Neuropathy, Hereditary Sensory, Type If

A number sign (#) is used with this entry because of evidence that hereditary sensory neuropathy type IF (HSN1F) is caused by heterozygous mutation in the ATL3 gene (609369) on chromosome 11q13.

Description

Hereditary sensory neuropathy type IF is an autosomal dominant sensory neuropathy affecting the lower limbs. Distal sensory impairment becomes apparent during the second or third decade of life, resulting in painless ulceration of the feet with poor healing, which can progress to osteomyelitis, bone destruction, and amputation. There is no autonomic involvement, spasticity, or cognitive impairment (summary by Kornak et al., 2014).

For a discussion of genetic heterogeneity of HSN, see HSAN1A (162400).

Clinical Features

Kornak et al. (2014) reported a 4-generation German family in which 8 individuals had sensory neuropathy. Four living affected individuals were studied in detail. The patients first noticed abnormal calluses on the feet and valgus deformity of the great toes between ages 14 and 33 years. Thereafter, the patients developed painless chronic ulcerations and fractures of the distal lower limbs, with delayed healing and occasional bone destruction. Radiographs showed osteomyelitis and acroosteolysis. The most severely affected individual had to have amputation below the knees. Sensory nerve conduction studies indicated an axonal sensory neuropathy. Motor nerve conduction was normal, consistent with lack of muscle atrophy or pes cavus. The upper limbs were not affected, and autonomic function was normal. All had normal psychomotor development; spasticity was not present. Two sisters from a 3-generation Spanish family had a similar disorder. They developed bilateral hyperkeratosis and plantar ulcers at ages 14 and 16 years, respectively. They had distal sensory impairment of the lower limbs, affecting touch, pain, and temperature. Muscle strength was normal, although tendon reflexes were diminished and absent at the ankles. Electrophysiologic studies showed a sensory axonal neuropathy in the lower extremities. Radiographs of both patients showed bone destruction of some toes, necessitating amputation. The mother and maternal grandmother reportedly had similar features.

Inheritance

The transmission pattern of HSN1F in the families reported by Kornak et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In affected members of a German family with autosomal dominant hereditary sensory neuropathy, Kornak et al. (2014) identified a heterozygous missense mutation in the ATL3 gene (Y192C; 609369.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Screening of the ATL3 gene in 115 probands with various types of sensory neuropathy identified the same heterozygous Y192C substitution in 3 affected members of a Spanish family with a similar phenotype. Haplotype analysis suggested a founder effect. In vitro functional expression studies in COS-7 cells showed that the Y192C mutation caused mislocalization of the protein and had a dominant-negative disruptive effect on the regular structure of the endoplasmic reticulum. The findings contributed to the concept that pathogenic alterations in membrane-shaping proteins contribute to axonal degeneration.