Cowchock Syndrome

A number sign (#) is used with this entry because Cowchock syndrome (COWCK), also known as X-linked recessive Charcot-Marie-Tooth disease-4 (CMTX4), is caused by mutation in the AIFM1 gene (300169) on chromosome Xq26.

Description

Cowchock syndrome (COWCK) is an X-linked recessive neuromuscular disorder characterized by early childhood onset of a slowly progressive axonal sensorimotor neuropathy associated in some patients with sensorineural deafness and cognitive impairment (summary by Rinaldi et al., 2012).

Clinical Features

Cowchock et al. (1985) reported a large Italian American family with early childhood onset of a slowly progressive axonal sensorimotor neuropathy associated with deafness and cognitive impairment. The transmission pattern was consistent with X-linked recessive inheritance. Minor abnormalities in sensory nerve conduction, electromyography, and hearing loss were found in females, but were deemed insufficiently consistent to be useful in carrier identification. This family was reported also by Sladky and Brown (1984) and was included in a study of 4 families by Fischbeck et al. (1986).

Priest et al. (1995) provided follow-up of the family reported by Cowchock et al. (1985). The family included 7 affected males, 3 obligate carrier females, and 4 unaffected males. The patients were severely affected within the first few years of life with distal weakness, muscle atrophy, sensory loss, areflexia, pes cavus, and hammertoes. Deafness was associated in 5 of the 7 affected males, and 3 of these 5 also showed mental retardation or social developmental delay. Motor nerve conduction velocities in affected males were normal to mildly delayed, and sensory conduction was markedly abnormal. Heterozygous females were asymptomatic.

Rinaldi et al. (2012) provided another follow-up of the family reported by Cowchock et al. (1985). Clinical features included distal muscle weakness and atrophy and sensory loss affecting the lower more than the upper limbs. Some patients had cognitive impairment and some had hearing loss. Laboratory studies showed increased serum transaminases and increased serum creatine kinase. Muscle biopsy showed neurogenic atrophy, and electron microscopy showed increased numbers of abnormally shaped mitochondria in subsarcolemmal areas. Some patients had cognitive impairment and some had hearing loss. Brain MRI of 2 patients showed T2-weighted hyperintensities in the supratentorial white matter. Only males were affected.

Inheritance

Cowchock et al. (1985) observed 7 affected males in 2 generations connected through females, consistent with X-linked recessive inheritance.

Mapping

In a study of 4 affected families, including the family reported by Cowchock et al. (1985), Fischbeck et al. (1986) found linkage to a region of the centromere of the X chromosome between marker DXYS1 on the proximal long arm and DXS14 on the proximal short arm. This location correlated with that indicated by linkage studies in 3 other families by the same workers and in several families of X-linked Charcot-Marie-Tooth disease studied by others. Fischbeck et al. (1987) found that the linkage relationships to PGK (311800) were different from those of X-linked Charcot-Marie-Tooth disease (CMTX1; 302800), indicating that this is a genetically as well as clinically distinct entity.

Priest et al. (1995) used DNA markers on the X chromosome to map the locus for the unusual form of X-linked recessive hereditary motor and sensory neuropathy with associated deafness and mental retardation in a 3-generation family originally reported by Cowchock et al. (1985). Linkage studies and haplotype analysis of 19 microsatellite markers on Xq demonstrated that DXS425 (Xq24) and HPRT (Xq26.1) were flanking markers.

Molecular Genetics

By exome sequencing of 1 of the patients from the original family reported by Cowchock et al. (1985), Rinaldi et al. (2012) identified a hemizygous mutation in the AIFM1 gene (E493V; 300169.0002). The mutation was confirmed by Sanger sequencing to segregate with the disorder in the family. Studies of the recombinant E493V mutant protein showed some structural changes that altered the redox properties of the protein without affecting activity of the respiratory chain complexes. Patient muscle biopsy showed an increased number of apoptotic cells compared to controls, suggesting activation of the caspase-independent cell death pathway.