Spastic Ataxia 1, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant spastic ataxia-1 (SPAX1) is caused by heterozygous mutation in the VAMP1 gene (185880) on chromosome 12p13.

Description

Hereditary spastic ataxia comprises a heterogeneous group of progressive neurodegenerative disorders characterized by lower-limb spasticity and generalized ataxia with dysarthria, impaired ocular movements, and gait disturbance. Spastic ataxia-1 (SPAX1) is an autosomal dominant form of the disorder with onset between the ages of 10 and 20 years. Other clinical features are supranuclear gaze palsy, hyperreflexia, hypertonicity, dystonia, pes cavus, mild ptosis, and decreased vibration sense in the lower limbs. Symptom severity is variable, but neither lipfe span nor cognition is affected (summary by Meijer et al., 2002 and Bourassa et al., 2012).

Genetic Heterogeneity of Spastic Ataxia

See also SPAX2 (611302), caused by mutation in the KIF1C gene (603060) on chromosome 17p13; SPAX3 (611390), caused by rearrangements of the MARS2 gene (609728) on chromosome 2q33; SPAX4 (613672), caused by mutation in the MTPAP gene (613669) on chromosome 10p11; SPAX5 (614487), caused by mutation in the AFG3L2 gene (604581) on chromosome 18p11; SPAX6 (270550), caused by mutation in the SACS gene (604490) on chromosome 13q12; SPAX7 (108650); SPAX8 (617560), caused by mutation in the NKX6-2 gene (605955) on chromosome 8q21; and SPAX9 (618438), caused by mutation in the CHP1 gene (606988) on chromsome 15q15.

Clinical Features

Mahloudji (1963) described a rare hereditary syndrome of spastic ataxia, closely resembling disseminated sclerosis (126200), in 18 persons in an Iranian family. The pedigree, covering 5 generations, strongly suggested autosomal dominant transmission. It appeared to be the same disorder as that reported by Ferguson and Critchley (1929). Gayle and Williams (1933) described 17 cases in 4 generations of a disorder beginning in the sixth decade with stiffness in the leg muscles, followed by stumbling, dysarthria, and loss of memory. Although progression to severe spastic paraplegia occurred, the disorder did not shorten life. These patients lived in Accomac and Northampton counties on the eastern shore of Virginia.

Meijer et al. (2002) described 3 large Newfoundland families with autosomal dominant hereditary spastic ataxia in which most affected individuals initially presented with progressive leg spasticity of variable degrees followed by ataxia in the form of involuntary head jerk, dysarthria, dysphagia, and ocular movement abnormalities with no signs of amyotrophy. The lower limbs showed hyperreflexia and hypertonicity. The ocular movement abnormalities included slow saccades, impaired vertical gaze, and, in some cases, lid retraction. A few patients had additional features, such as dystonia, pes cavus, mild ptosis, and decreased vibration sense in the lower limbs. This phenotype resembled that observed in autosomal recessive Charlevoix-Saguenay spastic ataxia (ARSACS; 270550); however, these families were from a different population and showed a clear pattern of dominant inheritance with a later age at onset than is seen in ARSACS. The severity of the phenotype in the 3 families studied by Meijer et al. (2002) varied greatly within and among the families, and the age at onset was from early childhood to early twenties, although most presented with onset of symptoms at age 10 to 20 years. Neuropathologic findings included degeneration of the corticospinal tracts and posterior columns. The life span and cognition of patients was not affected. There was no recognized kinship between these 3 families, although the detection of a shared disease haplotype suggested that they originated from a common ancestor.

In further studies of the 3 large families reported by Meijer et al. (2002) from a historically isolated cluster of rural communities, Grewal et al. (2004) assumed that the affected individuals had the same condition, although they were apparently unrelated. They noted that significant mobility problems were present by the fourth decade, with a broad-based ataxic and spastic gait. MRI scans of the brain and spinal cord were normal. Neuropathologic changes included midbrain neuronal loss. Variability of phenotypic expression could be observed even within the same sibship. Pedigree analysis showed no evidence of anticipation or any sex differences in severity. The condition was unusually prevalent in the province of Newfoundland, which is a characteristic of a founder effect followed by isolation and large family size.

Mapping

Meijer et al. (2002) performed linkage studies in 3 large Newfoundland families with autosomal dominant hereditary spastic ataxia. A genomewide scan was performed on 1 family and linkage to a novel locus was identified on 12p13, which the authors termed 'SAX1,' that remained to be identified. (The locus is referred to here as SPAX1, to prevent confusion with previously named gene symbols.) Fine mapping confirmed linkage in the 2 large families, and the third smaller family showed lod scores suggestive of linkage. It was found that affected individuals in all 3 families shared a disease haplotype. SAX1 was said to have been the first locus mapped for autosomal dominant hereditary spastic ataxia.

Grewal et al. (2004) reported fine mapping of the SAX1 locus on 12p13 that reduced the critical interval to 1.9 Mb.

Molecular Genetics

In multiple affected members of 4 large multigenerational families from Newfoundland with autosomal dominant SPAX1, as well as in 3 isolated cases from Ontario with a similar disease, Bourassa et al. (2012) identified a heterozygous mutation in the VAMP1 gene (185880.0001). Three of the families had been reported by Meijer et al. (2002). The mutation, which was found by sequencing genes within the candidate disease locus on chromosome 12p13, segregated with the disorder in the families. Considering the structure of the VAMP1 isoforms and their tissue-specific expression, Bourassa et al. (2012) concluded that the mutation results in alternative splicing with the production of an abnormal inactive isoform in neurons, resulting in haploinsufficiency of VAMP1 in the brain. This would result in decreased neurotransmitter exocytosis and neurologic symptoms. However, no biopsy or autopsy tissue from the patients was available.

History

In their classic study into the genetic nosology of spinocerebellar 'degenerations,' Bell and Carmichael (1939) classified the conditions as Friedreich ataxia, familial spastic ataxia, and hereditary spastic paraplegia. They recognized 2 forms of familial spastic ataxia, a dominant form with relatively late onset and a recessive form with onset at ages 10 to 12 years. It is difficult to know whether these dominant and recessive forms are entities separate from some of the other cerebelloparenchymal, olivopontocerebellar and spinocerebellar disorders listed here.