SPTBN4 disorder is typically characterized by severe-to-profound developmental delay and/or intellectual disability, although two individuals in one family had a milder phenotype, including one individual with normal cognitive development. Speech and language skills are often severely limited. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Affected individuals typically have congenital hypotonia that may transition to hypertonia. Axonal motor neuropathy leads to hyporeflexia/areflexia and weakness, which can result in respiratory difficulties requiring ventilatory support. Most affected individuals require tube feeding for nutrition. Half of affected individuals develop seizures. Cortical visual impairment and auditory neuropathy have also been reported.

Autosomal recessive childhood-onset nemaline myopathy-5B (NEM5B) is a skeletal muscle disorder in which patients usually present with proximal muscle weakness of the lower and upper limbs in a limb-girdle distribution, resulting in gait abnormalities; however, most remain ambulatory even into late adulthood. Some affected individuals show delayed motor development. There is axial weakness and atrophy of the paraspinal muscles, along with kyphosis, scoliosis, and rigid spine, as well as variable limitations of the large joints. Most patients develop restrictive respiratory insufficiency with decreased forced vital capacity; some need noninvasive ventilation. Serum creatine kinase may be elevated. Muscle biopsy can show variable features, including nemaline rods, multiminicore lesions, endomysial fibrosis, and myofibrillar changes (Pellerin et al., 2020; Lee et al., 2022). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).

Oculopharyngeal muscular dystrophy-2 (OPMD2) is an autosomal dominant muscle disorder characterized by early-onset ptosis, ophthalmoplegia, dysphagia, variable respiratory insufficiency, and proximal limb muscle weakness. Most patients have onset in the first years of life, although rare patients have onset in their teens. The disorder is slowly progressive and the severity is highly variable; the most severely affected individuals lose ambulation and may require tube-feeding or noninvasive ventilation (Kim et al., 2022). For a discussion of genetic heterogeneity of OPMD, see OPMD1 (164300).