Rhabdomyolysis in the Military: Recognizing Late-Onset Very Long-Chain Acyl Co-A Dehydrogenase Deficiency

Military Medicine, Jul 2006 by Hoffman, Jodi D, Steiner, Robert D, Paradise, Lori, Harding, Carey O, Et al

Very long-chain acyl Co-A dehydrogenase deficiency, an inborn error of lipid metabolism, is commonly thought of as a disease of infancy or early childhood. However, several cases of late-onset very long-chain acyl Co-A dehydrogenase have been reported. This report of two military men who survived basic training before their disease presentation broadens the spectrum of late-onset disease, presents two previously unreported mutations, and demonstrates the fine line between athletic, active lifestyle and severe disease presentation.

Introduction

When considering the etiology of new onset rhabdomyolysis in adults, few physicians initially pursue the possible diagnosis of a rare inborn error of metabolism. However, several cases of late-onset very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, a fatty acid oxidation defect, have been reported.1-5 This report of two affected military men broadens the spectrum of clinical disease and stresses the importance of early disease identification and treatment.

Clinical Reports

Patient 1

A 35-year-old man complained of 10 episodes of intermittent rhabdomyolysis and acute renal failure over the previous 15 years. These episodes usually followed increased exercise or dehydration. There was no hypoglycemia or hyperthermia. The patient, a drill sergeant, usually exercised vigorously without muscle fatigue. The initial episode of rhabdomyolysis occurred during military training while climbing a mountain at a low temperature, and required airlift rescue due to severe myalgia. During his most severe episode, creatine kinase was 62,000 U/L, blood urea nitrogen was 50 to 60 mg/dL, and serum creatinine was 7 to 8 mg/dL. He requires antihypertensive medication for renal insufficiency that resulted from a severe episode of rhabdomyolysis which required dialysis. Cardiomyopathy developed on several occasions, but has resolved.

His family history is unremarkable for rhabdomyolysis. He has one, healthy son. He is of European and Korean descent.

A plasma acylcarnitine profile after an overnight fast revealed marked elevations of tetradecanoyl, tetradecadienoyl, palmitoyl, oleoyl, and linoleoyl carnitine, consistent with VLCAD deficiency. Skin biopsy was performed for biochemical studies in fibroblasts. The biopsies failed to grow in culture on two occasions. Molecular analyses for common mutations of carnitine palmitoyl transferase II (Ser113Leu) and myophosphorylase (codons 49 and 204) were normal. Molecular analysis of the VLCAD gene revealed two mutations (Table I), one of which was previously unreported. and a third sequence difference that is a polymorphism (128G[arrow right]A), common only among Asians.13 During an asymptomatic period, urine organic acid and blood acylcarnitine assays were normal; blood creatine kinase, ammonia, and lactate were mildly elevated.

Patient 2

A 30-year-old man had five episodes of intermittent leg cramping and myoglobinuria in the previous 10 years. Each episode was preceded by exercise, heat exposure, lack of adequate calories, or dehydration. The first episode occurred while on an extended military march. Creatine kinase peaked at 98.000. A second severe episode occurred while mountain climbing and required airlift rescue due to severe muscle weakness. He has a history of two childhood seizures and one recent seizure, of unknown etiology.

His family history is unremarkable; his parents are nonconsanguineous. He has four healthy daughters.

An acylcarnitine profile showed elevations of tetradecenoyl, tetradecanoyl, and tetradecadienoyl, consistent with VLCAD deficiency. Molecular analysis in blood revealed two mutations (Table I) in the VLCAD gene, one of which was previously unreported.

Treatment

Both patients were advised to avoid long fasts, minimize vigorous activity (especially at temperature extremes), maintain good hydration, and eat a mildly fat-restricted diet. Patient 2 started carnitine therapy after two more episodes of rhabdomyolysis. despite following the treatment regimen described previously. He has had no further episodes of rhabdomyolysis since the initiation of carnitine therapy.

Discussion

VLCAD catalyzes the initial rate-limiting step in mitochondrial fatty acid oxidation, the main source of energy in heart and skeletal muscle. There are more than 100 known mutations in the VLCAD gene leading to a wide spectrum of VLCAD deficiency manifestations encompassing the severe childhood, milder childhood, and adult onset forms.7 There are significant genotype-phenotype correlations.

Early onset VLCAD deficiency, overall, has a high mortality rate (75%). In this severe childhood form, in which there is no residual enzyme activity, affected children are symptomatic within the first few months of life. These infants are generally hypotonie, hypoglycemic, hypoketotic, and have a high incidence of cardiomyopathy. Children with the milder form have an enzyme with residual activity but decreased thermal stability.6 These children present with hypoketotic hypoglycemia and hypotonia, within the first few years of life, and mortality is low.