Spastic Ataxia 5, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive spastic ataxia-5 (SPAX5) is caused by homozygous mutation in the AFG3L2 gene (604581) on chromosome 18p11.

Heterozygous mutation in the AFG3L2 gene causes autosomal dominant spinocerebellar ataxia-28 (SCA28; 610246).

Description

Spastic ataxia-5 (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (summary by Pierson et al., 2011).

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

Clinical Features

Pierson et al. (2011) reported 2 brothers, born of consanguineous Hispanic parents from Colombia, with early-onset spinocerebellar ataxia with spasticity and myoclonic epilepsy. Their disease courses were similar, although the younger sib had a more severe phenotype and died of pneumonia at age 13 years. The older brother developed spastic gait at age 2 years and eventually lost the ability to ambulate independently, whereas the younger brother never acquired independent ambulation. Both developed progressive myoclonic epilepsy associated with generalized tonic-clonic seizures at age 8 years. This was followed by progressive dysarthria, dysphagia, motor degeneration, and lower extremity weakness with distal muscle atrophy. The older brother showed dysmetria, dysdiadochokinesia, ataxic dysarthria, ptosis, oculomotor apraxia, and dystonic movements. Cognition was normal. Brain MRI showed moderate cerebellar atrophy, and nerve conduction studies showed an axonal sensorimotor neuropathy of the lower extremities. Electron microscopy of skeletal muscle showed misplaced mitochondria associated with large lipid droplets, and there was decreased mtDNA copy number. Both parents were without neurologic complaints and had normal neurologic and ophthalmological exams, although the mother had mild cerebellar atrophy on brain imaging.

Clinical Variability

Muona et al. (2015) reported 2 Italian patients, not known to be related, who presented with severe progressive myoclonus at age 10 years after normal early development. One patient had a single tonic-clonic seizure, ataxia, and mild cognitive decline. He was wheelchair-bound at age 22 years. The other patient had a single tonic-clonic seizure at age 22, ataxia, and mild cognitive impairment. She became wheelchair-bound at age 48 years. Neither patient had early spasticity or neuropathy. Muona et al. (2015) noted that the phenotype in these 2 patients was not as severe as that reported by Pierson et al. (2011).

Inheritance

The transmission pattern of spastic ataxia in the family reported by Pierson et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

By whole-exome sequencing in 2 brothers with early-onset spastic ataxia, Pierson et al. (2011) identified a homozygous mutation in the AFG3L2 gene (Y616C; 604581.0010). Both parents, who were heterozygous carriers of the mutation, were without neurologic complaints and had normal neurologic and ophthalmologic exams, although the mother had mild cerebellar atrophy on brain imaging. In vitro functional expression studies in yeast showed that Y616C was a hypomorphic allele, resulting in decreased activity of the homooligomeric enzyme, but not in complete inhibition. The Y616C mutant protein also showed impaired ability to assemble with itself or with paraplegin (SPG7; 602783) in protease complexes, resulting in low levels of functionally active protease complexes and a functional paraplegin defect. The report expanded the phenotype associated with AFG3L2 mutations and was reminiscent of a combined SCA28/SPG7 (607259) phenotype with some features of a mitochondrial disorder.

In 2 unrelated Italian patients with a variant of SPAX5 presenting as severe progressive myoclonus and ataxia, Muona et al. (2015) identified a homozygous missense mutation in the AFG3L2 gene (M625I; 604581.0011). Functional studies of the variant were not performed. The patients were ascertained from a cohort of 84 individuals with progressive myoclonic epilepsy who underwent exome sequencing.