Brody Myopathy

A number sign (#) is used with this entry because of evidence that Brody myopathy is caused by homozygous or compound heterozygous mutation in the ATP2A1 gene (108730), which encodes the fast-twitch skeletal muscle sarcoplasmic reticulum Ca(2+) ATPase (SERCA1), on chromosome 16p11.

Description

Brody myopathy, a disorder of fast-twitch skeletal muscle function, is characterized by exercise-induced impairment of skeletal muscle relaxation, stiffening, and cramps, predominantly in the arms, legs, and eyelids (summary by Odermatt et al., 2000).

Clinical Features

Brody (1969) defined a disorder of muscle function that is characterized by painless muscle cramping and exercise-induced impairment of muscle relaxation. In a normal muscle contraction/relaxation cycle, Ca(2+) is released from the sarcoplasmic reticulum into the cytoplasm, where it binds to troponin in the thin filament, releasing constraints on the interaction between actin and myosin and inducing muscle contraction. Ca(2+) is then pumped back into the lumen of the sarcoplasmic reticulum by the Ca(2+) pump to initiate relaxation. In his studies of a skeletal muscle biopsy, Brody (1969) showed that the sarcoplasmic reticulum from his patient was deficient in both Ca(2+) uptake and Ca(2+)-ATPase. Consequently he focused attention on the possibility that defects in the Ca(2+) pump might cause the disease. Brody patients frequently show an inability to relax skeletal muscle following contracture. A reduced rate of removal of Ca(2+) from the sarcoplasm would lead to a reduced rate of relaxation.

Benders et al. (1994) found 12 reported cases. They concluded that the clinical signs and symptoms are not specific. Exercise-induced impairment of muscle relaxation, stiffening and cramps, and muscle pain had been described. These symptoms sometimes exacerbated in the cold and were referred to as pseudomyotonia. Benders et al. (1994) found that 10 patients were distributed in 7 families: 2 were brother and sister, 2 other were brothers, and yet 2 others were mother and son. One of the patients had previously been reported by Wevers et al. (1992) and Poels et al. (1993). For all patients, myotonia was excluded by electromyography. Glycolytic, mitochondrial, and lipid storage myopathies were also excluded by appropriate investigations. Impaired muscle relaxation was absent in 4 patients of Benders et al. (1994) and in a patient reported by Taylor et al. (1988).

Zhang et al. (1995) reported clinical information on 2 patients with Brody disease. One was a 60-year-old man who first noted painless muscle cramps in his twenties. Cramping was most frequent after exercise. He worked as a policeman. The cramps became painful in his mid-fifties; they occurred mainly in proximal and axial muscles but occasionally in distal muscles, especially after exercise. For example, when repetitively firing a pistol, his fingers would 'freeze' on the trigger. A brother suffered from a similar disorder. Another patient reported by Zhang et al. (1995) was a 45-year-old woman who complained of stiffness in her legs exacerbated by walking since her late teens. She also complained of her hands 'locking' when she used them and a problem of her jaw 'locking.' There was a general problem of difficulty in relaxing her muscles after exercise. Her mother and all 8 of her sibs had complaints of leg cramps. Two sisters were disabled by severe difficulty in walking from severe spastic paraparesis, and a diagnosis of hereditary spastic paraparesis had been rendered. On examination the patient showed difficulty in relaxing muscles following contraction. She also showed difficulty and slowness in release following forceful closure of her eyes and after making a tight fist. No spasticity was demonstrated in the upper or lower limbs. Tendon reflexes were brisk but not excessively so.

Muscle biopsies from the 2 sisters in the family studied by Danon et al. (1988) showed a moderate degree of atrophy of type 2 fibers and an excess of internal nuclei. Microscopic immunocytochemistry, using a monoclonal antibody raised against purified chicken sarcoplasmic reticulum adenosine triphosphatase, showed severe reduction of immunoreactive protein limited to type 2 fibers. Immunoreactive Ca(2+)-ATPase of sarcoplasmic reticulum was markedly decreased on Western blots of muscle proteins.

Odermatt et al. (2000) described 2 brothers in a Swiss family with Brody myopathy. The proband was first brought to medical attention at the age of 5, because of inability to run as well as his friends. Thereafter, he was aware that muscle stiffness occurred during vigorous or sudden rapid movements, such as climbing stairs and running, or during rotational movements of his hands. The stiffness was painless and disappeared after several seconds at rest. A single episode of unexplained hyperthermia, which led to hospitalization for 48 hours, occurred during a journey in his twenties, but several episodes of unknown raised temperature were also described. A few episodes of carpopedal spasms had been observed, leading to the diagnosis of Gitelman syndrome (263800). His brother's earliest recollection of a disorder of muscle function was his inability to run in races at the age of 4 to 5 years. He had the same range of activities as his peers, but could not do them as quickly because he found that rapid movements forced him to stop. Neurologic examination in both brothers was normal except for slow relaxation of limb and face muscles.

Inheritance

Parental consanguinity in the family of Karpati et al. (1986) suggested autosomal recessive inheritance in at least some patients with Brody disease.

MacLennan (1996) suggested that Brody disease is likely to be recessive. He referred to a Turkish pedigree with 3 affected and 3 normal sibs. The unaffected parents and 4 sibs showed a haplotype pattern for 16p, clearly indicating recessive inheritance.

Possible autosomal dominant inheritance was found in the family reported by Danon et al. (1988): the mother, her son, and 2 daughters suffered from impaired muscle relaxation aggravated by exercise. Although clinically, electromyographically, and biochemically similar to the other cases, the mode of inheritance was apparently different.

Clinical Management

Wevers et al. (1992) and Benders et al. (1994) showed that dantrolene, which reduces myofibrillar Ca(2+) concentration by blocking Ca(2+) release from the sarcoplasmic reticulum, is effective in the treatment of Brody disease. Studies in cultured cells by Benders et al. (1994) suggested a beneficial clinical effect from dantrolene or verapamil.

Biochemical Features

It was postulated that Brody disease is the result of deficiency in SERCA1 (sarco(endo)plasmic reticulum Ca(2+) ATPase), which is encoded by the ATP2A1 gene (108730). Studies by Karpati et al. (1986), Danon et al. (1988), and Taylor et al. (1988) reported diminished Ca(2+)-ATPase activity in muscle. Studies with polyclonal and monoclonal antibodies by Karpati et al. (1986) and by Danon et al. (1988) showed deficiency of Ca(2+)-ATPase in type 2 (fast-twitch) fibers in skeletal muscle in 4 Brody patients. Using an antibody specific against SERCA1, Benders et al. (1994) estimated that 83% of the total Ca(2+)-ATPase in both Brody patients and control muscle homogenates was SERCA1. Moreover, the content of total Ca(2+)-ATPase protein and SERCA1 protein, measured both by immunoreactivity and by phosphorylation, was identical in the 2 sample populations. The Ca(2+)-stimulated ATPase activity in Brody muscle homogenates, however, was reduced to only 50% of the activity in comparable samples from normal patients. Whereas the studies of Karpati et al. (1986) were consistent with virtually 100% loss of SERCA1 protein and Ca(2+)-ATPase activity, the studies of Benders et al. (1994) were consistent with mutations in SERCA1 that did not effect its expression, but diminished its V(max) to about 50% of control values.

Molecular Genetics

The MacLennan group (Odermatt et al., 1996) identified 3 different mutations in the ATP2A1 gene in affected members of 2 families with Brody myopathy. One mutation occurred at the splice donor site of intron 3 (108730.0003), and the other 2 mutations (108730.0001, 108730.0002) led to premature stop codons, truncating SERCA1, and deleting essential functional domains. The findings raised the question as to how these patients with Brody myopathy partially compensate for the functional knockout of a gene product believed to be essential for fast-twitch skeletal muscle relaxation. The molecular genetic studies of these 2 families completely supported autosomal recessive inheritance.

Odermatt et al. (1997) identified a fourth mutation in the ATP2A1 gene (108730.0004) in brothers with autosomal recessive Brody disease.

Heterogeneity

Zhang et al. (1995) isolated and characterized cDNA and genomic DNA encoding SERCA1. Sequencing in 3 patients with Brody disease showed no mutations in the coding and splice junction sequences.

Odermatt et al. (1997) could not identify mutations in the ATP2A1 gene or in the sarcolipin gene (SLN; 602203) in the autosomal dominant form of Brody myopathy. The autosomal dominant families included patient 6 of Benders et al. (1994) and patient 3 of Zhang et al. (1995). Another patient thought to have the dominant form of the disorder had a long history of exercise- and cold-induced muscle stiffness, pain, and cramps. Treatment with verapamil produced impressive improvement in his symptoms. His mother and sister were said to suffer from similar symptoms, suggesting dominant inheritance of the disease. No myotonia was observed either clinically or on electrophysiologic testing. Creatine kinase was mildly elevated. Ischemic exercise testing showed normal elevation of serum lactate and ammonia. A muscle biopsy showed nonspecific, mixed myopathic and neuropathic changes.

Novelli et al. (2004) excluded linkage to ATP2A1 in 4 individuals from a 3-generation Italian family with Brody disease. The disease cosegregated in an autosomal dominant fashion with an apparently balanced constitutional translocation (2;7)(p11.2;p12.1). FISH analysis refined the breakpoint regions to 164- and 120-kb segments, respectively.