Hereditary sensory neuropathy type 1

Hereditary sensory neuropathy type 1 (HSN1) is a debilitating peripheral neuropathy predominantly affecting the distal lower extremities. In early stages of the disease, pain and temperature sensations are most affected . Symptoms begin with loss of sensation in the feet and the hands, progress to ulcers, and result in mutilating, hyperkeratotic lesions of the fingers and toes that often require amputation. As the disease progresses, there is also degeneration of motor neurons with secondary denervation atrophy and weakness of distal limb muscles . The mode of inheritance of HSN1 is autosomal dominant, with onset typically in the second or third decade . HSN1 is a clinically heterogeneous disease. The characteristic features described above may be associated with lancinating pain. Deafness has been reported in some families . The expression of the disease also varies by gender within the same family. The symptoms begin later in women than in men, and the progression is usually more severe in men . In addition to the clinical heterogeneity, HSN1 is characterized by a genetic heterogeneity, since at least three gene variants are reported. The genetic loci for two variants are defined, with linkage of HSN1 to both chromosome 9q22 and chromosome 3q13-22 Moreover, linkage to both the 9q and the 3q loci was excluded in two HSN1 families , indicating the presence of at least a third gene.

Three mutations, C133Y, C133W, and V144D, have been identified in HSN1 patients . These are located within a 12–amino acid segment encoded by exons 5 and 6 of the SPTLC1 gene (our own unpublished data). Dawkins et al. reported a higher synthesis of glucosylceramide (GlcCer) in cultured lymphocytes from HSN1 patients than in cell lines from healthy controls. Based on this observation, these authors suggested that these HSN1 mutations in the human LCB1 subunit were associated with an increase of SPT activity and represented gain-of-function mutations. However, the corresponding mutations in yeast have been shown recently to reduce SPT activity . Therefore, to begin to elucidate the mechanisms by which the mutations in the SPTLC1 gene cause HSN1, it is essential to clarify the impact of the mutations on the function of SPT in mammalian cells. In the present study we show that the two mutations in the LCB1 subunit that we have identified in our HSN1 families confer dominant negative effects on SPT activity in various cell types, including cultured lymphoblasts from HSN1 patients.

Family D1 is American and of German origin. This family has been described previously . In this family, the age of onset of the disease is usually in the second or third decade. The symptoms begin with subtle loss of pain and temperature perception and are followed by ulcers in the toes and fingers. Symptom onset is earlier and progresses faster in men than in women. Absence of a pinprick response is observed in the early teens, even in asymptomatic patients carrying the disease haplotype. Muscle weakness and atrophy are eventually evident in most patients and may be very severe, requiring mechanical assistance such as the use of splints and crutches. In the advanced cases, sensory potentials are absent, and motor nerve conduction velocities are decreased in the lower extremities . Most patients reported the sensation of shooting pain. Family N1 is Canadian and of English origin. In this family, the age and pattern of onset are equivalent to that in family D1. The sensory nerve action potentials are lost early, and the motor nerve conduction velocities are slower than expected from purely axonal lesions. Weakness of the hands and the legs also is evident, with shoulder pain and ulceration of the tip of the toes reported in later stages of the disease.