Objective: We reported three cases of SPG35 caused by compound heterozygous mutations in the FA2H gene, with ataxia as the initial clinical manifestation. Among the identified mutations, four are novel.

Background: SPG35 is caused by biallelic pathogenic variants in the FA2H, which encodes fatty acid 2-hydroxylase (FA2H). To date, genetically confirmed cases are relatively rare in the Chinese population.

Method: Probands and parents were neurologically assessed; blood DNA was sequenced (WGS, Sanger) identifying FA2H mutations, functionally assessed via cell assays (immunofluorescence, Western blot, co-IP).

Results: Patient A (FA2H c.129C>G/p.H43Q; c.794T>G/p.F265C) showed slurred speech, gait instability, dysmetria, hyperreflexia, Babinski signs, and cerebellar atrophy on MRI. Asymptomatic parents confirmed compound heterozygosity. Patient B (c.1006C>A/p.H336N; c.620C>T/p.T207M) had gait issues, tremor, bradykinesia, gaze palsy, falls, poor levodopa response; MRI showed hummingbird sign and atrophy. Patient C (c.1091C>G/p.P364R; c.488G>A/p.G163D) exhibited gait instability, hyperreflexia, Babinski signs, clonus, and cerebellar/brainstem atrophy. Four of six missense variants (p.H43Q, p.G163D, p.P364R, p.H336N) are novel. ACMG pathogenicity predictions are in Table 1. Functional studies showed normal localization; p.H43Q increased expression, while others reduced it.

Conclusion: We reported three cases of SPG35 caused by compound heterozygous mutations in the FA2H. Four FA2H mutations (p.H43Q, p. G163D, p.P364R and p.H336N) are reported globally for the first time, expanding the mutation spectrum of the FA2H and enhancing our understanding of the genotype-phenotype relationship.

Pathogenicity predictions and ACMG classifications

MRI and Genetics

Functional study

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-novel-fa2h-mutations-in-patients-with-hereditary-spastic-paraplegia-type-35-spg35/