Neuropathy, Hereditary Sensory, Type Iic

A number sign (#) is used with this entry because hereditary sensory neuropathy type IIC (HSN2C) is caused by homozygous or compound heterozygous mutation in the KIF1A gene (601255) on chromosome 2q37.

Mutation in the KIF1A gene can also cause hereditary spastic paraplegia-30 (SPG30; 610357).

Description

HSN2C is an autosomal recessive disorder characterized by onset in the first decade of progressive distal sensory loss leading to ulceration and amputation of the fingers and toes. Affected individuals also develop distal muscle weakness, primarily affecting the lower limbs (summary by Riviere et al., 2011).

For a discussion of genetic heterogeneity of HSN, see HSAN1 (162400).

Clinical Features

Riviere et al. (2011) reported 3 sibs, born of consanguineous Afghan parents, with childhood-onset of hereditary sensory neuropathy. Age at onset ranged between 6 and 10 years. The disorder was characterized by distal numbness of the hands and feet, resulting in ulcerative and mutilated lesions and amputation. There was also mild distal muscle weakness mainly in the lower limbs, associated with wasting of muscles in the lower leg. Vibration and position sense were absent in the feet and hands, but pinprick and touch were normal. Deep tendon reflexes were generally absent. Electrophysiologic studies showed decreased or absent sural, median, and ulnar nerve sensory potentials. Tibial and peroneal motor potentials were decreased or absent. A second family, of Turkish origin, had 2 affected sibs. Both had painless ulcerations, with amputations in 1. Both had distal weakness in the lower limb with milder weakness in the upper limbs. In a third family, 2 Belgian sibs, aged 61 years, had panmodal distal sensory loss with distal ulcerations and amputations of the fingers and toes. Each of these sibs had complete motor paralysis of 1 lower limb. In another Belgian family, an 8-year-old boy had a more severe disorder with panmodal sensory loss and additional features, including low IQ, slowed speech development, short stature, equinus deformities, and was wheelchair-bound.

Inheritance

The transmission pattern of hereditary sensory neuropathy in the families reported by Riviere et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

By genomewide homozygosity mapping followed by candidate gene analysis in a consanguineous Afghan family with HSN2C, Riviere et al. (2011) identified a homozygous truncating mutation in the KIF1A gene (601255.0002). Screening of this gene in 112 unrelated patients with HSAN identified 2 additional families with the same mutation and 1 patient who was compound heterozygous for 2 mutations (601255.0002 and 601255.0003).