Exertional Cramps Research Articles

EC.O.1 - Genetic and histological characterisation of excitation-contraction coupling related structural myopathy cohort

Tubular aggregates and cylindrical spirals appear to be related entities, both arising from the sarcoplasmic reticulum, and sometimes appearing in the same biopsy. Tubular aggregates are inclusions of regular arrays of membrane tubules, while cylindrical spirals are accumulations of spiral lamellae around a central core. Although these have been reported as secondary findings in a range of conditions, some pure genetic forms of myopathy are characterised by the presence of tubular aggregates or cylindrical spirals. Tubular aggregate myopathy typically presents in childhood, causing slowly progressive weakness and cramps. Cylindrical spiral myopathy variably causes weakness, myalgia and exertional cramps, with onset in adulthood. Both diseases are dominant. The scarcity of cases impedes genetic and functional investigation. We have a cohort of two families and 10 isolated probands with tubular aggregate myopathy or cylindrical spirals. They underwent histological investigation, electron microscopy and next-generation DNA sequencing. Tubular aggregate myopathy genetic findings include known ORAI1 mutation c.G325A, p.V109M, and a novel putative STIM1 mutation c.A356G:p.D119G, and other candidate genes. Compound heterozygous TTN variants c.28654C>T, p.Q9552* and c.A15925G, p.I5309V were found in a cylindrical spiral myopathy case. The TTN missense change is predicted to affect splicing. Functional characterisation is ongoing, including mutant cell lines, cDNA analysis and fluorescence-based calcium handling assays. Here, we describe the work to date on characterising this cohort, including the histological and genetic features.

A Diagnostic Algorithm for Metabolic Myopathies

Metabolic myopathies comprise a clinically and etiologically diverse group of disorders caused by defects in cellular energy metabolism, including the breakdown of carbohydrates and fatty acids to generate adenosine triphosphate, predominantly through mitochondrial oxidative phosphorylation. Accordingly, the three main categories of metabolic myopathies are glycogen storage diseases, fatty acid oxidation defects, and mitochondrial disorders due to respiratory chain impairment. The wide clinical spectrum of metabolic myopathies ranges from severe infantile-onset multisystemic diseases to adult-onset isolated myopathies with exertional cramps. Diagnosing these diverse disorders often is challenging because clinical features such as recurrent myoglobinuria and exercise intolerance are common to all three types of metabolic myopathy. Nevertheless, distinct clinical manifestations are important to recognize as they can guide diagnostic testing and lead to the correct diagnosis. This article briefly reviews general clinical aspects of metabolic myopathies and highlights approaches to diagnosing the relatively more frequent subtypes (Fig. 1). Fig. 1 Clinical algorithm for patients with exercise intolerance in whom a metabolic myopathy is suspected. CK-creatine kinase; COX-cytochrome c oxidase; CPT-carnitine palmitoyl transferase; cyt b-cytochrome b; mtDNA-mitochondrial DNA; nDNA-nuclear DNA; PFK-phosphofructokinase; PGAM-phosphoglycerate mutase; PGK-phosphoglycerate kinase; PPL-myophosphorylase; RRF-ragged red fibers; TFP-trifunctional protein deficiency; VLCAD-very long-chain acyl-coenzyme A dehydrogenase.

Aerobic conditioning: An effective therapy in McArdle's disease

Susceptibility to exertional cramps and rhabdomyolysis in myophosphorylase deficiency (McArdle's disease [MD]) may lead patients to shun exercise. However, physical inactivity may worsen exercise intolerance by further reducing the limited oxidative capacity caused by blocked glycogenolysis. We investigated whether aerobic conditioning can safely improve exercise capacity in MD. Eight MD patients (4 men and 4 women; age range, 33-61 years) pedalled a cycle ergometer for 30 to 40 minutes a day, 4 days a week, for 14 weeks, at an intensity corresponding to 60 to 70% of maximal heart rate. We monitored serum creatine kinase levels; changes in peak cycle work, oxygen uptake, and cardiac output; presence and magnitude of a spontaneous and glucose-induced second wind; and citrate synthase and beta-hydroxyacyl coenzyme A dehydrogenase enzyme activities in quadriceps muscle. The prescribed exercise program increased average work capacity (36%), oxygen uptake (14%), cardiac output (15%), and citrate synthase and beta-hydroxyacyl coenzyme A dehydrogenase enzyme levels (80 and 62%, respectively) without causing pain or cramping or increasing serum creatine kinase. A spontaneous and glucose-induced second wind was present and was of similar magnitude in each patient before and after training. Moderate aerobic exercise is an effective means of improving exercise capacity in MD by increasing circulatory delivery and mitochondrial metabolism of bloodborne fuels.

Cylindrical spirals of myofilamentous origin associated with exertional cramps and rhabdomyolysis

We describe the presence of cylindrical spirals on muscle biopsy from a 31-year-old man who developed rhabodomyolysis following a long run. He had a prior history of exertional cramps and myoglobinuria. His maternal grandfather had similar symptoms. Transmission electron micrographs demonstrated continuity between the lamellae of the cylindrical spirals and native myofilaments. Whether these unusual structures confer a derangement in myofilament function is uncertain.

Rhabdomyolyse révélatrice d'un déficit en AMP-déaminase

We report a case of AMP-deaminase deficiency revealed by rhabdomyolysis in a 45-year-old man. This autosomal recessive abnormality, relatively frequent (1 to 2 % of muscular biopsies), is usually featured by exertional cramps, but rhabdomyolysis seems to be exceptional.