Autosomal dominant hereditary sensory neuropathy type 1D is characterized by adult onset of a distal axonal sensory neuropathy affecting all modalities, often associated with distal ulceration and amputation as well as hyporeflexia, although some patients may show features ... Autosomal dominant hereditary sensory neuropathy type 1D is characterized by adult onset of a distal axonal sensory neuropathy affecting all modalities, often associated with distal ulceration and amputation as well as hyporeflexia, although some patients may show features suggesting upper neuron involvement (summary by Guelly et al., 2011). For a discussion of genetic heterogeneity of HSAN, see HSAN1A (162400). Spastic paraplegia-3A (SPG3A; 182600) is an allelic disorder with a different phenotype.
Guelly et al. (2011) reported a 4-generation family with hereditary sensory neuropathy inherited in an autosomal dominant pattern. Onset of the disorder occurred in early adulthood, when most affected individuals showed trophic skin and nail changes and repeated ... Guelly et al. (2011) reported a 4-generation family with hereditary sensory neuropathy inherited in an autosomal dominant pattern. Onset of the disorder occurred in early adulthood, when most affected individuals showed trophic skin and nail changes and repeated foot ulcerations, leading to osteomyelitis and subsequent foot or toe amputations. These features were associated with severe distal sensory loss and distal amyotrophy in the lower limbs, but absent or minimal distal amyotrophy in the upper limbs. Patellar tendon reflexes ranged from normal to increased, and ankle reflexes ranged broadly from absent to increased, indicating upper motor-neuron involvement in some patients. Electrophysiologic studies showed a sensorimotor axonal neuropathy. One affected individual had a history of spastic cerebral palsy in infancy. Two additional families with HSN1D identified by Guelly et al. (2011) showed similar features with some variability: 1 proband had progressive, ascending, severe sensory loss affecting all modalities in the lower legs, but no foot ulcerations or paresis. He had hyporeflexia. The proband in the other family had adult-onset sensory neuropathy with ulcerations, lack of pain perception, paresthesias in the fingers, and occasional lancinating pains in his ankles. Patellar tendon reflexes were brisk, and Achilles tendon reflexes were absent. Muscle weakness and autonomic symptoms were not present. Guelly et al. (2011) noted the variable involvement of upper neuron signs and trophic complications in this disorder.
By genomewide linkage analysis followed by array-based exonic sequencing of candidate genes in a family with autosomal dominant hereditary sensory neuropathy, Guelly et al. (2011) identified a heterozygous mutation in the atlastin-1 gene (N355K; 606439.0010). Screening of this ... By genomewide linkage analysis followed by array-based exonic sequencing of candidate genes in a family with autosomal dominant hereditary sensory neuropathy, Guelly et al. (2011) identified a heterozygous mutation in the atlastin-1 gene (N355K; 606439.0010). Screening of this gene in 115 additional probands with a similar disorder identified 2 additional heterozygous mutations in the ATL1 gene in 2 unrelated probands (606439.0011 and 606439.0012). In vitro functional expression studies in COS-7 cells did not reveal a common pathogenetic mechanism, and there was no clear functional distinction between mutations causing SPG3A and HSN1D, but Guelly et al. (2011) postulated that a defect in the tubular endoplasmic reticulum may underlie both disorders.