Exercise Intolerance and Rhabdomyolysis Due to Dystrophinopathy: A Pseudometabolic Presentation

Dystrophinopathies represent a group of X-linked disorders resulting from mutations in the DMD gene that encodes dystrophin. The clinical spectrum of dystrophinopathy is comprised of Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked cardiomyopathy.[1] [2] Pseudometabolic presentation of exercise-induced muscle cramps and myoglobinuria due to mutations in DMD gene is increasingly identified.[3] [4] Here we describe a young boy with exercise-induced muscle cramps and rhabdomyolysis due to deletion in DMD gene.

Our patient is a 13-year-old boy, who presented at the age of 9 years with two episodes of exercise-induced muscle cramps, myalgia, and elevated serum creatinine kinase (CK). First episode occurred when he was 7 years old after excessive physical activity resulting in severe chest pain, muscle pain, and muscle cramps. He was noted to have rhabdomyolysis and was hospitalized for 3 days for management. Second episode occurred when he was 9 years old and was characterized by exercise-induced muscle cramps, elevated serum CK (5617 units per liter, reference: 4–87), and myalgia without rhabdomyolysis. He had normal birth and development. There was no family history of neuromuscular disorders. His physical and neurological examination was unremarkable. Baseline serum CK levels ranged between 522 and 957 units/L. Serum lactate, pyruvate, acyl carnitines, carnitines, plasma amino acids, and urine organic acids were within normal limits. Sequencing and deletion duplication analyses panel testing involving 29 genes associated with myopathy-rhabdomyolysis including McArdle disease, and carnitine palmitoyl transferase II deficiency revealed a heterozygous likely pathogenic variant, c.959A > T; p.Lys320Ile, in AMPD1 gene suggesting that our patient is a carrier of myoadenylate deaminase deficiency. This condition is autosomal recessively inherited and carriers are not affected. Single nucleotide polymorphism (SNP) microarray detected a hemizygous 104 kb deletion within chromosome Xp21.1 [(31,761,311–31,864,900) × 0]. This deletion encompasses the exons 49–51 of the DMD gene. He has not had any further episodes of rhabdomyolysis. He continues to experience intermittent exercise-induced muscle cramps and myalgias. Cardiac evaluation including electrocardiogram and echocardiogram was normal.

Rhabdomyolysis is characterized by myalgias, dark red urine due to myoglobinuria, and elevated serum CK levels. Exertional myalgia, muscle cramps, and rhabdomyolysis are typically attributed to an underlying metabolic problem, such as glycogen storage disorder, fatty acid oxidation disorder, or mitochondrial cytopathy.[5] Though thorough evaluation for these disorders is warranted, DMD gene analysis is not typically considered in the absence of fixed muscle weakness or hypertrophy. Exercise-induced myalgia, muscle cramps, stiffness, and exertional rhabdomyolysis related to mutations in DMD gene have been increasingly reported emphasizing the need to consider DMD molecular genetic analysis in these patients.[3] The resemblance in clinical presentation makes it challenging to recognize the underlying issue and to manage these patients effectively.

Our patient was noted to have Xp21.1 deletion involving in-frame deletion of DMD exons 49–51 by SNP microarray. Reports have not typically highlighted this specific deletion in the rod domain of dystrophin resulting in exercise intolerance and rhabdomyolysis without muscle weakness emphasizing the uniqueness of this patient's presentation. It is suggested that mutations involving proximal and distal rod domains of dystrophin do not alter protein function significantly causing a milder phenotype.[3] Xp21.1 deletion has been associated with instances of congenital adrenal hypoplasia and glycerol kinase deficiency.[6] However, deletion detected in our patient did not include these regions and he does not have clinical features suggesting these disorders. On the other hand, Xp21.1 gain-of-function mutation on chromosomal microarray, and an in-frame duplication of exons 17–25 of the dystrophin gene, was previously described in a child with asymptomatic rhabdomyolysis.[7]

In summary, our report highlighted the importance of considering dystrophinopathy while evaluating a patient with exertional muscle cramps and myalgia, with or without rhabdomyolysis. Physicians should be aware of these relatively rare pseudometabolic clinical presentations of dystrophinopathy for prompt recognition and appropriate management.

Publication History

Received: 14 February 2021

Accepted: 01 March 2021

Article published online:
21 May 2021

• References

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