glycogen storage disease type 6

Deficiency of liver glycogen phosphorylase in glycogen storage disease (GSD) type VI results in a reduced ability to mobilize glucose from glycogen.

There is heterogeneity in the clinical symptoms observed in affected individuals. These varied from hepatomegaly and subclinical hypoglycaemia, to severe hepatomegaly with recurrent severe hypoglycaemia and postprandial lactic acidosis.

Deficiency of liver glycogen phosphorylase is predominantly the result of missense mutations affecting enzyme activity. There are no common mutations and the severity of clinical symptoms varies significantly.

Clinical synopsis

The clinical picture is one of mild to moderate hypoglycemia, mild ketosis, growth retardation, and prominent hepatomegaly. Heart and skeletal muscle are not affected. The prognosis seems to be excellent.

The most common presentation is in children aged 1-5 years, with a history of protuberant abdomen, growth retardation, and slight delay in motor milestones.

These children may also have histories of mild fasting hypoglycemia and hypotonia. Some patients remain asymptomatic, and routine physical examination reveals hepatomegaly.

Although children may have growth delay and short stature, adolescents and adults often have normal stature.

The abdomen of a child with glycogen-storage disease type VI (GSD VI) usually protrudes, and abdominal examination reveals hepatomegaly and increased liver span. In some cases, hepatomegaly may be massive. However, splenomegaly is always absent.

Adult patients may have mild or no hepatomegaly. Delay in motor milestones may be noted in a young child, and mild hypotonia and muscle weakness may be present.

In an adolescent or adult, muscle strength and tone are usually normal. Some patients may have signs of peripheral neuropathy upon examination.

GSD VI has a rather benign course, with risk of growth retardation, mild fasting hypoglycemia, hypotonia, and delayed motor milestones in early childhood. These clinical features gradually normalize before or at puberty. Adult patients exhibit normal stature, motor function, and biochemical parameters.

A subset of patients with the autosomal recessive form of GSD VI due to deficiency of phosphorylase kinase activity may be at increased risk for liver cirrhosis. 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.
The accumulated glycogen (ie, alpha particles, rosette form) appears frayed or burst and is less compact than the glycogen present in glycogen-storage disease types I (GSD1) or III (GSD3).

Interlobular fibrous septa and low-grade inflammatory changes may be seen.

Liver glycogen content may also be increased as much as 4-fold, although muscle glycogen remains normal in structure and quantity.

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. Phosphorylase b kinase is a multimeric unit consisting of 4 different subunits, each coded by a unique gene located on different chromosomes. Mutations in 3 genes (PHKA2, PHKB, and PHKG2) have been demonstrated in patients with phosphorylase b kinase deficiency.

In addition, several subtypes of phosphorylase kinase deficiency have been identified, based on the tissues affected and the mode of inheritance (autosomal recessive or X-linked recessive). The most common subgroup is the X-linked recessive form.

Classic GSD VI results from a primary deficiency of liver phosphorylase (PYGL). Patients with a defect of the cAMP-dependent protein kinase have been infrequently reported.

The PYGL gene encodes the liver isoform of the enzyme. The majority of the PYGL mutations were missense, resulting in the substitution of highly conserved residues.

Mutations could be grouped into those that were predicted to affect substrate binding (p.V456M, p.E673K, p.S675L, p.S675T), pyridoxal phosphate binding (p.R491C, p.K681T), or activation of glycogen phosphorylase (p.Q13P) or that had an unknown effect (p.N632I and p.D634H).

Two mutations were predicted to result in null alleles, p.R399X and [c.1964_1969inv6;c.1969+1_+4delGTAC].

Only 30% reported PYGL alleles carry nonsense, splice site or frameshift mutations compared to 68-80% of affected alleles of the highly homologous muscle glycogen phosphorylase gene, PYGM, that underlie McArdle disease.

Links

 eMedecine

References

 High frequency of missense mutations in glycogen storage disease type VI. Beauchamp NJ, Taybert J, Champion MP, Layet V, Heinz-Erian P, Dalton A, Tanner MS, Pronicka E, Sharrard MJ. J Inherit Metab Dis. 2007 Oct;30(5):722-34. PMID: 17705025

 Mutations in the liver glycogen phosphorylase gene (PYGL) underlying glycogenosis type VI. Burwinkel B, Bakker HD, Herschkovitz E, Moses SW, Shin YS, Kilimann MW. Am J Hum Genet. 1998 Apr;62(4):785-91. PMID: 9529348

 Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI. Chang S, Rosenberg MJ, Morton H, Francomano CA, Biesecker LG. Hum Mol Genet. 1998 May;7(5):865-70. PMID: 9536091