Spastic Paraplegia 6, Autosomal Dominant

A number sign (#) is used with this entry because of evidence that spastic paraplegia-6 (SPG6) is caused by heterozygous mutation in the NIPA1 gene (608145) on chromosome 15q11.

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

Clinical Features

Fink et al. (1995) reported a family in which hereditary spastic paraplegia had been diagnosed in 31 living subjects. The disorder developed insidiously with progressive gait disturbance at age 12 to 35 years. The unimodal distribution of age at onset of symptoms (mean 22.0 +/- 5.3 years) was similar to that of type I familial spastic paraplegia reported by Harding (1981), who found a mean age at onset of 20.5 +/- 17.9 years. Neurologic examination of affected subjects revealed hyperreflexia and spasticity in the lower limbs, weakness of hip flexion and ankle dorsiflexion, extensor plantar responses, diminished vibratory sense in the feet, and pes cavus. Muscle atrophy, when present, was noted only in the shins. Bladder disturbance was present in 3 affected subjects.

Reed et al. (2005) reported a large British family in which 14 members had spastic paraplegia inherited in an autosomal dominant pattern. The mean age at onset was 16.5 years (range 9 to 23), and most developed marked lower limb spasticity with hyperreflexia and extensor plantar responses. Mild bladder disturbances were also found, and most patients had pes cavus. Five affected individuals had generalized tonic-clonic seizures, and 3 developed a postural tremor in the upper limbs in their thirties.

Mapping

In a large kindred extensively affected with autosomal dominant, uncomplicated familial spastic paraplegia, Fink et al. (1995) demonstrated linkage to a group of markers on chromosome 15q (maximum 2-point lod score = 9.70 at theta = 0.05); this locus was designate SPG6. Previous physical mapping of the microsatellite markers allowed Fink et al. (1995) to assign the SPG6 locus to 15q11.1. In this same family, Fink et al. (1996) observed obligate recombinants for polymorphisms immediately adjacent to the genes encoding the alpha-5 subunit of the GABA receptor (137142) and the beta-3 subunit of the GABA receptor (137192), excluding these as possible candidates.

Dube et al. (1997) referred to the chromosome 15-linked form of hereditary spastic paraplegia as SPG4a.

Molecular Genetics

Rainier et al. (2003) analyzed a large kindred in which autosomal dominant hereditary spastic paraplegia mapped to the SPG6 locus (Fink et al., 1995) and found no evidence of genetic imprinting. Therefore, they analyzed as SPG6 candidates the 4 unique, nonimprinted, and highly evolutionarily conserved genes mapped proximal to the imprinted domain and within the pericentromeric region of 15q (Chai et al., 2003). In 28 SPG6 patients, Rainier et al. (2003) identified a mutation in the NIPA1 (608145.0001).

In affected members of a large British family with SPG6, Reed et al. (2005) identified a heterozygous mutation in the NIPA1 gene (608145.0004).