Neuronopathy, Distal Hereditary Motor, Type Viia

A number sign (#) is used with this entry because autosomal dominant distal hereditary motor neuronopathy type VIIa (HMN7A) is caused by heterozygous mutation in the SLC5A7 gene (608761) on chromosome 2q12.

See also HMN7B (607641), caused by mutation in the DCTN1 gene (601143) on chromosome 2p13.

Description

Distal hereditary motor neuronopathy type VIIa is an autosomal dominant neurologic disorder characterized by onset in the second decade of progressive distal muscle wasting and weakness affecting the upper and lower limbs and resulting in walking difficulties and hand grip. There is significant muscle atrophy of the hands and lower limbs. The disorder is associated with vocal cord paresis due to involvement of the tenth cranial nerve (summary by Barwick et al., 2012).

For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMN type I (HMN1; 182960).

Clinical Features

Young and Harper (1980) described a large kindred with autosomal dominant inheritance of a peculiar form of spinal muscular atrophy and vocal cord paralysis. The disorder presented in the teens with small muscle wasting in the hands, particularly involving median nerve musculature. This was followed by distal muscle wasting and weakness in the lower limbs resulting in difficulty walking. Other features include pes cavus, hyporeflexia, and husky voice. Vocal cord paralysis was a characteristic and potentially hazardous feature.

Serratrice et al. (1984) reported a similar patient with a somewhat later onset. His sister (not examined) was said to be similarly affected. No information was available on their parents. Pridmore et al. (1992) reported a family with the combination of distal spinal muscular atrophy and vocal cord paralysis in at least 3 successive generations. Their family and the family of Young and Harper (1980) were Welsh.

Boltshauser et al. (1989) described 3 persons in successive generations, grandfather, daughter, and granddaughter, who likewise had distal spinal muscular atrophy associated with vocal cord paralysis. However, the 3 affected persons also had progressive sensorineural hearing loss. Electrophysiologic and histologic studies did not exclude the possibility of involvement of sensory neurons, a possibility that would make classification of this disorder as a form of spinal muscular atrophy untenable. Boltshauser et al. (1989) concluded that it is uncertain whether the disorder in their family represents the same disease entity as that reported by Young and Harper (1980), with variable hearing impairment, or whether it is a different disorder.

McEntagart et al. (2001) noted that distal HMN VII shows considerable overlap with HMSN IIc (CMT2C; 606071), but is distinguished by the presence of sensory involvement.

Inheritance

The transmission pattern of HMN type VII in the family reported by Young and Harper (1980) was consistent with autosomal dominant inheritance.

Mapping

McEntagart et al. (2001) performed linkage analysis in the large Welsh kindred described by Young and Harper (1980). A genomewide screen established linkage to 2q14. Analysis in a second family, previously reported by Pridmore et al. (1992), confirmed the linkage to 2q14, and haplotype analysis provided evidence for a founder mutation segregating in the 2 pedigrees. Indeed, further study demonstrated a genealogic connection. The maximum 3-point lod score in the combined pedigree was 7.49 at marker D2S274. The mutant gene in these families is presumably expressed in the spinal cord. Engrailed-1 (131290), a transcription factor strongly expressed in the spinal cord, was excluded as a candidate gene.

Dick et al. (2008) refined the dHMN-VII locus in the family reported by Young and Harper (1980) using 2 newly affected individuals. Two distinct regions on chromosome 2q14.2, comprising 9.2 Mb and 4.3 Mb separated by an unusual double recombination event, cosegregated with the disease phenotype. The proximal linked region was defined by markers D2S3038-D2S160, and the distal region by D2S2970-D2S2969.

Molecular Genetics

In affected members of a large multigenerational Welsh family with HMN7A reported by McEntagart et al. (2001), Barwick et al. (2012) identified a heterozygous truncating mutation in the SLC5A7 gene (608761.0001). The mutation, which was identified by exome sequencing and segregated with the disorder in this family, was not found in genomic databases. In vitro functional expression assays showed that the mutation resulted in reduced protein levels and reduced choline transport, and exhibited a dominant-negative effect when coexpressed with the wildtype cDNA. Given the role of SLC5A7 at the neuromuscular junction (NMJ), Barwick et al. (2012) commented on the lack of features usually associated with congenital myasthenic syndromes (see, e.g., 608931), which are caused by mutations in genes involved in synaptic transmission at the NMJ.

Animal Model

Ferguson et al. (2004) disrupted the Cht gene in mice. Although morphologically normal at birth, Cht -/- mice became immobile, breathed irregularly, appeared cyanotic, and died within an hour. Hemicholinium 3-sensitive choline uptake and subsequent ACh synthesis were specifically lost in Cht -/- mouse brains. There was also a time-dependent loss of spontaneous and evoked responses at Cht -/- neuromuscular junctions. Consistent with defects in synaptic ACh availability, Cht -/- mice had developmental changes in neuromuscular junction morphology reminiscent of changes in mutant mice lacking ACh synthesis. Adult Cht +/- mice overcame reductions in Cht protein levels and sustained choline uptake activity at wildtype levels through posttranslational mechanisms.