A Thermolabile Aldolase A Mutant Causes Fever-Induced Recurrent Rhabdomyolysis without Hemolytic Anemia

Abstract

Aldolase A deficiency has been reported as a rare cause of hemolytic anemia occasionally associated with myopathy. We identified a deleterious homozygous mutation in the ALDOA gene in 3 siblings with episodic rhabdomyolysis without hemolytic anemia. Myoglobinuria was always triggered by febrile illnesses. We show that the underlying mechanism involves an exacerbation of aldolase A deficiency at high temperatures that affected myoblasts but not erythrocytes. The aldolase A deficiency was rescued by arginine supplementation in vitro but not by glycerol, betaine or benzylhydantoin, three other known chaperones, suggesting that arginine-mediated rescue operated by a mechanism other than protein chaperoning. Lipid droplets accumulated in patient myoblasts relative to control and this was increased by cytokines, and reduced by dexamethasone. Our results expand the clinical spectrum of aldolase A deficiency to isolated temperature-dependent rhabdomyolysis, and suggest that thermolability may be tissue specific. We also propose a treatment for this severe disease.

Rhabdomyolysis: a genetic perspective

“…Electron microscopy (EM) revealed accumulation of lipid, increased variation in mitochondrial size and shape, variation in myofibrilar diameter and increased intermyofibrillar space [ 21 ]. The presence of lipid droplets accumulation in oil-red-O histochemistry was reported in another patient [ 23 ]. Diagnosis is confirmed by finding homozygous or compound heterozygous mutations in ALDOA.…”

“…Rare cases with myopathic manifestations including muscle pain and weakness, exercise intolerance and RM [ 21 , 22 ]. RM may be seen during the first months of life [ 23 ].…”

Synaptic energy metabolism and neuronal excitability, in sickness and health

“…Diseases that result from defects in these pathways typically present with intellectual disability, seizures, movement disorders, and/or ataxia, among other neurological deficits. Given the importance of glycolysis in active synapses, it is striking that only a few inherited disorders of glycolytic enzymes involve the nervous system . Instead, the majority of them present with hemolytic anemia and/or myopathy because glycolysis is the most important energy source for erythrocytes and for some types of skeletal muscle fibers.…”

“…Given the importance of glycolysis in active synapses, it is striking that only a few inherited disorders of glycolytic enzymes involve the nervous system. [86][87][88][89] Instead, the majority of them present with hemolytic anemia and/or myopathy because glycolysis is the most important energy source for erythrocytes and for some types of skeletal muscle fibers. Other metabolic processes that have been associated with brain dysfunction in animal models but not in humans (yet) include defects of transport of glucose through GLUT3 and GLUT4 and of monocarboxylates through MCT2 and MCT4.…”

Non-traumatic and non-drug-induced rhabdomyolysis

“…It usually affects muscle cells and erythrocytes. Patients may present with haemolytic anaemia, muscle pains, exercise intolerance, fatigue and episodes of RM [33][34][35], which can appear in the first months of life [32,34].…”