| #306000 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GLYCOGEN STORAGE DISEASE IXa1; GSD9A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GSD IXa1 LIVER GLYCOGENOSIS, X-LINKED, TYPE I; XLG1 GLYCOGEN STORAGE DISEASE VIII, FORMERLY GSD VIII, FORMERLY; GSD8, FORMERLY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GLYCOGEN STORAGE DISEASE IXa2, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GSD IXa2, INCLUDED; GSD9A2, INCLUDED LIVER GLYCOGENOSIS, X-LINKED, TYPE II, INCLUDED; XLG2, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because glycogen storage disease type IXa (GSD9a) is caused by mutation in the gene encoding the alpha-2 subunit of hepatic phosphorylase kinase (PHKA2; 300798). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Glycogen storage disease type IX is a metabolic disorder resulting from a deficiency of hepatic phosphorylase kinase, a hexadecameric enzyme comprising 4 copies each of 4 unique subunits encoded by 4 different genes: alpha (PHKA2), beta (PHKB; 172490), gamma (PHKG2; 172471), and delta (CALM1; 114180). Mutations within the PHKA2, PHKB, and PHKG2 genes result in GSD9a, GSD9b (261750), and GSD9c (613027), respectively. GSD9a is an X-linked recessive disorder, whereas the others are autosomal recessive. See also X-linked muscle PHK deficiency (GSD9D; 300559), caused by mutation in the gene encoding the muscle-specific alpha PHK subunit (PHKA1; 311870). GSD IXa has been further divided into types IXa1 (GSD9A1), with no PHK activity in liver or erythrocytes, and IXa2 (GSD9A2), with no PHK in liver, but normal activity in erythrocytes. The clinical presentation of both subtypes is the same, and both are caused by mutations in the PHKA2 gene. However, mutations that result in IXa2 are either missense or small in-frame deletions or insertions enabling residual enzyme expression in erythrocytes (Keating et al., 1985; Hendrickx et al., 1994; Beauchamp et al., 2007). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Glycogen storage disease IXa is one of the mildest of the glycogenoses of man. Clinical symptoms include hepatomegaly, growth retardation, elevation of glutamate-pyruvate transaminase and glutamate-oxaloacetate transaminase, hypercholesterolemia, hypertriglyceridemia, and fasting hyperketosis These clinical and biochemical abnormalities gradually disappear with age, and most adult patients are asymptomatic (Schimke et al., 1973; Willems et al., 1990). Hendrickx et al. (1998) presented clinical, biochemical, and molecular findings in a patient with GSD IXa2 who had been followed for 40 years. Although growth was retarded early in life, he achieved a height of 182 cm at the age of 33 years. Thyroid therapy appeared to be helpful in this patient. Five male relatives also had liver glycogenosis. Genetic analysis identified a mutation in the PHKA2 gene (R186H; 300798.0008) Beauchamp et al. (2007) reported 10 patients from 8 families with GSD IXa confirmed by genetic analysis. Age at diagnosis ranged from 12 months to 7 years. Clinical features were variable, and included hepatomegaly, short stature, liver dysfunction, hypoglycemia, hyperuricemia, hyperlipidemia, fasting ketosis, and mild motor delay. Five of the 8 probands had a demonstrable reduction of PHK activity in erythrocytes, consistent with GSD IXa1. The majority of patients had private mutations. The authors emphasized that molecular analysis results in accurate diagnosis for GSD IX when enzymology is uninformative, and thus allows for proper genetic counseling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 4 boys with X-linked PHK-deficient glycogenosis, aged 29 months to 43 months, Garibaldi et al. (1978) found that dextrothyroxine (D-T4) had dramatic effects: the liver, previously greatly enlarged, returned to normal size; serum GOT, GPT, and triglycerides fell to normal; and hypoglycemia was corrected. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inheritance | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Williams and Field (1961) found low leukocyte phosphorylase activity in 2 affected brothers, and normal activity in an unaffected brother and in the father. An intermediately low level in the mother, together with affected males, suggested X-linked inheritance. Wallis et al. (1966) restudied the family and with new methods found support for X-linkage. Huijing and Fernandez (1969) studied 2 kindreds, one of which had 6 affected males and 2 possibly affected males. The other had 20 affected males, 2 affected females, and 7 probably affected males. X-linked inheritance was suggested. Huijing and Fernandez (1970) suggested that affected females studied by Hug et al. (1969) were heterozygotes. By cloning cells of an obligate heterozygous female with GSD due to phosphorylase kinase deficiency, Migeon and Huijing (1974) demonstrated that some fibroblasts had enzymatic levels similar to those of affected hemizygotes. This was presented as proof of X-linkage and X-inactivation of the phosphorylase kinase locus. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Willems et al. (1991) performed linkage analysis with X-chromosomal polymorphic DNA markers in 2 families with X-linked liver glycogenosis. Multipoint linkage analysis indicated that the mutation responsible for X-linked liver glycogenosis was located on Xp22 between DXS143 and DXS41. Linkage to the muscle PHKA1 region on Xq12-q13 was excluded. Hendrickx et al. (1992, 1993) found a combined multipoint lod score of 16.79 for linkage of X-linked liver glycogenosis to chromosome Xp22. Hendrickx et al. (1994) performed linkage analysis in 4 families with GSD IXa2, who had residual PHK activity in erythrocytes, and showed that this form was also linked to Xp22. The authors concluded that this biochemical variant type was allelic to GSD IXa1, and that both diseases are likely caused by mutations in PHKA2. Hendrickx et al. (1994) proposed the classification of XLG into types I and II. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of 4 unrelated families with GSD IXa1, Hendrickx et al. (1995) identified 4 different mutations in the PHKA2 gene (300798.0001-300798.0004). Clinical features were somewhat variable, but included growth retardation, hepatomegaly, elevated liver enzymes, and normalization of symptoms with age. PHK activity was decreased to less than 20% of control values in erythrocytes and in liver, when measured. Van den Berg et al. (1995) identified mutations in the PHKA2 gene (300798.0005 and 300798.0006) in affected members of 2 Dutch families with GSD IXa1. One of the families had been reported by Huijing and Fernandez (1969). Burwinkel et al. (1996) identified mutations in the PHKA2 gene in patients with GSD IXa2 (see 306000.0008-306000.0010). The mutations appeared to cluster in limited sequence regions. Burwinkel et al. (1996) stressed that the clustering of type II mutations would further facilitate analysis by RT-PCR of blood cell mRNA and thus help avoid liver biopsy in the diagnosis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genotype/Phenotype Correlations | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 4 unrelated patients with GSD IXa2, Hendrickx et al. (1996) identified 4 different mutations in the PHKA2 gene (306000.0011-306000.0014). The mutations resulted in minor abnormalities in the primary structure of the protein. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that may be involved in the regulation of PHK. Hendrickx et al. (1996) postulated that PHK activity may be regulated by phosphorylation of these sites and that type II GSD9a may be due to impaired activation of PHK activity. The findings may explain why the in vitro PHK enzymatic activity is not deficient in type II, whereas it is in type I. Burwinkel et al. (1998) described 8 new mutations and phenotypic consequences in patients with X-linked liver glycogenosis. One of the patients reported by Burwinkel et al. (1998) had low PHK activity in the liver but elevated levels in erythrocytes, typical of XLG type II. This patient had a lys189-to-glu missense mutation (K189E; 306000.0015). The authors noted that this observation adds to the growing body of evidence that the XLG phenotype is associated with missense mutations clustering at a few sites in the PHKA2 gene. Hendrickx et al. (1999) identified PHKA2 mutations in 10 patients with XLG types I and II. They proposed that mutations in XLG type I, in which PHK activity is decreased in both liver and erythrocytes, results from truncation or disruption of the PHKA2 protein. In contrast, all type II mutations, which result in residual activity in erythrocytes, were missense mutations or small in-frame deletions and insertions. These results suggested that the biochemical differences between the 2 types of XLG are due to the different nature of the disease-causing mutations in PHKA2. Type I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas type II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nomenclature | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The classification, particularly the numbering, of the glycogenoses has long been a matter of dispute. For example, Huijing (1970) referred to this disorder as glycogen storage disease type VIA; Hug (1974) assigned number VIII to a presumedly recessive form of phosphorylase deficiency with brain involvement and number IX to phosphorylase kinase deficiency (see Schimke et al., 1973). McAdams et al. (1974) presented information on classification and morphology of the glycogenoses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Schneider et al. (1993) reviewed the animal mutants that result in PHK-linked glycogenoses. Two different X-linked disorders are known, as well as an autosomal recessive PHK deficiency affecting the liver and most other tissues but not muscle, in the rat. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Goji et al. (1985); Hers (1959); Huijing (1967); Huijing (1970); Varsanyi et al. (1980) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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