ALDOA – Glycogen Storage Disease Due to Aldolase A Deficiency

ALDOA-related glycogen storage disease is inherited in an autosomal recessive manner and has been reported in three unrelated families. A homozygous thermolabile ALDOA variant was identified in 3 siblings presenting with febrile-induced recurrent rhabdomyolysis without hemolytic anemia (3 siblings)[PMID:25392908]. A separate patient of Sicilian descent harbored compound heterozygous ALDOA mutations Arg303Ter/Cys338Tyr and exhibited both transfusion-dependent hemolytic anemia and rhabdomyolysis (1 patient)[PMID:14615364]. More recently, an ultra-rare case with hemolytic anemia, rhabdomyolysis, and dermatological findings was associated with a novel likely pathogenic c.971C>T (p.Ala324Val) variant in ALDOA (1 patient)[PMID:34171939].

Functional studies demonstrate that aldolase A activity in patient myoblasts declines at elevated temperatures, correlating with lipid droplet accumulation and cytokine sensitivity, and is selectively rescued by arginine supplementation, highlighting a tissue-specific thermolability mechanism consistent with the human phenotype[PMID:25392908].

Key Take-home: Autosomal recessive ALDOA mutations cause a temperature-dependent glycogen storage disorder marked by febrile rhabdomyolysis with or without hemolytic anemia; genetic testing enables definitive diagnosis and guides potential arginine-based interventions.

References

• PLoS genetics • 2014 • A thermolabile aldolase A mutant causes fever-induced recurrent rhabdomyolysis without hemolytic anemia. PMID:25392908
• Blood • 2004 • Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr). PMID:14615364
• Journal of pediatric endocrinology & metabolism : JPEM • 2021 • Glycogen storage disease type XII; an ultra rare cause of hemolytic anemia and rhabdomyolysis: one new case report. PMID:34171939

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