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.
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  . 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 .
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 . 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 .
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 . 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  . Cardiomyopathy is a rare complication of liver pathology in GSD VI .
Entire Body System
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]
[…] 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]
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]
Liver, Gall & Pancreas
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]
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]
These patients present with hepatomegaly (liver enlargement) and growth retardation early in childhood. [agsdus.org]
Lack of energy, irritability, and abnormal sweating are all symptoms that result from a low blood sugar. This type of glycogen disease is relatively mild. [wohproject.org]
Other symptoms and signs include irritability, lethargy, weakness, abnormal sweating, difficulty awakening in the morning and poor linear growth. [academic.oup.com]
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]
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]
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]
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  .
- 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 .
- Genetic testing for asymptomatic carriers, as well as prenatal testing in affected families.
- Sequence analysis for the recognition of variant gene alterations .
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]
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]
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.