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Glycogen Storage Disease Type 6

Hers Disease

Glycogen storage disease type 6, also called Hers disease, is a condition where glycogenolysis fails to take place due to a deficiency in the enzyme glycogen phosphorylase. Hepatomegaly and hypoglycemia are common consequences, although the symptoms are usually mild.


Presentation

Glycogen storage disease type 6 (GSD VI) is an inborn error of metabolism that has an autosomal recessive inheritance pattern. Glycogen phosphorylase, liver form (PYGL) gene mutation has been shown to be responsible for the ailment. GSD VI occurs when there is reduced activity of glycogen phosphorylase in the liver, consequently resulting in a buildup of glycogen in addition to systemic hypoglycemia [1] [2]. GSD VI usually presents in early childhood, as a mild and self-limiting disorder that completely regresses by adolescence or early adulthood. The exception is women who are pregnant, and women who consume alcohol, as they may experience hypoglycemia as adults. Certain mutations allow for enough residual activity of the enzyme that patients experience even milder symptoms and show no biochemical signs [3].

Typical clinical features include hepatomegaly, impaired growth, hypoglycemia after periods of fasting, and possibly distension of the abdomen. Moreover, ketosis may occur as a result of longer fasts (notably overnight) or vigorous physical activity [4]. Some cases experience no hypoglycemia at all. Elevations in liver enzymes, plasma cholesterol, and triglycerides are a documented finding, although the derangements are not pronounced.

In less common forms of the disease, symptoms (particularly hypoglycemia and hepatomegaly) may be severe and patients may even develop metabolic (lactic) acidosis after meals [5].

If left untreated, affected individuals may have delayed attainment of motor developmental milestones, and skeletal abnormalities exemplified by continued growth retardation and osteoporosis. The former may also encounter easy fatigability during physical exertion, in addition to decreased muscle tone [5]. Conversely, the disease is not usually associated with intellectual disability. It is further postulated in the literature, that sufferers of GSD VI are at a higher risk of developing hepatic adenoma and liver cirrhosis [6] [7]. Cardiomyopathy is a rare complication of liver pathology in GSD VI [6].

Camping
  • Patients with a defect of the cAMP-dependent protein kinase have been infrequently reported. Prevention - Glycogen storage disease type 6- due to phosphorylation Not supplied.[checkorphan.org]
  • Patients with a defect of the cAMP-dependent protein kinase have been infrequently reported. The PYGL gene encodes the liver isoform of the enzyme.[humpath.com]
  • Pathophysiology Hepatic glycogen phosphorylase, the rate-limiting enzyme of glycogenolysis, or glycogen breakdown, is activated (active in its phosphorylated form) by a cascade of enzymes, including adenyl cyclase, phosphorylase b kinase, and cAMP-dependent[emedicine.medscape.com]
Failure to Thrive
  • […] to thrive in infancy Faltering weight in infancy Weight faltering in infancy When there are mutations in the PYGL gene, there is not enough functioning glycogen phosphorylase to break down glycogen.[rarediseases.info.nih.gov]
  • 'The affected puppies showed a general failure to thrive, hypoglycemia (low blood sugar), mental depression, poor body condition and failure to nurse (symptoms of fading puppy syndrome)'.[americanmaltese.org]
  • The classical clinical presentation for GSD IV is hepatomegaly with failure to thrive, followed by progressive liver failure and death by the age of 5 years. 1 Variable expression of GSD IV has been reported. 2-4 A patient, diagnosed at the age of 2 years[adc.bmj.com]
  • We do not endorse non-Cleveland Clinic products or services Policy Until the early 1970s, the most severe and well-known form of hepatic glycogen storage disease (GSD) was almost always fatal, marked by extreme failure to thrive, life-threatening hypoglycemia[consultqd.clevelandclinic.org]
  • […] to thrive, death by 5 years Rare nonprogressive form: no cirrhosis, live to adulthood; adult onset progressive neurogenic bladder, gait difficulties (i.e. spasticity and weakness) from mixed upper and lower motor neuron involvement, sensory loss predominantly[pathologyoutlines.com]
Hepatomegaly
  • Typical clinical features include hepatomegaly, impaired growth, hypoglycemia after periods of fasting, and possibly distension of the abdomen.[symptoma.com]
  • Hepatomegaly usually improves with age and disappears entirely at puberty. Etiology Transmission is autosomal recessive and mutations in the PYGL gene (14q21-q22) have been identified in patients.[orpha.net]
  • GSD VI should be considered in any child with hepatomegaly and ketotic hypoglycemia. Children with unexplained hepatomegaly with mild-moderate elevation of transaminase concentrations should have a fasting glucose and ketones check.[ncbi.nlm.nih.gov]
  • Findings from imaging studies may reveal hepatomegaly. Liver biopsy may be required to diagnose the cause of hepatomegaly. Diagnosis by DNA analysis is considered preferable to liver biopsy so as to avoid an invasive procedure.[emedicine.com]
  • These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis.[humpath.com]
Liver Fibrosis
  • Liver fibrosis and hepatocellular carcinoma have been reported in patients with GSD VI. Obtain a creatine kinase level in all cases of suspected glycogen storage disease (GSD).[emedicine.com]
  • Rarely, liver fibrosis develops in GSD VI, and a cardiomyopathy can occur from over storage of carbohydrate [ 111 ].[doi.org]
Normal Stature
  • Although children may have growth delay and short stature, adolescents and adults often have normal stature.[humpath.com]
  • Adults with GSD VI exhibit normal stature, motor function, and biochemical parameters.[emedicine.medscape.com]
  • Prognosis is good; adult patients have normal stature and minimal hepatomegaly.[ommbid.mhmedical.com]
Peripheral Neuropathy
  • Rare variants may cause muscle dysfunction, peripheral neuropathy, proximal renal tubule acidosis, or severe cardiomyopathy. Pathology Histological analysis of the liver typically reveals glycogen-distended hepatocytes.[humpath.com]
  • Rare variants of GSD VI may manifest as proximal renal tubule acidosis, myopathy, peripheral neuropathy, or fatal cardiomyopathy. GSD VI is caused by a deficiency in the hepatic glycogen phosphorylase enzyme.[emedicine.medscape.com]
  • Although these cases may be termed distal myopathy, peripheral neuropathy due to debrancher deficiency may contribute to this pattern of weakness.[nature.com]
Polyneuropathy
  • Liver glycogenoses: are they a possible cause of polyneuropathy? A cross-sectional study. J Trop Pediatr. 2004 Aug. 50(4):196-202. [Medline]. Newgard CB, Fletterick RJ, Anderson LA.[emedicine.medscape.com]
  • Liver glycogenoses: are they a possible cause of polyneuropathy? A cross-sectional study. J Trop Pediatr 2004; 50 : 196–202. 24. Labrune P, Huguet P, Odievre M.[nature.com]
Forgetful
  • Don’t forget to check for the latest news. Go to the home page, the news section, and look through the latest news items.[agsd.org.uk]

Workup

Clinical diagnosis of glycogen storage disease type 6 entails the detection of the recognizable features of the medical entity, such as hepatomegaly, delayed growth, hypoglycemia with or without a ketotic state, after fasting or illness.

Biochemical testing confirms the diagnosis. The following laboratory investigations are performed:

  • Serum alanine transaminase (ALT), aspartate transaminase (AST) and lipids may be increased, while creatinine kinase, uric and lactic acid levels remain normal. Liver failure is uncommon in GSD VI.
  • Some people will show no responsive rise in blood glucose levels after administration of glycogen.
  • Blood glycogen phosphorylase enzyme assay may be performed on non-hepatic cells, but normal levels do not exclude its deficiency in hepatic tissue.
  • Genetic testing of the affected individual, for detection of a defective PYGL gene. It is also a useful diagnostic tool in individuals whose biochemical results are normal [3] [8].
  • Liver biopsy: This reveals excess glycogen, as well as low levels of the hepatic glycogen phosphorylase enzyme. Signs of hepatocellular adenoma may also be identified in this way [7].
  • Genetic testing for asymptomatic carriers, as well as prenatal testing in affected families.
  • Sequence analysis for the recognition of variant gene alterations [9].
Fasting Hypoglycemia
  • Most affected individuals exhibit resolution of hepatomegaly, hypotonia, muscle weakness, risk of fasting hypoglycemia, and abnormal biochemical parameters before or at puberty.[emedicine.medscape.com]
  • These children may also have histories of mild fasting hypoglycemia and hypotonia. Some patients remain asymptomatic, and routine physical examination reveals hepatomegaly.[humpath.com]
  • In individuals experiencing fasting hypoglycemia, a high carbohydrate diet and frequent feedings may be recommended. Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.[rarediseases.org]
  • Though each form of GSD is distinct in presentation (Table 1), all forms manifest as fasting hypoglycemia and metabolic acidosis if untreated.[consultqd.clevelandclinic.org]
Hyperlactacidemia
  • Phenotype and clinics Patients have poor tolerance to fasting (with hypoglycemia and hyperlactacidemia after 3 to 4 hours of fasting), marked hepatomegaly, full-cheeked round face, growth retardation (small stature and delayed puberty), generally improved[atlasgeneticsoncology.org]

Treatment

  • Management and treatment A diet with high carbohydrate intake and regular meals prevents hypoglycemia in children, but most patients require no specific treatment. Prognosis Prognosis is usually good.[orpha.net]
  • Washout period (1 week): Subjects receive no treatment Treatment period #2 (2 weeks): Subjects who received Triheptanoin oil in the first treatment period, now receive placebo oil and vice versa.[clinicaltrials.gov]
  • Treatment: Treatment with cornstarch and a high protein diet is recommended in an effort to achieve normal labs and normal growth.[agsdus.org]
  • Treatment: The phenotype is mild and requires little treatment. Fasting should be avoided and hypoglycemia should be treated. Prognosis: Excellent. Ancillary treatments and support: Adequate diet, regular pediatric check-ups.[wohproject.org]
  • Treatment of Manifestations Some individuals with glycogen storage disease type VI (GSD VI) may not require any treatment, but most have better growth and stamina with therapy.[ncbi.nlm.nih.gov]

Prognosis

  • Prognosis Prognosis is usually good. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • Prognosis Individuals with GSD VI have an excellent prognosis for normal stature and development, even without dietary management during childhood.[emedicine.medscape.com]
  • Prognosis - Glycogen storage disease type 6- due to phosphorylation Not supplied. Treatment - Glycogen storage disease type 6- due to phosphorylation Not supplied. Resources - Glycogen storage disease type 6- due to phosphorylation Not supplied.[checkorphan.org]
  • Prognosis: Excellent. Ancillary treatments and support: Adequate diet, regular pediatric check-ups. Specialists and specialty centers: Nutritionist, pediatrician.[wohproject.org]

Etiology

  • Etiology Transmission is autosomal recessive and mutations in the PYGL gene (14q21-q22) have been identified in patients.[orpha.net]
  • Etiology GSD VI results from a deficiency in the activity of one of several enzymes in the phosphorylase-activating cascade. Most cases result from defects of phosphorylase b kinase, an enzyme that activates phosphorylase by phosphorylation.[humpath.com]
  • Ongoing controversies regarding etiology, diagnosis, treatment In 2002, guidelines from the European Study on Glycogen Storage Disease Type I (ESGSDI) recommended liver transplantation in patients with type I GSD and unresectable hepatocellular adenomas[clinicaladvisor.com]
  • 3584, EA Utrecht, The Netherlands (2) Beatrix Children’s Hospital, University Medical Centre Groningen, Hanzeplein1, 9700, Groningen, The Netherlands References Chou JY, Jun HS, Mansfield BC: Glycogen storage disease type I and G6Pase-beta deficiency: etiology[ojrd.biomedcentral.com]

Epidemiology

  • […] gene that is responsible for phosphorylating (and thus activating) liver glycogen phosphorylase. [4] The presentation of GSD type IX is therefore similar to that of GSD type VI, so next-generation sequencing should be used to confirm the diagnosis. [5] Epidemiology[emedicine.medscape.com]
  • The GSD classification is based on the enzyme deficiency and the affected tissue. [ 3 ] Epidemiology The overall GSD incidence is estimated at 1 case per 20,000-43,000 live births. [ 4 ] Type I is the most common (25% of all GSDs).[patient.info]
  • Diabetes I Glucose-6-Phosphatase Hypoglycemia FTT /developmental delay Hepatomegaly III Debranching Hepatomegaly Hypoglycemia Hepatitis VI Phosphorylase Hepatomegaly Ketotic Hypoglycemia IX Phosphorylase kinase Hepatomegaly Ketotic Hypoglycemia Table 3 Epidemiology[doi.org]
Sex distribution
Age distribution

Pathophysiology

  • Pathophysiology Hepatic glycogen phosphorylase, the rate-limiting enzyme of glycogenolysis, or glycogen breakdown, is activated (active in its phosphorylated form) by a cascade of enzymes, including adenyl cyclase, phosphorylase b kinase, and cAMP-dependent[emedicine.medscape.com]
  • 雑誌 Mol Genet Metab 104:137-43 (2011) DOI: 10.1016/j.ymgme.2011.05.010 文献 PMID: 25633903 著者 Derks TG, van Rijn M タイトル Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions.[kegg.jp]
  • Insights into the pathophysiology of Pompe disease. Clin Ther 2008;30 Suppl 1:S3. McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD:The Johns Hopkins University;Entry No:232300. Available at:[rarediseases.org]
  • Pathophysiology Metabolic Pathway Metabolic pathways showing defects in various glycogen storage diseases, (ɔ) Image courtesy of WikiDoc.org, by " Dr.[wikidoc.org]

Prevention

  • Management and treatment A diet with high carbohydrate intake and regular meals prevents hypoglycemia in children, but most patients require no specific treatment. Prognosis Prognosis is usually good.[orpha.net]
  • Prevention of primary manifestations: Hepatomegaly and hypoglycemia may be prevented by administration of uncooked cornstarch one to three times a day.[ncbi.nlm.nih.gov]
  • PYGL gene mutations prevent liver glycogen phosphorylase from breaking down glycogen effectively.[ghr.nlm.nih.gov]
  • In GSD6 the defective enzyme prevents glucose from being properly extracted and so glycogen continues to build up in the body. This accounts for the enlarged liver and swollen abdomen and produces symptoms of low blood sugar.[agsd.org.uk]
  • Prevention - Glycogen storage disease type 6- due to phosphorylation Not supplied. Diagnosis - Glycogen storage disease type 6- due to phosphorylation Not supplied. Prognosis - Glycogen storage disease type 6- due to phosphorylation Not supplied.[checkorphan.org]

References

Article

  1. Brown LM, Corrado MM, van der Ende RM, et al. Evaluation of glycogen storage disease as a cause of ketotic hypoglycemia in children. J Inherit Metab Dis. 2015 May;38(3):489-493.
  2. Parker EI, Xing M, Moreno-De-Luca A, Harmouche E, Terk MR. Radiological and clinical characterization of the lysosomal storage disorders: non-lipid disorders. Br J Radiol. 2014;87(1033):20130467.
  3. Tang NL, Hui J, Young E, et al. A novel mutation (G233D) in the glycogen phosphorylase gene in a patient with hepatic glycogen storage disease and residual enzyme activity. Mol Genet Metab. 2003;79(2):142-145.
  4. Hoogeveen IJ, van der Ende RM, van Spronsen FJ, de Boer F, Heiner-Fokkema MR, Derks TG. Normoglycemic ketonemia as biochemical presentation in ketotic glycogen storage disease. JIMD Rep. 2016;28:41-47.
  5. Beauchamp NJ, Taybert J, Champion MP, et al. High frequency of missense mutations in glycogen storage disease type VI. J Inherit Metab Dis. 2007;30(5):722–34.
  6. Roscher A, Patel J, Hewson S, et al. The natural history of glycogen storage disease types VI and IX: Long-term outcome from the largest metabolic center in Canada. Mol Genet Metab. 2014;113(3):171-176.
  7. Manzia TM, Angelico R, Toti L, et al. Glycogen storage disease type Ia and VI associated with hepatocellular carcinoma: two case reports. Transplant Proc. 2011;43(4):1181-183.
  8. Burwinkel B, Bakker HD, Herschkovitz E, Moses SW, Shin YS, Kilimann MW. Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Am J Hum Genet. 1998;62(4):785-791.
  9. Chang S, Rosenberg MJ, Morton H, Francomano CA, Biesecker LG. Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI. Hum Mol Genet. 1998;7(5):865–870.

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Last updated: 2019-06-28 09:38