Neuropathy, Hereditary Sensory, With Spastic Paraplegia, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive sensory neuropathy with spastic paraplegia is caused by mutations in the CCT5 gene (610150).

Clinical Features

Cavanagh et al. (1979) described a seemingly unique form of sensory neuropathy with mutilating ulcerations of the hands and feet similar to that described in entry 162400 except for the additional feature of spastic paraplegia. Three of the patients, 2 of whom were thought to be half sibs (different paternity), developed paraplegia in the first 2 years of life; this was associated at an early stage with the clinical features of a peripheral neuropathy. In contrast, the other 2 patients, a brother and sister, demonstrated paraplegia and neuropathy much later, although it was difficult to date the onset precisely.

Thomas et al. (1994) described progressive sensory neuropathy in association with spastic paraplegia and a mutilating acropathy of the lower limbs in 5 patients, including 2 pairs of sibs who were the offspring of normal consanguineous parents. Nerve biopsy in 3 of the patients showed an axonopathy with loss of myelinated nerve fibers of all diameters as well as loss of unmyelinated axons.

Bouhouche et al. (2006) reported a consanguineous Moroccan family in which 4 sibs had a severe mutilating sensory neuropathy with spastic paraplegia. Age at onset ranged from 1 to 5 years. The clinical features included lower limb spasticity, hyperreflexia with clonus, positive Babinski sign, and subtle distal amyotrophy with normal motor function. Affected members had distal sensory loss for all modalities in the upper and lower limbs, particularly in the feet. Two patients had 'deformities' of the hands and feet, and most had deep perforating ulcers of the extremities. The oldest patient, aged 34, had scars of healed ulcers in the hands and a history of osteomyelitis of the feet leading to amputation of both legs up to his thighs. Although the progression of spasticity was slow, the sensory neuropathy was rapidly progressive and severe. Electrophysiologic studies showed normal or mildly decreased motor nerve conduction velocities consistent with a sensory axonal neuropathy. MRI of 2 patients showed severe atrophy of the spinal cord, and laboratory investigations of 2 patients showed decreased serum apolipoprotein B (APOB; 107730), total cholesterol, and triglycerides.

Mapping

By genomewide analysis of a consanguineous Moroccan family with sensory neuropathy and spastic paraplegia, Bouhouche et al. (2006) identified a candidate disease locus within a 25-cM region on chromosome 5p15.31-p14.1 between markers D5S2054 and D5S648 (maximum lod score of 3.92).

Molecular Genetics

In 4 affected members of a Moroccan family reported by Bouhouche et al. (2006), Bouhouche et al. (2006) identified a homozygous mutation in the CCT5 gene (610150.0001).