Nemaline Myopathy 3

A number sign (#) is used with this entry because of evidence that nemaline myopathy-3 (NEM3) is caused by homozygous, compound heterozygous, or heterozygous mutation in the alpha-actin-1 gene (ACTA1; 102610) on chromosome 1q42.

Description

Nemaline myopathy is a form of congenital myopathy characterized by abnormal thread- or rod-like structures in muscle fibers on histologic examination ('nema' is Greek for 'thread'). The clinical phenotype is highly variable, with differing age at onset and severity. Muscle weakness typically involves proximal muscles, with involvement of the facial, bulbar, and respiratory muscles (Ilkovski et al., 2001). Attempts at classification of nemaline myopathies into clinical subtypes have been complicated by the overlap of clinical features and a continuous phenotypic spectrum of disease (North et al., 1997; Wallgren-Pettersson et al., 1999; Ryan et al., 2001; Sanoudou and Beggs, 2001). In general, 2 clinical groups can be readily distinguished: 'typical' and 'severe.' Typical nemaline myopathy is the most common form, presenting as infantile hypotonia and muscle weakness. It is slowly progressive or nonprogressive, and most adults achieve ambulation. The severe form of the disorder is characterized by absence of spontaneous movement or respiration at birth, arthrogryposis, and death in the first months of life. Much less commonly, late-childhood or even adult-onset can occur. However, adult-onset nemaline myopathy is usually not familial and may represent a different disease (Wallgren-Pettersson et al., 1999; Sanoudou and Beggs, 2001).

Myopathy caused by mutations in the ACTA1 gene can show a range of clinical and pathologic phenotypes. Some patients have classic rods, whereas others may also show intranuclear rods, clumped filaments, cores, or fiber-type disproportion (see 255310), all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. The spectrum of clinical phenotypes caused by mutations in ACTA1 may result from different mutations, modifying factors affecting the severity of the disorder, variability in clinical care, or a combination of these factors (Nowak et al., 1999; Kaindl et al., 2004).

Genetic Heterogeneity of Nemaline Myopathy

See also NEM1 (609284), caused by mutation in the tropomyosin-3 gene (TPM3; 191030) on chromosome 1q22; NEM2 (256030), caused by mutation in the nebulin gene (NEB; 161650) on chromosome 2q23; NEM4 (609285), caused by mutation in the beta-tropomyosin gene (TPM2; 190990) on chromosome 9p13; NEM5 (605355), also known as Amish nemaline myopathy, caused by mutation in the troponin T1 gene (TNNT1; 191041) on chromosome 19q13; NEM6 (609273), caused by mutation in the KBTBD13 gene (613727) on chromosome 15q22; NEM7 (610687), caused by mutation in the cofilin-2 gene (CFL2; 601443) on chromosome 14q13; NEM8 (615348), caused by mutation in the KLHL40 gene (615340), on chromosome 3p22; NEM9 (615731), caused by mutation in the KLHL41 gene (607701) on chromosome 2q31; NEM10 (616165), caused by mutation in the LMOD3 gene (616112) on chromosome 3p14; and NEM11 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21. Several of the genes encode components of skeletal muscle sarcomeric thin filaments (Sanoudou and Beggs, 2001).

Mutations in the NEB gene are the most common cause of nemaline myopathy (Lehtokari et al., 2006).

Clinical Features

Early Descriptions

The condition described by Gibson (1921) as 'muscular infantilism' in a family spanning 3 generations may have been nemaline myopathy.

Shy et al. (1963) reported a slowly progressive 'new congenital myopathy' in 2 sibs. One patient was a 4-year-old girl. Muscle biopsy showed subsarcolemmal aggregates of abnormal rod-shaped or thread-like structures. Electron microscopy showed that the rod-like bodies were composed of abnormal fibrillar material. The parents showed minor abnormalities, which were interpreted as possible heterozygous effects. At the same time, Conen et al. (1963) reported a child with hypotonia and muscle weakness who had 'myogranules' on skeletal muscle biopsy.

Spiro and Kennedy (1965) observed affected mother and daughter. Gonatas et al. (1966) reported the pathologic features of nemaline myopathy in 2 brothers whose parents were unaffected but who were related to the cases of Spiro and Kennedy (1965); the father of the 2 brothers was a brother to the mother in the Spiro-Kennedy report. The mother and daughter described by Ford (1961) as cases of 'congenital universal muscular hypoplasia of Krabbe' (159100) were shown by Hopkins et al. (1966) to have nemaline myopathy. Engel et al. (1964) reported a 16-year-old girl with nemaline myopathy and suggested that she had slow progression of the disease through late childhood.

Price et al. (1965) reported 3 cases. An 8.5-year-old white girl had generalized muscle weakness and hypotonia since birth. She walked with difficulty at age 17 months, and had difficulty arising from the floor. Her face was elongated, with decreased expression and a high-arched palate. She had proximal girdle muscle weakness and hypo- or areflexia. Two sibs were similarly affected. Two African American girls, aged 11 and 12 years, had diffuse muscle weakness from birth. Motor milestones were delayed. Both girls had elongated, dysmorphic, expressionless facies, jaw weakness, and very high-arched palate. One child was limited to a wheelchair, and the other walked only with great difficulty.

Pearson et al. (1967) described 3 affected sibs out of 8. The mother, although clinically normal, had minor histologic alterations of skeletal muscle. In 3 affected brothers born of unaffected parents, Danowski et al. (1973) found a distinct beta globulin peak upon serum protein electrophoresis. This sharp beta peak was caused by an increase in the C3 component of serum complement.

Jenis et al. (1969) described a white girl, born of unrelated parents, who showed extreme muscular weakness and hypotonia from birth and died of respiratory insufficiency at 2 months of age. Intranuclear and sarcoplasmic rod inclusions were found in muscle cells.

Typical Nemaline Myopathy

Scarlato et al. (1982) reported affected sisters with congenital nemaline myopathy. In both cases, type 1 fibers predominated, and almost 70% of muscle fibers contained rods which were selectively localized in the type 1 fibers. In 1 case, many fibers contained 1 or more core-like lesions. Muscle biopsy was normal in the father, but in the mother showed slight type 1 fiber predominance without rods or other signs of myopathy. The authors concluded that inheritance was autosomal recessive.

Wallgren-Pettersson (1989) reported follow-up of 12 patients with congenital nemaline myopathy. Ten showed clinical deterioration and 2 showed improvement. Muscle weakness was most severe in the facial muscles, flexors of the neck and trunk, dorsiflexors of the feet, and extensors of the toes. Distal limb muscles and limb-girdle muscles were more severely affected than proximal limb muscles. There were no signs of central nervous system involvement. Prognosis was influenced mainly by the presence of scoliosis and restricted respiratory capacity.

Topaloglu et al. (1994) described a brother and sister, aged 20 and 19 years, respectively, with a 10-year history of spinal rigidity and scoliosis. Muscle biopsies were consistent with nemaline myopathy. The parents were first cousins.

Maayan et al. (1986) described sleep hypoventilation in a brother and sister, aged 14.5 and 11.5 years, respectively, with nemaline myopathy.

Ryan et al. (2001) reviewed 143 Australian and North American cases of primary nemaline myopathy. As classified by the guidelines of the European Neuromuscular Centre, 23 patients had severe congenital, 29 intermediate congenital, 66 typical congenital, 19 childhood-onset, and 6 adult-onset nemaline myopathy. Inheritance was autosomal recessive in 29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate in 1. Prenatal expression of nemaline myopathy was reflected in its association with the fetal akinesia sequence and the frequency of obstetric complications, which occurred in 35 cases (51%), including polyhydramnios (29%), decreased fetal movements (39%), and abnormal presentation of fetal distress (49%). Significant respiratory disease occurred in the first year of life in 75 patients, and 79 had feeding difficulties. Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures. Progressive distal weakness developed in a minority of patients. Thirty patients died, most of them during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients. Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management was considered warranted in most cases of congenital nemaline myopathy.

Ilkovski et al. (2001) reported 5 unrelated patients with nemaline myopathy caused by 5 different heterozygous mutations in the ACTA1 gene. Three patients had the typical form of the disorder with onset in childhood. One (see 102610.0007) had no problems during the neonatal period. At age 5 years, he presented with inability to run and frequent falls. He had poor muscle bulk, pes cavus, and bilateral foot drop. By age 10 years, he showed slowly progressive weakness and involvement of the proximal muscles. The second patient (see 102610.0008) was a 45-year-old man who was physically active and regularly engaged in long-distance competitive cycling, although he had a weak cough and frequent respiratory infections. He had been weak and hypotonic at birth, and showed delayed motor development. The third patient (see 102610.0002) was a 35-year-old woman who had typical congenital nemaline myopathy with neonatal onset of feeding difficulties, respiratory tract infections, hypotonia, facial diplegia, and proximal muscle weakness in the first weeks of life. Her disease was very slowly progressive or nonprogressive. She had an affected younger sib and an affected daughter, consistent with autosomal dominant inheritance. Skeletal muscle biopsy from all patients showed nemaline bodies, although there was marked variability in the percentage of fibers with rods.

Hutchinson et al. (2006) reported 4 patients from a 3-generation family with autosomal dominant nemaline myopathy with intranuclear rods. Three of the patients had onset in infancy with hypotonia and failure to thrive; the fourth patient had onset before age 5 years. All had muscle weakness throughout life and a thin face with thin limbs. Skeletal muscle biopsies showed variation in fiber diameter, type 1 fiber predominance, and intranuclear rods within muscle fibers, although the number of rods varied between patients. Genetic analysis identified a heterozygous mutation in the ACTA1 gene (102610.0014) that segregated with the disorder.

In affected individuals from 2 unrelated families with myopathy, Kaindl et al. (2004) reported 2 unrelated families with onset of proximal or generalized weakness in early childhood. There was moderate muscle weakness with delayed motor milestones, facial weakness, and mild skeletal anomalies, including scoliosis, high-arched palate, genu valgum or varum, and funnel chest. One family had onset in infancy. In the second family, 2 affected individuals developed hypertrophic cardiomyopathy associated with respiratory difficulties in the middle adult years. The disease course in both families was nonprogressive. Histologically, 'cores' were detected in the muscle fibers of at least 1 patient in each family, whereas nemaline bodies or rods and actin filament accumulation were absent. The cores were unstructured, poorly circumscribed, central or eccentric, and were atypical of central core disease (CCS; 117000). One patient did not have cores on biopsy. There was type 1 fiber type predominance. Genetic analysis identified missense mutations in the ACTA1 gene in the 2 families (102610.0009 and 102610.0010, respectively). Kaindl et al. (2004) concluded that their findings established mutation in the ACTA1 gene as a cause of dominant congenital myopathy with cores, and delineated another clinicopathologic phenotype for ACTA1.

Gatayama et al. (2013) reported a 9-year-old Japanese boy with NEM3 confirmed by genetic analysis (102610.0017) who developed fatal dilated cardiomyopathy in childhood. The patient had normal motor development in early childhood, but showed mild nonprogressive skeletal muscle weakness, such as slowed running compared to his peers. Other features included hypotonia, myopathic facies, high-arched palate, and mild weakness of proximal and distal muscles. He presented at age 9 years with acute deterioration of cardiac function, and died of cardiac failure 6 months later. Postmortem examination of cardiac muscle showed variation in myocardial fiber size and a few electron-dense fine structures related to Z lines. Skeletal muscle biopsy had previously shown typical nemaline rods. Gatayama et al. (2013) noted that childhood-onset dilated cardiomyopathy is rare in patients with ACTA1 mutations.

Severe Nemaline Myopathy

McMenamin et al. (1984) reported 2 infants with fatal nemaline myopathy. One presented at birth with severe hypotonia, respiratory failure, and contractures, and died shortly after the neonatal period. The other patient presented at age 2 months with hypotonia, and died of respiratory failure at age 7 months. Pathologic findings in both cases showed numerous rod bodies in the diaphragm and limb muscles. No abnormalities were seen in the central or peripheral nervous systems.

Schmalbruch et al. (1987) described the early fatal form of nemaline myopathy in 1 case and reviewed 13 reported cases. All died within the first year of life. Three affected sibs were reported by Neustein (1973) and 2 affected sibs were reported by Gillies et al. (1979).

Vendittelli et al. (1996) described a severe form of nemaline myopathy associated with early death in the neonate. Decreased fetal movement was noted during pregnancy in each case. One infant was born with joint contractures of the hands and feet, severe hypotonia, and edema of the hands and feet. Chest radiographs showed lung hypoplasia, thin ribs, and an elevated diaphragm. He died at the age of 6 days from respiratory failure. The second patient, a girl, was born from a pregnancy characterized by hydramnios hand persistent breech presentation. She showed respiratory failure, hypotonia, and inability to swallow, and died from respiratory failure at the age of 68 days.

Goebel et al. (1997) reported 3 unrelated children with what the authors termed 'congenital actin myopathy with excess of thin myofilaments.' All patients were hypotonic at birth. Two died of cardiorespiratory failure at ages 3 and 4 months, respectively. Skeletal muscle biopsies of 2 of the patients, 1 of whom died as an infant, showed predominance of type 1 fibers, with homogeneous subsarcolemmal areas devoid of sarcomeres and filled with densely packed thin actin-immunopositive filaments. Intranuclear rods were present in these 2 biopsies. Biopsies from the third patient, who died at 3 months, showed similar findings without nemaline rods. The authors later suggested that an alternative diagnosis for 2 of the patients could be severe nemaline myopathy (Nowak et al., 1999). Nowak et al. (1999) identified heterozygous mutations in the ACTA1 gene in all 3 patients (102610.0003; 102610.0004).

Ilkovski et al. (2001) reported 5 unrelated patients with nemaline myopathy caused by 5 different heterozygous mutations in the ACTA1 gene. Two patients had the severe form of the disorder. A female infant (see 102610.0006) was born with severe neonatal hypotonia, minimal spontaneous movements, and fractures of both femurs. She did not achieve any motor milestones, and required a gastrostomy tube for feeding. She died of respiratory failure at age 6 months. The second patient, a male infant, was born with severe hypotonia, reduced muscle bulk, and facial diplegia. Decreased fetal movements were noted during the last few weeks of pregnancy. He died of respiratory failure at age 13 months.

Garcia-Angarita et al. (2009) reported a male infant with severe fatal nemaline myopathy. He had decreased movements in utero, breech presentation, and congenital contractures. After birth, there was severe hypotonia, lack of spontaneous movements, and death from respiratory failure at age 2 months. Skeletal muscle biopsy showed myofibrillar disorganization and nemaline rods. Genetic analysis showed heterozygosity for an allele carrying 2 de novo mutations in cis affecting adjacent nucleotides in the ACTA1 gene (E74D and H75Y; 102610.0015). Neither unaffected parent carried either of the mutations, suggesting possible germline mosaicism.

Atypical Nemaline Myopathy With Hypertonia

Jain et al. (2012) reported an unusual phenotype of nemaline myopathy-3 associated with a de novo heterozygous activating mutation in the ACTA1 gene (K328N; 102610.0016). The patient presented at age 6 weeks with recurrent apnea and was found to have muscle rigidity and stiffness with elbow and knee contractures and hyperreflexia. Percussion myotonia was present, but EMG showed no evidence of myotonia. Medical treatment was ineffective, and he died at age 9 months in an asystolic episode. Muscle biopsy showed nemaline bodies and 32% mutant actin. In vitro motility analysis of actin thin filaments derived from the patient's tissue showed increased sensitivity to calcium, indicating an activated state. Expression of the mutation in mouse muscle cells did not result in the formation of rod-like structures, suggesting a different mechanism of nemaline body formation. The report expanded the phenotypic spectrum associated with ACTA1 mutations to include stiffness, rigidity, and hypertonicity.

Adult Form of Nemaline Myopathy

Meier et al. (1983, 1984) described nemaline myopathy as the cause of fatal cardiomyopathy in a 29-year-old woman. She had a leptosomal habitus but no neuromuscular abnormalities. Quadriceps biopsy showed type 1 fiber predominance and nemaline rods in about 50% of muscle fibers by trichrome staining and electron microscopy. Autopsy showed nemaline bodies in the myocardium, including the conducting tissue. The patient's mother and 1 of her sisters suffered sudden unexplained death at ages 47 and 37, respectively; sections of the sister's myocardium showed nemaline bodies.

Harati et al. (1987) reported a case of adult-onset nemaline myopathy presenting as diaphragmatic paralysis.

Falga-Tirado et al. (1995) reported a case of adult-onset nemaline myopathy presenting as respiratory insufficiency without generalized muscle weakness. Serum muscle enzymes were normal, but biceps muscle biopsy showed abundant nemaline bodies. Diaphragmatic movement appeared to be normal by ultrasound of the chest and esophageal tonometry. The patient was successfully treated with nasal intermittent pressure ventilation.

Inheritance

Nemaline myopathy shows both autosomal dominant and autosomal recessive inheritance.

Arts et al. (1978) suggested the existence of both dominant and recessive forms of nemaline or rod myopathy. The 2 forms could not be distinguished on clinical or histopathologic grounds. The authors found in 2 families that both parents of each index patient had rods and an increased number of fibers with central nuclei, a presumed heterozygous manifestation. Kondo and Yuasa (1980) reviewed all reported cases and concluded that autosomal dominant inheritance was the only acceptable genetic hypothesis.

Wallgren-Pettersson et al. (1990) studied 13 patients from 10 Finnish families and their 20 parents. Four of the families had been included in the review by Kondo and Yuasa (1980). None of the parents were affected, and 3 families had 2 affected children. Nine of the 13 patients were female. Of the parents, 15 showed deficiency of type 2B muscle fibers, and all except 1 father showed some other minor neuromuscular abnormality, suggesting heterozygous manifestations. Most of the ancestors of the patients came from sparsely populated rural communities in the west of Finland. The authors concluded that most cases of nemaline myopathy in Finland were consistent with autosomal recessive inheritance.

Seidahmed et al. (2016) reported 2 brothers, born of consanguineous and unaffected Saudi parents, with severe congenital NEM3 resulting in death in infancy. Two older deceased brothers were similarly affected. Although the consanguinity and familial recurrence suggested autosomal recessive inheritance, sequencing of a miltigene panel showed that the 2 brothers carried a heterozygous missense mutation in the ACTA1 gene (D290N). Neither parent carried this mutation in blood, indicating that 1 of the parents was gonadal mosaic for the mutation. The authors emphasized the difficulty in discerning the pattern of inheritance in a family due to history alone.

Pathogenesis

By pathologic investigations of muscle biopsies from 3 patients with nemaline myopathy, Price et al. (1965) determined that the pathologic fibrillar material was similar to and continuous with the material that constituted the Z band, and suggested that it was excessive accumulation of tropomyosin B (190990). Price et al. (1965) noted that central core disease (117000) and nemaline myopathy had been reported in the same family (Afifi et al., 1965).

Jennekens et al. (1983) reviewed the evidence that the nemaline bodies could be derived from lateral expansions of Z discs, and found that alpha-actinin (see, e.g., ACTN2; 102573) was one of the main protein components of both the Z disc and the nemaline body. The defect in alpha-actinin was restricted to skeletal muscle cells; there was no abnormality of actin or alpha-actinin in nonmuscle cells.

Wallgren-Pettersson et al. (1988) studied repeated biopsies for periods varying from 5 to 18 years in 13 patients with congenital nemaline myopathy. Their most important conclusion was that this is a progressive disorder. One of the patients, a brother of the proband, had no nemaline bodies in his first biopsy, taken from the same muscle as the later biopsy which was diagnostic. A deficiency of type 2 fibers was suggested as the basis of the inability of the patients to run and otherwise engage in fast gross motor activity. In 9 of 13 patients with nemaline myopathy, Wallgren-Pettersson et al. (1990) found reduced or absent alpha-actinin, which led them to conclude that the abnormality in this disorder resides in that molecule.

Rifai et al. (1993) compared the muscle pathology and clinical course in 8 patients with congenital nemaline myopathy. The family history was positive in 2 cases: one had 2 affected sisters and another had a single affected sister. In 1 patient with a negative family history and a rapid, fatal course, they found an abundance of large intranuclear rods in the muscle fibers, whereas these were absent in the muscles of the other 7 patients with a benign course. The large intranuclear rods and the smaller sarcoplasmic rods were similar ultrastructurally and exhibited positive immunoperoxidase staining with anti-alpha-actinin antibodies. Rifai et al. (1993) suggested that the accumulation of alpha-actinin within myonuclei may reflect a severe disturbance of normal intracellular processes regulating myofibrillar synthesis. Since 2 previously reported infants with intranuclear nemaline rods also had a fatal outcome, Rifai et al. (1993) suggested that the presence of intranuclear rods may represent a marker for a severe form of congenital nemaline myopathy.

Tahvanainen et al. (1994) excluded linkage to 2 alpha-actinin genes, ACTN2 (102573) and ACTN3 (102574), in 5 families with autosomal recessive nemaline myopathy. Each family had 2 affected children.

By immunoblot analysis, Ilkovski et al. (2004) showed that muscle from nemaline myopathy (NM) patients had increased levels of gamma-filamin (FLNC; 102565), myotilin (TTID; 604103), desmin (DES; 125660), and alpha-actinin (ACTN1; 102575), consistent with accumulation of Z line-derived nemaline bodies. Intranuclear aggregates were observed upon transfecting myoblasts with V163L- (102610.0004), V163M-, and R183G-null acting transgene constructs, and modeling showed these residues to be adjacent to the nuclear export signal of actin. Transfection studies further showed significant alterations in the ability of V136L and R183G actin mutants to polymerize and contribute to insoluble acting filaments. In vitro studies suggested that abnormal folding, altered polymerization, and aggregation of mutant actin isoforms may be common properties of NM ACTA1 mutants. A combination of these effects may contribute to the common pathologic hallmarks of NM, namely intranuclear and cytoplasmic rod formation, accumulation of thin filaments, and myofibrillar disorganization.

Molecular Genetics

In 10 unrelated patients with nemaline myopathy of varying severity, Nowak et al. (1999) identified 10 different heterozygous mutations in the ACTA1 gene (see, e.g., 102610.0002). In 1 family, a mother and 2 children were affected, indicating autosomal dominant inheritance.

In 2 infant sibs with severe nemaline myopathy leading to death at ages 5 days and 19 days, Nowak et al. (1999) identified compound heterozygosity for 2 mutations in the ACTA1 gene (102610.0001; 102610.0005).

Ilkovski et al. (2001) identified 5 different heterozygous mutations in the ACTA1 gene (see, e.g., 102610.0006-102610.0008) in 5 of 35 unrelated probands with nemaline myopathy. Severity of the disorder in these patients ranged from severe congenital myopathy with early death to childhood onset and survival into middle age.

Animal Model

In a review, Shelton and Engvall (2005) stated that models of nemaline rod myopathy had been described in Border Collie and Schipperke dogs and a family of cats.