75%. Liver failure may also ensue due to severe hepatic decompensation.
Nephropathy: Kidney complications are usually silent to start with, later progressing to albuminuria and renal failure. Focal segmental glomerulosclerosis, hypercalcuria and kidney stones are other recognized renal complications in these patients. Other known sequels include hyperlipaemia, xanthomas, Lipemia retinalis and gout.
In addition to these signs, patients with GSDIb sub types suffer from recurrent infectious diseases and gastrointestinal mucosal ulcerations. These may sometimes present as unexplained fever, abdominal cramps and ulceration in the peri anal area.
Diagnosis
Complete sequencing of the G6PC (GSDIa) and SLC374A (GSDIb) genes is now the standard diagnostic modality of choice in patients with suggestive clinical signs and biochemical abnormalities. (Froissart, Piraud, Boudjemline, Vianey-Saban, Petit, Hubert-Buron, Eberschweiler, Gajdos, and Labrune, 27) This has largely rendered liver biopsy redundant as a diagnostic means. With the proven success of dietary therapy, prenatal testing for GSD-1 is rarely done. Prior to identification of genes, fetal liver biopsy was the only means for prenatal diagnosis. However, in cases where familial mutations are known, the prenatal diagnosis of GSDIa and GSDIb is quite straightforward. Minimally invasive techniques also enable Fetal DNA extraction from placental tissue or amniotic fluid. (Froissart, Piraud, Boudjemline, Vianey-Saban, Petit, Hubert-Buron, Eberschweiler, Gajdos, and Labrune, 27)
Management
In general, there is no specific treatment for glycogen storage diseases (GSDs). However regular metabolic control is known to afford symptom relief, reduce liver size, prevent bouts of hypoglycemia and even normalize the growth and development to a large extent. Therefore meticulous adherence to a dietary regimen is often the only viable option for relieving symptoms, normalizing growth and forestalling the onset of complications.
Diet therapy: Mechanism of action
Dietary therapy aims to utilize the alternative metabolic pathways. It invariably involves frequent daytime feedings with typical nutrient composition of 65% carbohydrate, 10% to 15% protein, and 25% fat. Supplementation of uncooked cornstarch and overnight continuous gastric high-carbohydrate feedings are also known to mitigate symptoms. High-protein diets are also associated with slowing disease progression and improving tolerance to physical exercise in these patients. (Froissart, Piraud, Boudjemline, Vianey-Saban, Petit, Hubert-Buron, Eberschweiler, Gajdos, and Labrune, 27).
Recognition, prevention and management of hypoglycemia is a major challenge in infancy. Continuous nocturnal drip-feeding is often the only resort available. Positive results have been seen with use of uncooked starch in older children. ((Bhattacharya, Orton, Qi, Mundy, Morley, Champion, Eaton, Tester, and Lee, 350)
Shah KK et al reported superior outcomes with intermittent corn starch (uncooked) than continuous dextrose administration for preventing nocturnal hypoglycaemia. (Shah, O'Del, 329-339). Evidence suggests that properly instituted dietary therapy may ward off hepatic disease including hepatocellular carcinoma.
Supplementation of iron, calcium, Vitamins B1 and D are helpful in preventing diet induced deficiencies. Angiotensin-Converting Enzyme Inhibitors and Allopurinol are recommended in patients with microalbuminuria and hyperuricemia, respectively.
Prognosis
Patients with sub type GSD Ib run the risk of fulminant disease and are more resistant to therapy owing to recurrent infections and gastro intestinal mucosal inflammation. Kidney involvement is a near universal sequel in these patients even in those who otherwise have responded favorably to treatment. Lastly, in a subset of patients, the disease progress is relentless requiring liver and/or kidney transplant.
Genetic counseling
The figure shows a schematic illustration of the Autosomal Recessive mode of inheritance of GSD-1. It shows the chances of development of GSD-1 disorder if both parents are carriers of the mutated gene. Of note, carriers of GSD -1 have one inherited mutation in the SLC37A4 gene and as such do not manifest the disease. However, presence of 2 mutations is diagnostic of GSD and implies inheritance of 1 mutation each from both parents. It follows that detection of carrier state in both parents implies a 1 in 4 risk of a child being born with the disease. Therefore, partner testing is a standard procedure in case a carrier status for GSD-Type 1 is detected in one of the parents. Due to the risk of life-long debilitating disorder in the progeny, pregnancy should be avoided in such cases. However, with proper dietary modifications and follow up, the disease is no longer a death sentence. Therefore it’s the responsibility of the affected individuals to take an informed decision after detailed proper genetic testing and counseling.
This exercise was a fascinating study of the complexity of human body and how both nature and nurture have a bearing on the health of an individual. It also shows how scientific advances have furthered the ability of medicine to treat diseases that were once considered untreatable. It is a powerful example of genetics as a diagnostic, preventive and therapeutic tool in modern medicine. Lastly, the research showed that genet
ic investigation can help individuals with GSD-1 lead a normal life given proper dietary modifications, supportive treatment and prompt detection and management of any complications. In individuals with family history of GSDs, genetic testing and premarital counseling are important measures to help the concerned individuals take an informed decision with respect to the risk of disease development in their future progeny.
Works Cited
Austin SL, El-Gharbawy AH, Kasturi VG, James A, Kishnani PS. "Menorrhagia in patients with type I glycogen storage disease." Obstetrics and Gynaecology.(2013) 122.6: 1246-54. Web. 27 Nov. 2014. <doi: 10.1097/01.AOG.0000435451.86108.82>.
Bhattacharya, K., R. C. Orton, X. Qi, H. Mundy, D. W. Morley, M. P. Champion, S. Eaton, R. F. Tester, and P. J. Lee. "A novel starch for the treatment of glycogen storage diseases." Journal of Inherited Metabolic Disease 30.3 (2007): 350. Web. 27 Nov. 2014. <http://www.ncbi.nlm.nih.gov/pubmed/17514432>.
Chou, J. Y. "The Molecular Basis of Type 1 Glycogen Storage Diseases." Current Molecular Medicine 1.1 (2001): 25-44. Web 26.11.2014. <http://www.ncbi.nlm.nih.gov/pubmed/11899241>
Ekstein, Josef, Berish Y. Rubin, Sylvia L. Anderson, David A. Weinstein, Gideon Bach, Dvorah Abeliovich, Michael Webb, and Neil Risch. "Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population." American journal of genetics Part A 129.2 (2004): 162-164. Web. 28 Nov. 2014. <doi: 10.1186/1750-1172-6-27>.
Roseline Froissart, Monique Piraud, Alix Mollet Boudjemline, Christine Vianey-Saban, François Petit, Aurélie Hubert-Buron, Pascale Trioche Eberschweiler, Vincent Gajdos and Philippe Labrune. “Glucose-6-Phosphatase Deficiency.” Orphanet Journal of Rare Diseases 6 (2011): 27. PMC. Web. 26 Nov. 2014. <http://www.ojrd.com/content/6/1/27>
Jun, Hyun S., Brian C. Mansfield, and Janice Y. Chou. "Glycogen storage disease type I and G6Pase-? deficiency: etiology and therapy." Nature Reviews Endocrinology 6.12 (2010): 676-688. Print.
Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, Chung WK, Dagli AI, Dale D, Koeberl D, Somers MJ, Burns Wechsler S, Weinstein DA, Wolfsdorf JI, Watson MS. “Diagnosis and management of glycogen storage disease type I: A practice guideline of the American College of Medical Genetics and Genomics." Genetics in Medicine: Official journal of the American College of Genetics (2014). Web. 26 Nov. 2014. <doi: 10.1038/gim.2014.128>.
Marcolongo P, Fulceri R, Gamberucci A, Czegle I, Banhegyi G, Benedetti A. "Multiple roles of glucose-6-phosphatases in pathophysiology: State of the art and future trends." Biochimica et Biophysica acta 1830.3 (2013): 2608-18. Web. 27 Nov. 2014. <http://www.ncbi.nlm.nih.gov/pubmed/23266497>.
Moses, Shimon W. "Historical highlights and unsolved problems in glycogen storage disease type 1." European Journal of Pediatrics 161.1 (2002): S2-9. Web. 26 Nov. 2014. <http://www.ncbi.nlm.nih.gov/pubmed/12373565/>.
Rake, Jan P., Annelies M. Berge, Gepke Visser, Edwin Verlind, Klary E. Niezen-Koning, Charles H. Buys, G. P. Smit, and Hans Scheffer. "Glycogen storage disease type Ia: Recent experience with mutation analysis, a summary of mutations reported in the literature and a newly developed diagnostic flowchart." European Journal of Pediatrics 159.5 (2000): 322-330. Print.
Rake, Jan, Gepke Visser, Philippe Labrune, James V. Leonard, Kurt Ullrich, and Peter G. Smit. "Glycogen storage disease type I: Diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I)." European Journal of Pediatrics 161.1 (2002): Suppl 20-34. Web. 26 Nov. 2014. <http://www.ncbi.nlm.nih.gov/pubmed/12373567/>.
Sechi A, Deroma L, Paci S, Lapolla A, Carubbi F, Burlina A, Rigoldi M, Di Rocco M. “Quality of Life in Adult Patients with Glycogen Storage Disease Type I: Results of a Multicenter Italian Study.” JIMD Reports 14 (2014): 47–53. PMC. Web. 28 Nov. 2014.
Shah, KK, O'Del SD. "Effect of dietary interventions in the maintenance of normoglycaemia in glycogen storage disease type 1a: A systematic review and meta-analysis." Journal of human nutrition and dietetics: The official journal of the British dietetic association 26.4 (2013): 329-339. d.o.i. :10.1111/jhn.12030. Epub 2013 Jan 7. Web.
Veiga-da-Cunha, Maria, Isabelle Gerin, and Emile V. Schaftingen. "How many forms of glycogen storage disease type I?" European Journal of Pediatrics 159.5 (2000): 314-318. Web. 27 Nov. 2014.
Note for point no. 7
You will have to draw a Pedigree of the family of the case of Von Gierke disease (patient) assigned to you as part of your assignment. The drawing will be in the form shown in the sample diagram below. Darkened circles represent a female family member with mutation in her genes (detected by genetic testing). The darkened square, similarly, refers to a male with mutation in his genes. The white circles and squares represent normal females and males (respectively) in the patient’s extended family.
You have to take history from the patient assigned to you about his family details (from his parents upto his children and draw a family tree).
