A number sign (#) is used with this entry because of evidence that megaconial-type congenital muscular dystrophy (MDCMC) is caused by homozygous or compound heterozygous mutation in the CHKB gene (612395) on chromosome 22q13.

Megaconial-type congenital muscular dystrophy (MDCMC) is an autosomal recessive disorder characterized by early-onset muscle wasting and impaired intellectual development. Some patients develop fatal cardiomyopathy. Muscle biopsy shows peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center (summary by Mitsuhashi et al., 2011).

Nishino et al. (1998) studied 4 patients with congenital muscular dystrophy from 3 unrelated families with the merosin-positive form; all were mentally retarded and shared the particular morphologic changes of mitochondrial depletion in muscle biopsies in addition to dystrophic changes. All had hypotonia from birth and delayed psychomotor development. The disorder was slowly progressive, and 1 patient died from dilated cardiomyopathy at the age of 13 years. In addition to dystrophic changes with necrosis and regeneration in muscle, the most striking finding was mitochondrial depletion in the center of the sarcoplasm. Mitochondria at the periphery of fibers were markedly enlarged ('megaconial' appearance) with complicated cristae, and contained a normal amount of mitochondrial DNA by in situ hybridization. Nishino et al. (1998) suggested that mitochondrial enlargement may represent functional compensation for mitochondrial depletion in the central sarcoplasm, where myofibrillar degeneration occurred. Mitsuhashi et al. (2011) reported follow-up of the patients reported by Nishino et al. (1998). The surviving individuals were ages 29 and 22 years; 1 patient had died at age 23. Three had cardiomyopathy, and 3 had seizures.

Mitsuhashi et al. (2011) reported 11 unrelated patients, including 10 of Turkish origin and 1 of British origin, with congenital muscular dystrophy and mental retardation similar to that reported by Nishino et al. (1998). All affected individuals had early-onset muscle weakness, and about half had infantile hypotonia. Some had delayed walking, whereas others never achieved independent ambulation. Most never acquired meaningful language. Most had microcephaly, but brain imaging showed no developmental defects. Four had cardiomyopathy, 1 had an atrial septal defect, and 1 had mitral valve prolapse. Two died of cardiomyopathy in the first decade of life. Five patients had ichthyosiform changes in the skin. None had seizures. Muscle biopsies showed necrotic and regenerating fibers, endomysial fibrosis, and enlarged mitochondria at the periphery of muscle fibers.

Castro-Gago et al. (2014) reported a 13-year-old Spanish boy, born of unrelated parents, with MDCMC confirmed by genetic analysis. He presented at 2.5 years of age with proximal muscle weakness of the lower limbs resulting in frequent falls and difficulty standing up, running, and climbing stairs. He had mild hypotonia, Gowers sign, wide-based waddling gait, and hyporeflexia. Laboratory studies showed mildly increased serum creatine kinase, and EMG showed a myopathic pattern. Skeletal muscle biopsy showed variation in fiber size, increased internal nuclei, fatty infiltration, degenerating fibers, and enlarged mitochondria at the periphery of most fibers, leaving the central areas devoid of cytochrome c oxidase immunostaining. There was also a combined decrease in mitochondrial respiratory chain enzymes, as well as a depletion of mtDNA content. At age 12, cardiac examination revealed a slight alteration in repolarization and a long QT interval. At age 13, he had muscle atrophy of all 4 limbs, waddling gait, mild mental retardation, and attention deficit-hyperactivity disorder.

The transmission pattern of MDCMC in the families reported by Mitsuhashi et al. (2011) was consistent with autosomal recessive inheritance.

Based on the phenotype of the rostrocaudal muscular dystrophy (rmd) mouse due to a deletion in the Chkb gene (Sher et al., 2006), Mitsuhashi et al. (2011) screened the CHKB gene in 15 patients with congenital muscular dystrophy, mental retardation, and enlarged mitochondria and identified homozygous or compound heterozygous mutations in all patients (see, e.g., 612395.0001-612395.0005). Eleven mutations were identified, including 6 nonsense, 2 missense, a deletion, and 2 splice site mutations. Skeletal muscle biopsies had no detectable choline kinase (CHK) activity, consistent with a loss of function, and also showed decreased amounts of phosphatidylcholine. The findings indicated that this muscle disease is caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the important role of phosphatidylcholine in muscle and brain.

In a Spanish boy with MDCMC and a combined defect of mitochondrial respiratory chain enzyme activity, Castro-Gago et al. (2014) identified a homozygous truncating mutation in the CHKB gene (Y270X; 612395.0001). The mutation was found by whole-exome sequencing and segregated with the disorder in the family. Additional genetic causes for the respiratory chain deficiency were excluded, suggesting that a defect in phospholipid metabolism can result in mitochondrial dysfunction.

Sher et al. (2006) reported a spontaneous autosomal recessive mouse model of rostrocaudal muscular dystrophy (rmd) characterized by early-onset of progressive muscle wasting and hindlimb weakness and an outward rotation of the forelimbs associated with defective bone morphology. Affected rmd/rmd mice developed severe hindlimb control by 2 to 3 months of age. Hindlimb muscles showed severe dystrophic features, with centralized nuclei, fatty infiltration, and loss of muscle fibers, with subtle disruption of the sarcolemmal membrane apparent on electron microscopy. However, affected muscles contained extremely large mitochondria without abnormal respiratory chain immunostaining in affected muscles. Positional cloning allowed identification of a 1.6-kb deletion in the Chkb gene as causative for the rmd phenotype. Western blot analysis confirmed complete loss of the Chkb protein, and there was decreased enzymatic activity of Chk and decreased levels of phosphatidylcholine.