Spastic Ataxia 2, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive spastic ataxia-2 (SPAX2) is caused by homozygous mutation in the KIF1C gene (603060) on chromosome 17p13.

Description

Autosomal recessive spastic ataxia is a neurologic disorder characterized by onset in the first 2 decades of cerebellar ataxia, dysarthria, and variable spasticity of the lower limbs. Cognition is not affected (summary by Dor et al., 2014).

For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600).

Clinical Features

Bouslam et al. (2007) reported a consanguineous Moroccan family in which 4 sibs had spastic ataxia. All had onset of dysarthria at age 14 years followed by gait ataxia, and 3 developed mild spasticity in all limbs. All had hyperreflexia of the lower limbs, 2 had extensor plantar responses, and 3 had amyotrophy of the distal limbs. Fasciculations were present in all patients. Two patients had horizontal nystagmus. There were no skeletal deformities, sphincter disturbances, extrapyramidal signs, or cognitive impairments. Brain imaging was not performed.

Dor et al. (2014) reported a large consanguineous Palestinian kindred in which 3 sibs and a first cousin had onset of tremor, dysarthria, and frequent falls between ages 6 and 10 years after normal early development. Physical examination showed lower limb spasticity with hyperreflexia, extensor plantar responses, and clonus, as well as cerebellar signs, including ataxia, nystagmus, head titubation, and dysmetria. The spasticity was not progressive, and the patients remained ambulatory, but the cerebellar ataxia was progressive over a 5-year follow-up. Brain MRI of 1 patient at age 18 years showed no atrophy of the cerebellum, corpus callosum, or brainstem, but there was some evidence of demyelination in the posterior limb of the internal capsule and occipital white matter. Cognitive function was intact, and sphincter disturbances were absent. Three sibs from a consanguineous Moroccan family presented with cerebellar ataxia with a variable age at onset (1, 7, and 16 years, respectively). These sibs did not have overt spasticity, but had some pyramidal signs, such as hyperreflexia. Initial symptoms included frequent falls, gait instability, and/or head tremor. The disorder was slowly progressive, and all remained ambulatory. One patient each had cervical dystonia, nystagmus with decreased visual acuity, and neuropathy. CT scan showed cerebral and cerebellar atrophy in 1 patient at age 22 years. None presented with intellectual deterioration, sphincter disturbances, or deep sensory loss.

Novarino et al. (2014) reported 2 consanguineous families with spastic ataxia, which the authors called spastic paraplegia-58 (SPG58). In 1 family (family 803), 2 sisters presented at 2.5 years of age with tiptoe walking. When they were last examined in their teens, they both had abnormal gait and dysarthria, and 1 had mild intention tremors. Both had increased reflexes and clonus as well as normal brain MRIs and normal cognition. Both were very short, with microcephaly. In another family (family 789), 2 sets of sibs, who were related as double first cousins, presented with ataxia between 3 and 4 years of age; in late childhood, they had ataxia, spasticity, and dysarthria, including extrapyramidal chorea and fragmentary clonus. They all had increased deep tendon reflexes and white matter abnormalities on brain MRI. Two had developmental delay, and 2 had mild mental retardation. All affected individuals had hypodontia, which appeared to be an independent phenotype in this highly consanguineous family.

Inheritance

The transmission pattern of SPAX2 in the families reported by Dor et al. (2014) was consistent with autosomal recessive inheritance.

Mapping

By genomewide screening and haplotype analysis of a Moroccan family with autosomal recessive spastic ataxia, Bouslam et al. (2007) identified a 6.1-cM candidate locus, designated SPAX2, on chromosome 17p13 (maximum multipoint lod score of 3.21 between D17S1845 and D17S1854). Mutations were excluded in the coding regions of the ANKFY1 (607927), ARRB2 (107941), and KIF1C (603060) genes. Three additional smaller families with a similar disorder showed suggestive linkage to this locus.

Molecular Genetics

In affected members of 2 unrelated families with SPAX2, Dor et al. (2014) identified 2 different homozygous mutations in the KIF1C gene (R731X, 603060.0001 and R169W, 603060.0002). The mutations were found using a combination of homozygosity mapping and whole-exome sequencing. Functional studies were not performed.

In 2 consanguineous families with SPAX2, Novarino et al. (2014) identified homozygous mutations in the KIF1C gene: the R731X mutation previously identified by Dor et al. (2014) and a splice site mutation (603060.0003). Novarino et al. (2014) also identified a homozygous deletion of exons 14-18 of the KIF1C gene (603060.0004) in affected members of the Moroccan family with SPAX2 reported by Bouslam et al. (2007).