Spinocerebellar Ataxia 34

A number sign (#) is used with this entry because of evidence that spinocerebellar ataxia-34 (SCA34) is caused by heterozygous mutation in the ELOVL4 gene (605512) on chromosome 6q14.

Description

Spinocerebellar ataxia-34 is an autosomal dominant disorder characterized by slowly progressive cerebellar ataxia. The age at onset is usually during the young adult years, and most patients remain ambulatory until late in life. One family with SCA34 also had onset of erythema and hyperkeratosis in early childhood (Cadieux-Dion et al., 2014), whereas other families have additional neurologic signs, including ocular movement disturbances and pyramidal tract signs (Ozaki et al., 2015).

For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Clinical Features

Giroux and Barbeau (1972) reported an apparently distinct neurocutaneous syndrome in 25 persons spanning 5 generations of a French Canadian kindred. The syndrome was characterized by the appearance, soon after birth, of papulosquamous erythematous ichthyosiform plaques, which tended to subside during the summer. The lesions resembled those typically observed in erythrokeratodermia variabilis (EKVP; 133200), and tended to be on the extremities. The skin lesions almost completely disappeared by age 25 in most patients, sometimes to reappear after the age of 40. At the latter age, a slowly progressive neurologic syndrome with decreased tendon reflexes, nystagmus, dysarthria, and severe ataxia of gait became the predominant feature. Many patients became wheelchair-bound late in life. Cognition and sensation were not affected.

In a follow-up of the family reported by Giroux and Barbeau (1972), Turcotte Gauthier (2010) noted that the neurologic manifestations were consistent with a pure form of autosomal dominant spinocerebellar ataxia. Because the skin lesions were those typically observed in EKVP, the author searched for mutations in the GJB3 (603324) and GJB4 (605425) genes but found none. Cadieux-Dion et al. (2014) noted that affected individuals in the SCA34 family reported by Giroux and Barbeau (1972) did not have macular degeneration and had normal blood levels of long chain fatty acids. Brain imaging showed cerebellar and pontine atrophy.

Ozaki et al. (2015) reported 2 unrelated Japanese families with SCA34 not associated with skin abnormalities. There were 11 affected individuals, but only 9 patients were still alive and able to be examined. The mean age at onset was 33.9 years (range 13 to 56), and the patients presented with slowly progressive ataxia; however, most patients did not need to use a cane or walker until after age 60 years. All patients had truncal and limb ataxia and dysarthria. Additional common features included horizontal gaze nystagmus (78%) and pyramidal tract signs, such as extensor plantar responses (89%). Less common signs included supranuclear ophthalmoplegia (33%), mildly impaired smooth pursuit (56%), and autonomic symptoms, such as bladder disturbance (44%) and constipation (22%), although none had obvious orthostatic hypotension. None had dermatologic features of EKVP. Brain imaging showed cerebellar and pontine atrophy. In addition, 4 patients had cruciform hyperintensities ('hot cross bun sign'), and 2 other patients had pontine midline linear hyperintensity, both of which often appear in patients with multiple system atrophy.

Inheritance

The transmission pattern of SCA34 in the family reported by Giroux and Barbeau (1972) was consistent with autosomal dominant inheritance and incomplete penetrance.

Mapping

By genomewide linkage analysis of the family reported by Giroux and Barbeau (1972), Turcotte Gauthier (2010) identified a disease locus, termed spinocerebellar ataxia-34 (SCA34), on chromosome 6p12.3-q16.2. Three additional families of European origin with unexplained SCA also showed linkage to this region.

Molecular Genetics

In affected members of a large French Canadian family with spinocerebellar ataxia-34, originally reported by Giroux and Barbeau (1972), Cadieux-Dion et al. (2014) identified a heterozygous missense mutation in the ELOVL4 gene (L168F; 605512.0007). The mutation was found by a combination of linkage analysis and whole-exome sequencing. Four unaffected family members also carried the mutation, indicating incomplete penetrance. Functional studies of the variant were not performed. Screening of 95 additional patients with SCA did not identify any other ELOVL4 mutations.

In affected members of 2 unrelated Japanese families with SCA34 without skin lesions, Ozaki et al. (2015) identified a heterozygous missense mutation in the ELOVL4 gene (W246G; 605512.0008). The mutation, which was found by a combination of linkage analysis and exome sequencing in 1 family, and confirmed by Sanger sequencing in both families, segregated with the disorder in both families. Haplotype analysis indicated that the families were unlikely to share a common ancestor. Functional studies of the variant were not performed. VLCFA up to C22 in length were normal in 2 patients studied; VLCFA with C28 or longer chains were not analyzed.