A number sign (#) is used with this entry because of evidence that autosomal recessive severe infantile nemaline myopathy-5A (NEM5A), also known as Amish nemaline myopathy, is caused by homozygous or compound heterozygous mutation in the gene encoding troponin T1 (TNNT1; 191041) on chromosome 19q13.

Autosomal recessive severe infantile nemaline myopathy-5A (NEM5A) is a skeletal muscle disorder characterized by symptom onset soon after birth or in early infancy. Affected infants show axial hypotonia, stiffness, rigid spine with progressive kyphosis, pectus deformities, and contractures or limited movement of the large joints. Some patients show transient tremors. There is muscle atrophy and poor gross motor development. Respiratory insufficiency develops in the first years of life, often leading to death. Muscle biopsy shows nemaline rods (Johnston et al., 2000; Geraud et al., 2021).

For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).

Between 1988 and 2000, Johnston et al. (2000) treated or obtained clinical information on 71 infants and young children from 33 nuclear families with an apparently unique form of nemaline myopathy. Since the disorder occurred among the Old Order Amish of Lancaster County, Pennsylvania, the authors referred to the autosomal recessive disorder as Amish nemaline myopathy (ANM). All neonates with ANM had tremors that were evident at birth or within a few days of birth and involved most skeletal muscle groups, especially the muscles of the jaw and lower limbs. These tremors subsided over the first 2 to 3 months of life. Mild proximal contractures present at birth gradually worsened with age, such that hip abduction was often limited to 10 degrees or less by age 12 months. Progressive muscle atrophy and weakness developed simultaneously with the contractures. Gross motor development was limited to rolling side to side, but forearm and hand function was normal, as was apparent intelligence. The characteristic severe pectus carinatum deformity, with rigidity of the chest wall, developed along with the proximal contractures. The authors suspected that tremors both in utero and for several weeks after birth might be a carrier manifestation: several sibs of affected individuals with normal outcomes had had abnormal trembling both in utero and for several weeks after birth. Neurologic examinations and, in one case, tests for hypoglycemia and hypocalcemia, were normal in these sibs. The disorder showed progressive worsening, resulting in death from respiratory insufficiency, usually in the second year of life.

Fox et al. (2018) described the natural history of ANM in 106 patients of Amish ancestry who were born between 1923 and 2017. In 18 patients for whom detailed developmental history was documented, birthweight was normal but 94% had growth failure by 9 months of age. Eleven patients rolled from supine to prone, but all subsequently lost this skill, and only 2 sat independently. Abnormalities in the neonatal period included axial hypotonia, limb and chin tremors, and sustained provoked clonus. The tremors subsided in the first few months as contractures developed. Muscle atrophy and weakness progressed with the development of contractures, and the patients developed pectus carinatum. Patients had recurrent upper and lower respiratory tract infections. Management was palliative in all of the patients, and there was no correlation between date of birth and length of survival. Among 82 patients for whom the data were available, median survival was 18 months with a range of 0.2 to 66 months. Fox et al. (2018) examined skeletal muscle from 2 patients with AMN, which showed absent TNNT1, decreased slow skeletal TNNI1 (191042), and increased cardiac TNNT2 (191045). Histologic findings included abnormalities of myofiber size, increased numbers of internally nucleated fibers, and nemaline rods.

Van der Pol et al. (2014) reported 3 patients from a large Dutch family with NEM5A. The proband presented at 2 months of age with stiffness, rigid spine, reduced cervical motion, and limited movements of the shoulders, hips, and knees. Reflexes were absent and tremors were not noted. Other features included kyphosis and pectus carinatum. By age 2 years, he developed respiratory insufficiency and feeding difficulties as well as diaphragmatic hernia, requiring surgery, tracheostomy, and gastrostomy. Family history revealed 2 paternal cousins who died at 3 and 5 years of age, respectively, due to respiratory insufficiency. They had severe hypotonia, joint contractures, pectus carinatum, and kyphosis. Muscle biopsy of the proband showed nemaline myopathy.

Geraud et al. (2021) reported 3 unrelated patients with NEM5A resulting in death from respiratory failure between 6 and 29 months of age. The patients had axial and peripheral hypotonia, delayed motor development, hyporeflexia, and progressive respiratory insufficiency. The older patients showed progressive kyphosis with rigid spine, limited hip and knee movement, and pectus deformities. Additional variable features included tongue fasciculations, tremor, torticollis, diaphragmatic palsy, facial hypomimia, high palate, and failure to thrive. Skeletal muscle biopsy showed fiber size variation, rods, and sarcomeric disorganization; endomysial fibrosis was sometimes seen.

The transmission pattern of NEM5A in the families reported by Johnston et al. (2000) was consistent with autosomal recessive inheritance.

Using a genealogy database, automated pedigree software, and linkage analysis of DNA samples from 4 sibships segregating Amish nemaline myopathy, Johnston et al. (2000) identified an interval of approximately 2 cM on 19q13.4 that was homozygous in all affected individuals.

Because the TNNT1 gene mapped within the candidate region on chromosome 19q13 for nemaline myopathy, Johnston et al. (2000) sequenced the gene in Amish patients with the disorder and identified homozygosity for a nonsense mutation (E180X; 191041.0001).

In a Dutch boy with NEM5A, van der Pol et al. (2014) identified compound heterozygous mutations in the TNNT1 gene: a splice site mutation (191041.0002) and an intragenic deletion (ex14del; 191041.0003). The mutations were inherited from the unaffected parents. Homozygosity for the splice site mutation was identified in 2 paternal cousins with a similar disorder who died in childhood of respiratory insufficiency.

In 3 unrelated patients with NEM5A, Geraud et al. (2021) identified homozygous or compound heterozygous mutations in the TNNT1 gene (see, e.g., 191041.0004-191041.0006). Western blot analysis of skeletal muscle from the patients showed absence of the TNNT1 protein.

Johnston et al. (2000) estimated that NEM5A has an incidence of 1 in 500 among the Amish.