#611881
ICD+
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| GLYCOGEN STORAGE DISEASE XII; GSD12 | |||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||
| GSD XII ALDOLASE A DEFICIENCY ALDOA DEFICIENCY ALDOLASE DEFICIENCY, RED CELL RED CELL ALDOLASE DEFICIENCY | |||||||||||||||||||||
| Phenotype Gene Relationships | |||||||||||||||||||||
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| TEXT | |||||||||||||||||||||
| A number sign (#) is used with this entry because aldolase A deficiency, also known as glycogen storage disease XII (GSD12), is caused by mutation in the ALDOA gene (103850). | |||||||||||||||||||||
| Description | |||||||||||||||||||||
| Aldolase A deficiency is an autosomal recessive disorder associated with hereditary hemolytic anemia (Kishi et al., 1987). | |||||||||||||||||||||
| Clinical Features | |||||||||||||||||||||
| Beutler et al. (1973) described a son of first-cousin parents who had nonspherocytic hemolytic anemia, mental retardation, and increased hepatic glycogen due, apparently, to deficiency of red cell aldolase. Puzzlingly, both parents had normal levels of red cell aldolase. The patient was presented again at the Birth Defects Conference in Vancouver in 1976 (Lowry and Hanson, 1977). He showed many dysmorphic features, some of which (ptosis, epicanthi, short neck, and low posterior hairline) were reminiscent of Noonan syndrome (163950). The patient reported by Beutler et al. (1973) had an unstable enzyme that became depleted in enucleated erythrocytes. Consequently, energy production was impaired and membrane stability decreased with declining ion transport activity. Hurst et al. (1987) described a brother and sister with mental retardation, short stature, delayed puberty, hemolytic anemia, and abnormal facial appearance. The similarities to the boy reported by Beutler et al. (1973) were striking. Miwa et al. (1981) reported 2 patients with red cell aldolase deficiency associated with congenital nonspherocytic hemolytic anemia. The proband was a 14-month-old Japanese boy whose parents were probably consanguineous. He had mild to moderate anemia that was aggravated by upper respiratory infections, 1 cm hepatomegaly, and 2.5 cm splenomegaly, but showed no growth or mental retardation and did not have dysmorphic features. Red cell aldolase activity was 6% of the normal mean. The enzyme was unstable with respect to heat, and Km for fructose 1,6-diphosphate was high. The parents and other heterozygotes showed intermediate enzyme activity between that of the proband and that of normal subjects. The other affected patient reported by Miwa et al. (1981) was the 13-year-old nephew of the proband's maternal grandmother, and he presented with a phenotype similar to that of the proband. Kreuder et al. (1996) described a boy with aldolase deficiency who presented with predominantly myopathic symptoms, including muscle weakness and premature muscle fatigue. He had episodes of anemia and jaundice and was prone to episodes of rhabdomyolysis during febrile illness. Biochemical assays revealed a profound reduction in muscle and red cell aldolase levels and a decrease in thermostability of residual enzyme. | |||||||||||||||||||||
| Mapping | |||||||||||||||||||||
| Aldolase A deficiency is caused by mutation in the ALDOA gene, which maps to chromosome 16p11.2 (Amberger, 2008). | |||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||
| Kishi et al. (1987) studied a patient with red cell aldolase deficiency reported by Miwa et al. (1981) and identified a mutation in the ALDOA gene that resulted in an asp128-to-gly (D128G; 103850.0001) substitution in the protein. The patient's enzyme from red cells and from cultured lymphoblastoid cells was highly thermolabile, and the enzyme expressed in E. coli was likewise thermolabile. The parents had intermediate levels of red cell aldolase A. Southern blot analysis of genomic DNA showed that the patient was homozygous for a mutation that was heterozygous in both parents. In a boy they reported with aldolase A deficiency, Kreuder et al. (1996) identified a homozygous germline mutation in the ALDOA gene that resulted substitution of a negatively charged glutamic acid with a positively charged lysine at the highly conserved residue 206 (E206L; 103850.0002). | |||||||||||||||||||||
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