Spastic Paraplegia 8, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant spastic paraplegia-8 (SPG8) is caused by heterozygous mutation in the KIAA0196 gene (WASHC5; 610657) on chromosome 8q24.

Description

Spastic paraplegia-8 is an autosomal dominant neurologic disorder characterized by adult onset of progressive lower limb spasticity and hyperreflexia resulting in difficulty walking. Some patients may become wheelchair-bound after several decades. Other features may include upper limb spasticity, impaired vibration sense in the distal lower limbs, and urinary urgency or incontinence (summary by de Bot et al., 2013).

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

Clinical Features

De Bot et al. (2013) reported a large Dutch family in which 10 individuals had spastic paraplegia. The mean age at symptom onset was 38.7 years (range, 21-57). All patients had lower limb spasticity with hyperreflexia, extensor plantar responses, and weakness causing impaired gait. The severity was variable, but mostly severe. Most patients also had some upper extremity spasticity, and a few had upper limb ataxia. None had dysarthria, but 4 had mild dysphagia. All patients had impaired vibration sense in the lower legs without electrophysiologic signs of a peripheral neuropathy. Other features included urinary urgency, nonspecific lower back pain and joint pains, and leg tremor. Three patients were wheelchair-bound after a disease duration of several decades.

Inheritance

The transmission pattern of SPG8 in the family reported by de Bot et al. (2013) was consistent with autosomal dominant inheritance.

Mapping

Hedera et al. (1999) analyzed a Caucasian kindred with autosomal dominant hereditary spastic paraplegia and identified tight linkage of the disorder with microsatellite markers on chromosome 8q (maximum 2-point lod score = 5.51 at recombination fraction = 0.0). The location of the locus was thought to be 8q23-q24, spanning 6.2 cM between D8S1804 and D8S1774. They proposed that the new locus be designated SPG8.

Rocco et al. (2000) evaluated a Brazilian family in which 16 members had pure spastic paraplegia of adult onset. Analysis using markers flanking the SPG8 locus on chromosome 8q suggested linkage to this locus. Rocco et al. (2000) performed immunohistochemical and Western blot studies on one of the affected family members and found normal distribution, expression, and apparent molecular weight of the beta-1 syntrophin protein, suggesting that the SNTB1 gene (600026) is unlikely to be a candidate gene for SPG8.

Molecular Genetics

Valdmanis et al. (2007) commented that hereditary spastic paraplegia is one of the most genetically heterogeneous disorders, caused by mutations in at least 31 different genes. This means that as much as 0.1% of genes in the human genome can be mutated and result in 1 predominant neurologic outcome: degeneration of upper motor neuron axons. The 3 families linked to the SPG8 locus on 8q presented with relatively severe, pure spastic paraplegia. Valdmanis et al. (2007) identified 3 mutations in the KIAA0196 gene (610657), which maps to the SPG8 locus. One mutation, V626F (610657.0001), segregated in 3 large North American families with European ancestry and in 1 British family. An L619F mutation (610657.0002) was found in the Brazilian family described by Rocco et al. (2000). The third mutation, N471D (610657.0003), was identified in a smaller family of European origin and lies in a spectrin domain. The SPG8 mutations resulted in a pure form of hereditary spastic paraplegia with relatively little interfamilial variability in phenotype.

In 10 affected members of a large Dutch family with SPG8, de Bot et al. (2013) identified a heterozygous missense mutation in the KIAA0196 gene (G696A; 610657.0005). The mutation was found by targeted sequencing of the KIAA0196 gene in 21 index patients with autosomal dominant SPG; 2 index patients carried the mutation and were later found to be related. Functional studies of the variant were not performed.