Clinical, Radiological, and Genetic Profile of Patients with FA2H-Associated Neurodegeneration: Eight Cases from India and a Review of the Literature

TL;DR

This study reports on eight Indian patients with a rare neurodegenerative disorder caused by mutations in the FA2H gene, detailing their clinical, radiological, and genetic features.

Contribution

The study identifies novel FA2H gene variants and their potential roles in iron binding and loss of protein domains in FAHN patients.

Findings

Eight patients with FAHN presented with early-onset neurological symptoms and characteristic brain imaging findings.

Seven unique FA2H gene variants were identified, including missense, frameshift, and in-frame deletion/duplication mutations.

Some variants affect iron-binding regions or lead to loss of critical protein domains, potentially disrupting FA2H function.

Abstract

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.

To report the clinical, electrophysiological, radiological, and genetic profile of patients diagnosed with FAHN.

We performed a retrospective chart review of genetically proven cases of FAHN from our database.

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.

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.

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