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 ... 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.
Zhang et al. (1995) isolated and characterized cDNA and genomic DNA encoding SERCA1. Sequencing in 3 Brody disease patients showed no mutations in the coding and splice junction sequences.
The MacLennan group (Odermatt et al., 1996) ... Zhang et al. (1995) isolated and characterized cDNA and genomic DNA encoding SERCA1. Sequencing in 3 Brody disease patients showed no mutations in the coding and splice junction sequences. 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 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 the disorder. 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.