MedGen

Congenital myopathy-10A (CMYP10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (Logan et al., 2011). Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYP10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYP10B) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000). [from OMIM]

Optic atrophy-9 (OPA9) is characterized by onset of decreased visual acuity and optic disc pallor in the first decade of life, with severely reduced visual acuity and color vision deficits observed in the third decade. Although initially described as an autosomal recessive disease (Metodiev et al., 2014; Kelman et al., 2018; Gibson et al., 2020), autosomal dominant cases of OPA9 have also been reported (Charif et al., 2021). Mutation in the ACO2 gene also causes a neurodegenerative disorder, infantile cerebellar-retinal degeneration (ICRD; 614559), of which optic atrophy is a feature. Dominant and Recessive OPA9 From a cohort of approximately 1,000 patients with optic atrophy, Charif et al. (2021) identified 50 probands with dominant mutations in the ACO2 gene, and 11 patients with biallelic variants. There was no significant difference in distribution of mutation type, with two-thirds of all variants being missense mutations in both groups, and nonsense, frameshift, and splice site mutations comprising the remaining third. Age at onset of symptoms occurred during the first 2 decades, without significant difference between dominant and recessive cases. Visual acuity was significantly more affected in recessive cases than in dominant ones, with more than 60% of eyes from the recessive group having a visual acuity lower than 20/200, whereas more than 80% of eyes from the dominant group had a visual acuity above 20/200. Analysis of the optic disc as well as retinal nerve fiber layer thickness measurements indicated a preferential involvement of the temporal quadrant in both patient groups. Assessment of color vision revealed highly variable alterations, including protan, deutan, and tritan types of dyschromatopsia. Some patients had additional retinal changes, including macular microcysts as well as macular dystrophy in 1 case. Extraocular symptoms were observed in 6 (12%) of the dominant cases and in 3 (27%) of the recessive cases, including hearing impairment in 2 dominant cases, and late-onset cerebellar ataxia in 1 dominant case and in 1 recessive case. [from OMIM]

Congenital myopathy-10B (CMYP10B) is an autosomal recessive skeletal muscle disorder characterized by infantile- or childhood-onset myopathy, areflexia, dysphagia, and respiratory distress that usually requires nocturnal ventilation. Other common features include facial and neck muscle weakness, feeding difficulties, contractures, scoliosis, high-arched palate, hyporeflexia, and difficulties walking. The disorder is slowly progressive and most patients follow a chronic course. Muscle biopsy shows variable findings, including type 1 fiber predominance, minicore lesions, and myofibrillar disorganization (Boyden et al., 2012; Harris et al., 2018). Patients with missense mutations affecting conserved cysteine residues in the EGF-like domain show the mild variant phenotype (CMYP10B) with later onset of respiratory failure and minicores on muscle biopsy, whereas patients with more damaging mutations, including nonsense or frameshift null mutations, show the severe variant phenotype (CMYP10A) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYP1A (117000). [from OMIM]