Jones et al. (2003) identified a highly consanguineous family in which 3 infants presented in the newborn period with severe hypotonia and skeletal, bulbar, and respiratory weakness resulting in death within the first year of life. Serum creatine ... Jones et al. (2003) identified a highly consanguineous family in which 3 infants presented in the newborn period with severe hypotonia and skeletal, bulbar, and respiratory weakness resulting in death within the first year of life. Serum creatine kinase was not increased. Skeletal muscle biopsy showed myopathic changes, but not dystrophic changes. Immunohistochemical and Western blot analysis showed patchy, decreased, or absent beta-2-syntrophin (SNTB2; 600027) and alpha-dystrobrevin (DTNA; 601239) at the sarcolemma, consistent with a secondary abnormality of these proteins. Genetic analysis excluded pathogenic mutations in the SNTB2 and DTNA genes. Compton et al. (2008) provided follow-up of the family reported by Jones et al. (2003), and noted that they were of Egyptian origin. There were 4 affected infants. Reduced fetal movements were detected on ultrasound during the second and third trimesters consistent with fetal akinesia. All were born prematurely, and the pregnancies were complicated by multiple problems including polyhydramnios and growth retardation. Three of the children showed no spontaneous movements and died shortly after birth. One survived to 1 month of age, but required intubation and ventilation from birth. Other features included low birth weight, absent deep tendon reflexes, no suck or swallow, and an absent Moro reflex. Dysmorphic features including scaphocephaly, an oval face, hypertelorism, and a high-arched palate. The hands were small with simian creases, arachnodactyly with overlapping fingers, and marked camptodactyly. Flexion contractures were apparent. Skeletal muscle biopsy showed a minor variation in fiber size, and electron microscopy revealed that small numbers of contiguous sarcomeres were disrupted with disorganization of the Z-band and a reduced number of mitochondria. The myofilaments were also somewhat disordered within these foci, reminiscent of minicores. The nerve biopsy was histologically normal.
In affected infants from a consanguineous Egyptian family with lethal congenital myopathy, Compton et al. (2008) identified a homozygous mutation in the CNTN1 gene (600016.0001). Compton et al. (2008) proposed that reduced expression of CNTN1 at the neuromuscular ... In affected infants from a consanguineous Egyptian family with lethal congenital myopathy, Compton et al. (2008) identified a homozygous mutation in the CNTN1 gene (600016.0001). Compton et al. (2008) proposed that reduced expression of CNTN1 at the neuromuscular junction (NMJ) causes a defect in neuromuscular transmission, resulting in a severe myopathic phenotype. A loss of DTNA and SNTB2 at the sarcolemma was likely secondary to defective neuromuscular transmission or signaling. The findings emphasized an overlap in the clinical spectrum of congenital myopathies with fetal akinesia and congenital myasthenic syndromes (see, e.g., 608931), and suggested that proteins related to NMJ adhesion are important for normal muscle development and growth.