Glycogen Storage Disease Ixb

A number sign (#) is used with this entry because glycogen storage disease type IXb (GSD9B) is caused by compound heterozygous mutation in the PHKB gene (172490), which encodes the beta subunit of phosphorylase kinase, on chromosome 16q12.

For a discussion of genetic heterogeneity of GSD IX (GSD9), see X-linked GSD IXa (GSD9A; 306000).

Clinical Features

In an Israeli Arab family reported by Bashan et al. (1981), a 4-year-old brother and 2 sisters had marked hepatomegaly and marked accumulation of glycogen in both liver and muscle, without clinical symptoms. Liver phosphorylase kinase (PK) activity was 20% of normal, resulting in undetectable activity of phosphorylase a. Muscle PK was about 25% of normal, resulting in a marked decrease of phosphorylase a activity. This finding of a seemingly autosomal recessive form of phosphorylase kinase deficiency suggests that there are at least 2 different structural genes, only one of which is X-linked, that code for subunits of the enzyme.

Mild clinical manifestations of muscle involvement were observed by Fernandes et al. (1974) in a 4-year-old patient, and Abarbanel et al. (1986) found symptoms resembling McArdle disease (232600) in a 35-year-old man. Ohtani et al. (1982) reported histochemical and biochemical study of a female child who lacked phosphorylase kinase in muscle.

Gray et al. (1983) described affected sister and 2 brothers with unrelated parents. Normal level of enzyme activity in the mother and comparable levels in an affected brother and sister argued against X-linked inheritance (306000). The sister presented at 15 months with hepatomegaly, short stature, and acute attacks of diarrhea.

Burwinkel et al. (1997) reported 3 children, including 2 sibs, with GSD IXb. The first child was German, and presented at age 22 months with distended abdomen due to hepatomegaly. At the age of 4 years, the child had a height at the tenth percentile and weight at the fiftieth percentile, hepatomegaly, and a tendency to develop hypoglycemic symptoms after several hours of fasting or physical activity. There were no clinical indications of muscle involvement. The second child and his affected sister came to medical attention as infants because of hepatomegaly. Residual phosphorylase kinase activities were 18% of normal in red cells, 5% in liver of the sister, and 0 to 13% (depending on pH) in muscle of the male. At the age of approximately 25, both patients were fully capable of everyday physical activities, but tended to develop hypoglycemic symptoms upon activity or fasting that were ameliorated by carbohydrate intake. Hepatomegaly had receded; clinical muscle symptoms had never been noted.

Beauchamp et al. (2007) reported 3 patients from 2 families with GSD IXb confirmed by genetic analysis. Clinical features were variable, and included hepatomegaly, short stature, liver dysfunction, hypoglycemia, fasting ketosis, and hypotonia. The authors emphasized that molecular analysis results in accurate diagnosis for GSD IX when enzymology is uninformative, and thus allows for proper genetic counseling.

Roscher et al. (2014) reported on 21 patients (17 males and 4 females) from 17 unrelated families with glycogen storage disease (GSD) IXa (306000), GSD IXb, GSD IXc (613027), or GSD VI (232700), which are caused by phosphorylation deficiencies. The average age was 11.66 years, with a range of 3 to 18 years. Eleven patients (53%) had GSD IXa1; 3 (14%) had GSD IXb; 3 (14%) had GSD IXc; and 4 (19%) had GSD VI. The average age of initial presentation was 20 months (range 4-160 months). The GSD IXb patients presented earliest at the age of 5 months (range 4-6 months). Hepatomegaly was present in 95% of patients on physical examination and 100% on liver ultrasound. Four patients presented with failure to thrive, and 2 with short stature. None of the patients had intellectual disability or global developmental delay at most recent evaluation, although some had early developmental delay. Alanine transaminase (ALT) was elevated in 18 patients (86%), and aspartate transaminase (AST) was elevated in 19 (90%). Hypercholesterolemia was present in 14 of the 21 patients, and hypertriglyceridemia was present in 16. While previous reports noted hypoglycemia in 17 to 44% of patients with GSD VI or subtypes of GSD IX, hypoglycemia occurred in less than 5% of the patients in the cohort of Roscher et al. (2014). Two patients had developed likely liver adenomas at long-term follow-up, which had not been theretofore reported.

Molecular Genetics

In 1 female and 4 male patients with glycogen storage disease IXb, Burwinkel et al. (1997) identified mutations in the PHKB gene. There were 5 different nonsense mutations (see, e.g., 172490.0002), a 1-bp insertion (172490.0001), a splice site mutation, and a large deletion involving the loss of exon 8. Although the mutations severely disrupted translation and occurred in constitutively expressed sequences of the only known beta-subunit gene of phosphorylase kinase, they were associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and with a relatively high residual enzyme activity of approximately 10%. Inheritance was autosomal recessive.

Nomenclature

Lederer et al. (1975) pointed out that what had been numbered glycogen storage disease VI includes at least 3 different genetic defects: X-linked phosphorylase b kinase deficiency, in which the muscle enzyme is unaffected (called here glycogen storage disease VIII; 306000); the autosomal kinase deficiency discussed here; and deficiency of liver phosphorylase (called here glycogen storage disease VI; 232700).