A family study and literature review of ELOVL4-associated spinocerebellar ataxia type 34

Autosomal dominant disease-causing variants in the ELOVL4 gene (Elongation of Very Long Chain Fatty Acids-like 4) cause spinocerebellar ataxia type 34 (SCA34; ATX-ELOVL4), classically associated with a skin condition known as erythrokeratoderma. Here, we report a large Italian-Australian family with spinocerebellar ataxia. Notably, while there were dermatological manifestations (eczema), erythrokeratoderma was not present. Using a next generation sequencing panel, we identified a previously reported ELOVL4 variant, NM_022726.4: c.698C>T (p.Thr233Met). The variant was initially classified as a variant of uncertain significance, however, through segregation studies, we reclassified the variant as likely pathogenic. We subsequently performed the first dedicated literature review of ELOVL4 variants causing ataxia to gain further insights into genotype-phenotype relationships. We identified a total 59 reported cases of SCA34 to date. The majority had gait ataxia (88.1%), limb ataxia (76.3%), dysarthria (62.7%), and nystagmus (57.6%). Of note, skin lesions related to erythrokeratoderma were seen in a minority of cases (33.9%). Other extracerebellar manifestations included pyramidal tract signs, autonomic disturbances, retinitis pigmentosa and cognitive impairment. For brain MRI data, cerebellar atrophy was seen in all cases (100%), whereas the hot cross bun sign (typically associated with multiple-system atrophy type C) was seen in 30.3% of cases. Our family study and literature review highlight the variable phenotypic spectrum of SCA34. Importantly, it shows that erythrokeratoderma is not found in most cases and that, while a dermatological assessment may be helpful in these patients, SCA34 diagnosis should be considered irrespective of dermatological manifestations.