SCA34

Spinocerebellar ataxia 34 is an autosomal dominant disorder characterized by slowly progressive cerebellar ataxia that typically begins in young adulthood. Most patients are able to walk into old age. SCA34 is specifically associated with erythrokeratodermia figurata variabilis.

This is caused by mutations in the ELOVL4 gene. The enzyme elongase-4 (ELOVL4) encoded by this gene mediates the biosynthesis of both very long-chain (VLC) unsaturated fatty acids (PUFAs) and very long-chain (VLC) saturated fatty acids (VLC-SFAs). VLC-PUFAs play a critical role in retinal and sperm function, while VLC-SFAs are primarily associated with brain function and maintenance of the skin permeability barrier. While some ELOVL4 mutations cause autosomal dominant Stargardt-like macular dystrophy (STGD3), other ELOVL4 point mutations affect the brain and/or skin, leading to spinocerebellar ataxia-34 (SCA34) and erythrokeratodermia figurata variabilis. The mechanisms by which these ELOVL4 mutations alter VLC-PUFA and VLC-SFA biosynthesis to cause the various tissue-specific pathologies remain to be elucidated.

Very long-chain fatty acids (VLCFAs), which consist of more than 20 carbon atoms, are essential for the biosynthesis of cell membranes in the brain, skin and retina. VLCFAs are extended to over 28 carbon atoms by the enzyme ELOVL4.

Variants in ELOVL4 are associated with three Mendelian disorders:

• Autosomal dominant (AD) Stargardt-like macular dystrophy type 3
• Autosomal dominant spinocerebellar ataxia
• The autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR).

In some cases, erythema and hyperkeratosis may also occur in childhood, together with additional neurological signs such as eye movement disorders and pyramidal tract signs. This disorder belongs to the group of spinocerebellar ataxia, which is associated with progressive coordination problems due to cerebellar degeneration.

1. Alabdulrazzaq F et al. (2023) Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis. Mol Genet Genomic Med 11:e2256.
2. Coarelli G, Coutelier M, Durr A. Autosomal dominant cerebellar ataxias: new genes and progress towards treatments. Lancet Neurol. 2023 Aug;22(8):735-749.
3. Gyening YK et al. (2023) ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis. J Lipid Res 64:100317.