Nemaline Myopathy 1

A number sign (#) is used with this entry because of evidence that nemaline myopathy-1 (NEM1) is caused by heterozygous, homozygous, or compound heterozygous mutation in the alpha-tropomyosin-3 gene (TPM3; 191030) on chromosome 1q21. Cap myopathy-1 (CAPM1), an overlapping disorder, is also caused by heterozygous mutation in the TPM3 gene.

Description

Nemaline myopathy-1 is a disorder characterized by muscle weakness, usually beginning in early childhood. The severity and pattern of muscle weakness varies, but most affected individuals show mildly delayed motor development, hypotonia, generalized muscle weakness, and weakness of the proximal limb muscles and neck muscles, resulting in difficulty running and easy fatigability. Most patients have respiratory insufficiency due to muscle weakness. Other common features include myopathic facies, high-arched palate, and scoliosis. Histologic findings on skeletal muscle biopsy are variable, even in patients with the same mutation. Muscle fibers can contain nemaline rod inclusions, or so-called subsarcolemmal 'cap' structures, as well as show overall fiber-type disproportion. It has been suggested that unknown modifying factors confer a tendency to one or another pattern of inclusions on skeletal muscle biopsy in those with TPM3 mutations (summary by Waddell et al., 2010 and Malfatti et al., 2013).

For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.

Clinical Features

Laing et al. (1992) reported a large 5-generation family with childhood-onset nemaline myopathy inherited in an autosomal dominant pattern. The proband had normal motor development until approximately 10 years of age, when he developed symmetrical weakness in foot dorsiflexion. The weakness progressed during adolescence to involve the proximal limb muscles. He had difficulty running and dysphagia. He had atrophy of the lower limbs with pes cavus, but no sensory impairment. An affected uncle had facial weakness, mild weakness of the sternocleidomastoid and trapezius muscles, and wasting and weakness of the proximal and distal lower extremities. All affected members had onset by age 10 years. Biopsy of the proband showed marked variation in muscle fiber size with numerous nemaline bodies within type 1 fibers. Laing et al. (1992) concluded that this family had a childhood-onset form of nemaline myopathy.

Tan et al. (1999) reported an Iranian patient, born of consanguineous parents, with severe infantile nemaline myopathy. Although no neonatal problems were reported, the infant showed extremely delayed motor development and died at age 21 months due to respiratory insufficiency resulting from an infectious illness. Muscle biopsy showed type 1 fiber hypotrophy and atrophy, with a mild predominance of type 2 fibers. Nemaline bodies were present in type 1 fibers only.

Penisson-Besnier et al. (2007) reported a large French family in which 8 members spanning 4 generations had nemaline myopathy. Inheritance was autosomal dominant. Age at onset of significant disease was usually in adulthood, but milder symptoms were often present since childhood. Most had delayed motor development, and some reported poor physical performances in childhood. Affected individuals were able to walk unaided but had proximal muscle weakness. Other features included scoliosis, need for nocturnal ventilation, slender build, and long face. Skeletal muscle biopsies showed type 1 fiber predominance and nemaline rods in type 1 fibers.

Lehtokari et al. (2008) reported 2 unrelated Turkish families, each with 2 children affected with autosomal recessive nemaline myopathy. Only 1 of the families was known to be consanguineous. In the first family, 2 affected boys were born with contractures of the knees and ankles, and later showed delayed motor development with weakness of the neck and facial muscles. One child did not achieve walking, while the other walked slowly with a waddling gait from the age of 2.5 to 3 years. Both patients had restricted vital capacity requiring nocturnal noninvasive ventilation. Other features included pectus carinatum deformity and scoliosis. Skeletal muscle biopsy of 1 brother showed hypotrophic type 1 fibers containing nemaline bodies. In the second family, both children had muscle hypotonia during the first month of life. Particular features were pronounced facial weakness, lack of head control, lax distal joints, and scoliosis. Motor milestones were delayed, and both became wheelchair-bound in childhood. Both children developed generalized joint contractures and mild chest deformities.

Cap Myopathy 1

Ohlsson et al. (2009) reported a 38-year-old woman with congenital muscular dystrophy associated with cap structures on skeletal muscle biopsy who had previously been reported by Fidzianska (2002). The patient 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. Genetic analysis identified a heterozygous R168C mutation in the TPM3 gene (R168C; 191030.0009). The findings illustrated the phenotypic and histologic variability associated with TPM3 mutations, and suggested that cap disease is related to nemaline myopathy.

De Paula et al. (2009) reported a 42-year-old man with cap myopathy associated with a heterozygous de novo mutation in the TPM3 gene (R168H; 191030.0005). The patient showed hypotonia in the first months of life, delayed motor development, and distal weakness of the lower limbs with frequent falls in childhood. At age 7 years, he had flat feet in valgus, long narrow face, high-arched palate, and mild lumbar hyperlordosis. Tendon reflexes were absent. The clinical course was stable until presentation at age 42 with inability to run, difficulty climbing stairs, and predominant distal muscle weakness. Skeletal muscle biopsy at age 7 years showed type 1 fiber hypotrophy. Biopsy at age 42 years showed only type 1 fibers, irregularity of fiber size, occasional central nuclei, and peripheral eosinophilic-basophilic densely stained substances consistent with 'caps.' The caps were present in about 10 to 15% of muscle fibers, were negative for ATPase staining, were present just beneath the sarcolemma, and consisted of abnormally arranged myofibrils. Z lines were thickened with some rod-like structures. The authors noted that this case had first been reported as a congenital myopathy with selective hypotrophy of type 1 fibers (Serratrice et al., 1975), and that the biopsy results discussed in that report would have been consistent with congenital fiber-type disproportion (CFTD; 255310), a diagnosis of exclusion. The findings suggested a relationship between nemaline myopathy, CFTD, and cap myopathy, and indicated that cap structures may develop over time.

Waddell et al. (2010) reported a young man with cap myopathy associated with a de novo heterozygous mutation in the TPM3 gene (R168C; 191030.0009). 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. Waddell et al. (2010) noted that the R168C mutation had previously been reported in a patient with CFTD (patient 9 in Clarke et al., 2008). That patient had marked type 1 fiber hypotrophy and type 2 fiber hypertrophy, but no caps. 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. This clinical course was relatively stable over many years until age 32, when he had progressive dyspnea, severe fatigability, and respiratory failure associated with right cardiac failure. He recovered from this acute episode. 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 composed of irregular and 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.

Atypical Nemaline Myopathy With Hypertonia

Donkervoort et al. (2015) reported 2 unrelated children with a hypercontractile phenotype with congenital muscle stiffness resulting in arthrogryposis multiplex and significant disability. Both showed decreased fetal movements. One had transient respiratory distress in infancy and mildly delayed motor development. At age 4 years, he had stiff muscles, walked with a stiff gait, and showed thoracic kyphosis. The second child had similar features with more severe respiratory involvement and was ventilator-dependent. Neither child had muscle weakness, atrophy, or myokymia. Muscle biopsies in both patients showed mild myopathic changes, with variation in fiber size and mild type 1 or 2 fiber predominance. Although there was no clear evidence of nemaline rods, there were irregularities of the myofibrillar apparatus and 'mini-miliary' rods, as well as ultrastructural evidence of mitochondrial accumulation and/or Z-line streaming and broadening. In 1 patient, botulinum toxin injections resulted in improved range of motion. Each patient carried a de novo heterozygous deletion of a conserved residue in the TPM3 gene (E218del, 191030.0010 and E224del, 191030.0011). In vitro studies showed that both mutations resulted in increased calcium sensitivity, increased active interaction of actin and the myosin complex, and increased filament sliding motility, consistent with a gain of function.

Mapping

In a large kindred in which 10 living members had childhood-onset nemaline myopathy inherited in an autosomal dominant pattern, Laing et al. (1991, 1992) found linkage to the APOA2 gene (107670) on chromosome 1 (maximum lod score of 3.80). The findings indicated that the putative disease gene lies between the genes for nerve growth factor-beta (NGFB; 162030) at 1p13 and antithrombin III (AT3; 107300) at 1q23-q25.1.

Molecular Genetics

In affected members of a large family with autosomal dominant childhood-onset nemaline myopathy, Laing et al. (1995) identified a heterozygous mutation in the TPM3 gene (191030.0001).

Tan et al. (1999) identified a homozygous nonsense mutation in the TPM3 gene (191030.0004) in a patient with severe infantile nemaline myopathy who died at age 21 months. Among 40 unrelated patients with nemaline myopathy, Wattanasirichaigoon et al. (2002) identified 1 patient who was compound heterozygous for 2 mutations in the TPM3 gene (191030.0002-191030.0003). Each of his parents was heterozygous for one of the mutations. The authors noted that mutations in the TPM3 gene are a rare cause of nemaline myopathy.

In affected members of a French family with autosomal dominant nemaline myopathy, Penisson-Besnier et al. (2007) identified a heterozygous mutation in the TPM3 gene (191030.0005).

In affected members of 2 Turkish families with autosomal recessive nemaline myopathy, Lehtokari et al. (2008) identified a homozygous mutation in the TPM3 gene (191030.0006). Haplotype analysis suggested a founder effect.

Associations Pending Confirmation

For discussion of a possible association between nemaline myopathy and variation in the MYO18B gene, see 607295.0002.