ClinVar Genomic variation as it relates to human health

Muscular hypotonia (present) , Global developmental delay (present) , Myopathic facies (present) , Dysphagia (present) , Sleep apnea (present) , Pneumothorax (present) , Hyperbilirubinemia (present) , Decreased muscle mass (present) , Difficulty running (present) (less)

In a woman with congenital myopathy-4A (CMYO4A; 609284), Clarke et al. (2008) identified a heterozygous c.502C-T transition (c.502C-T, NM_152263.2) in exon 5 of the TPM3 gene, resulting in an arg168-to-cys (R168C) substitution in the alpha-helix domain. The patient had poor head control before 1 year of age, but normal walking at age 9 months, and could run in childhood. At age 32, she could walk stairs with difficulty and had impaired nocturnal ventilation, moderate proximal weakness, ptosis, and severe kyphoscoliosis. Skeletal muscle biopsy showed fiber-type disproportion (CFTD). The authors noted that several other mutations had been identified in this codon (see, e.g., R168G, 191030.0008). Ohlsson et al. (2009) identified a heterozygous R168C mutation in a 38-year-old woman with CMYO4A associated with cap structures on skeletal muscle biopsy. She had previously been reported by Fidzianska (2002). She had slowly progressive muscle weakness and scoliosis since childhood, but was not examined until age 18 years. At that time, she had long narrow face, high-arched palate, chest deformity, and thin underdeveloped muscles. Other features included impaired nocturnal ventilation. Skeletal muscle biopsy showed that 20 to 30% of muscle fibers had granular cap structures devoid of ATPase activities. Myofibrils forming the caps were clearly demarcated from the remaining fibers and had an abnormal sarcomere pattern. Nemaline rods and fiber-type disproportion were not observed. The findings illustrated the phenotypic and histologic variability associated with TPM3 mutations, and suggested that cap disease is related to nemaline myopathy and CFTD. Waddell et al. (2010) reported a young man with CMYO4A due to a de novo heterozygous R168C mutation. He had mildly delayed motor development in early childhood, generalized hypotonia, and muscle weakness, particularly of the proximal lower limbs, ankle dorsiflexors, and neck. He had a long myopathic face with open mouth, high-arched palate, retrognathia, narrow chest, and mild scoliosis. At age 20 years, his pulmonary vital capacity was 37% of that predicted. Muscle biopsy taken at age 3 years showed increased variation in fiber size and subsarcolemmal protein inclusions in 25% of fibers, typical of caps. There was also type 1 fiber predominance. Caps stained strongly for several proteins, including tropomyosin, and electron microscopy showed disorganized thin filament structures containing Z-band remnants. Nemaline rods were not present. Two-dimensional gel electrophoresis showed that the mutant protein accounted for about 50% of the TPM3 protein in sarcomeres, and Waddell et al. (2010) postulated a dominant-negative effect, perhaps resulting from altered protein-protein interactions. These findings indicated that the fiber type distribution pattern as well as the pattern of protein inclusions can vary widely even among patients with the same TPM3 mutation. Malfatti et al. (2013) reported a man of French Canadian origin, with early-onset myopathy and a de novo heterozygous R168C mutation in the TPM3 gene. He had typical clinical features of the disorder, with mildly delayed motor milestones, generalized hypotonia, proximal and distal muscle weakness, impaired respiratory function, long, narrow face, and high-arched palate. Muscle biopsy showed type 1 fiber uniformity, subsarcolemmal caps in about 20% of fibers, typical nemaline rods in about 10% of fibers, and both caps and rods in about 5% of fibers. Electron microscopy demonstrated that the cap structures were composed of disorganized myofibrils and thickened Z-bands; the nemaline rods had longitudinal and transverse striations and were surrounded by thin filaments. Some of the caps contained structures resembling small rods, and the intermyofibrillary network adjacent to caps or nemaline rods was irregular with jagged Z lines. Malfatti et al. (2013) emphasized that the combination of rods and caps had not previously been reported in the same patient, which suggested that the 2 patterns are pathogenetically related. The findings confirmed that nemaline myopathy and cap myopathy resulting from TPM3 mutations are part of a disease spectrum. (less)