Abstract
Background: Autosomal recessive spastic paraplegia 35 (SPG35), also known as Fatty acid hydroxylase-associated neurodegeneration (FAHN), is a rare recessive neurodegenerative disorder with or without ataxia, dystonia, and other neurological findings. It is caused by genetic variants in FA2H, which encodes fatty acid 2-hydroxylase.
Objective: To report the clinical, electrophysiological, radiological, and genetic profile of patients diagnosed with FAHN.
Methods: We performed a retrospective chart review of genetically proven cases of FAHN from our database.
Results: We identified eight patients (6 females) with genetically proven FAHN. All patients presented with first-decade onset pyramidal syndrome with or without ataxia and with radiological findings of callosal atrophy, peri-ventricular white matter hyperintensity, and cerebellar atrophy. Iron accumulation was observed in four of them. Whole exome sequencing revealed seven unique variants including three missense variants (c.83G>C;p.Arg28Pro, c.130C>A;p.Pro44Thr, and c.703C>T;p.Arg235Cys), a stop-gain variant (c.379C>T;p.Arg127Ter), a frameshift deletion variant (c.536delT;p.Leu179Argfs*62), a in-frame deletion variant (c.200_202del;p.His67del) and a in-frame duplication variant (c.86_97dup;p.Arg29_Arg32dup). The variants p.Pro44Thr, p.Arg28Pro, p.Arg29_Arg32dup, and p.His67del are located in the iron-binding region, and the p.Arg235Cys in the hydroxylase domain. The other two variants, p.Arg127Ter and p.Leu179Argfs*62, predictively cause protein truncation, leading to loss of the transmembrane domain and the fatty acid hydroxylase domain, which in turn may result in disruption of fatty acid alpha-hydroxylase activity of FA2H.
Conclusion: Our study identifies novel variants associated with FA2H in FAHN patients, highlighting their possible roles in iron binding and in the loss of the transmembrane and catalytic domains.