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Alternative titles; symbols. Other entities represented in this entry:. 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.
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. Hendrickx et al.
Although growth was retarded early in life, he achieved a height of cm at the age of 33 years. Thyroid therapy appeared to be helpful in this patient. Five male relatives also had liver glycogenosis. Beauchamp et al. 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.
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. Roscher et al. The average age was The average age of initial presentation was 20 months range months.
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.
Hypercholesterolemia was present in 14 of the 21 patients, and hypertriglyceridemia was present in Two patients had developed likely liver adenomas at long-term follow-up, which had not been theretofore reported. Williams and Field 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. Huijing and Fernandez studied 2 kindreds, 1 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 suggested that affected females studied by Hug et al.
By cloning cells of an obligate heterozygous female with GSD due to phosphorylase kinase deficiency, Migeon and Huijing 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. Willems et al. Clinical features were somewhat variable, but included growth retardation, hepatomegaly, elevated liver enzymes, and normalization of symptoms with age.
Van den Berg et al. One of the families had been reported by Huijing and Fernandez Burwinkel et al. The mutations appeared to cluster in limited sequence regions. The mutations resulted in minor abnormalities in the primary structure of the protein. The findings may explain why the in vitro PHK enzymatic activity is not deficient in type II, whereas it is in type I. One of the patients reported by Burwinkel et al. This patient had a lysto-glu missense mutation KE; 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.
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.
The classification, particularly the numbering, of the glycogenoses has long been a matter of dispute. For example, Huijing referred to this disorder as glycogen storage disease type VIA; Hug assigned number VIII to a presumably recessive form of phosphorylase deficiency with brain involvement and number IX to phosphorylase kinase deficiency see Schimke et al.
McAdams et al. Schneider et al. 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. Beauchamp, N. Glycogen storage disease type IX: high variability in clinical phenotype. Burwinkel, B. Variability of biochemical and clinical phenotype in X-linked liver glycogenosis with mutations in the phosphorylase kinase PHKA2 gene.
Garibaldi, L. Dextrothyroxine treatment of phosphorylase-kinase deficiency glycogenosis in four boys. Acta , Goji, K. Lymphocyte phosphorylase kinase activities in the sex-linked form of liver phosphorylase kinase deficiency.
Hendrickx, J. Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years. X-linked liver glycogenosis: localization and isolation of a candidate gene. Mutations in the phosphorylase kinase gene PHKA2 are responsible for X-linked liver glycogen storage disease. Localization of a new type of X-linked liver glycogenosis to the chromosomal region Xp22 containing the liver alpha-subunit of phosphorylase kinase PHKA2. Genomics , X-linked liver glycogenosis: localization and isolation of a strong candidate gene.
Abstract Am. Hers, H. Etudes enzymatiques sur fragments hepatiques: application a la classification des glycogenoses. Hug, G. Deficient activity of dephosphophosphorylase kinase and accumulation of glycogen in the liver. Personal Communication. Cincinnati, Ohio Huijing, F. X-chromosomal inheritance of liver glycogenosis with phosphorylase kinase deficiency. Liver glycogenosis and phosphorylase kinase deficiency.
Letter Am. Phosphorylase kinase in leucocytes of normal subjects and of patients with glycogen-storage disease. Glycogen-storage disease type VIa: low phosphorylase kinase activity caused by a low enzyme-substrate affinity.
Phosphorylase kinase deficiency. Keating, J. X-linked glycogen storage disease: a cause of hypotonia, hyperuricemia, and growth retardation. McAdams, A. Glycogen storage disease, type I to X: criteria for morphologic diagnosis. Migeon, B. Glycogen-storage disease associated with phosphorylase kinase deficiency: evidence for X inactivation.
Roscher, A. The natural history of glycogen storage disease types VI and IX: long-term outcome from the largest metabolic center in Canada. Schimke, R. Glycogen storage disease type IX: benign glycogenosis of liver and hepatic phosphorylase kinase deficiency.
Schneider, A. Phosphorylase kinase deficiency in I-strain mice is associated with a frameshift mutation in the alpha-subunit muscle isoform. Nature Genet. X-linked liver phosphorylase kinase deficiency is associated with mutations in the human liver phosphorylase kinase alpha subunit.
Varsanyi, M. X-linked dominant inheritance of partial phosphorylase kinase deficiency in mice. Wallis, P. Hepatic phosphorylase defect. Studies on peripheral blood.
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Krogstad P. Osteomyelitis and septic arthritis. Textbook of Pediatric Infectious Diseases. Candidemia in a tertiary care hospital: Epidemiology, risk factors and predictors of mortality.
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Alternative titles; symbols. Other entities represented in this entry:. 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. 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. Hendrickx et al.