FA2H – Fatty Acid Hydroxylase-Associated Neurodegeneration

Fatty acid 2-hydroxylase (FA2H) catalyzes the alpha-hydroxylation of long-chain fatty acids in sphingolipids, critical for myelin integrity. Biallelic pathogenic variants in FA2H cause fatty acid hydroxylase-associated neurodegeneration (FAHN, MONDO:0017999), a spectrum encompassing hereditary spastic paraplegia (SPG35), leukodystrophy, and brain iron accumulation ([PMID:31135052]).

Autosomal recessive inheritance of FAHN is supported by compound heterozygous and homozygous FA2H mutations in over 26 unrelated probands from at least eight families, with consistent segregation and absence of heterozygotes in affected individuals ([PMID:31837835]; [PMID:38275596]).

Case series have identified novel FA2H alleles, including c.75C>G (p.Cys25Trp) in a homozygous state in an 18-year-old male presenting with childhood-onset spastic gait disturbance, dystonia, ataxia, and cognitive impairment, supported by in silico loss-of-function modeling ([PMID:38275596]). Compound heterozygous missense variants c.445G>T (p.Val149Leu) and c.780C>G (p.His260Gln) exhibited residual enzyme activities correlating with a milder phenotype ([PMID:31837835]).

In a systematic cohort of 19 FAHN/SPG35 patients, common features included early childhood lower-limb spastic tetraparesis, truncal instability, dysarthria, dysphagia, cerebellar ataxia, cognitive deficits, and often exotropia. Imaging biomarkers (‘WHAT’ acronym: white matter changes, globus pallidus hypointensity, ponto-cerebellar atrophy, thin corpus callosum) were present in ≥85% of carriers ([PMID:31135052]).

Functional studies demonstrate that FA2H variants severely impair 2-hydroxylase activity in cell-based assays, with residual activity levels of ~0–80%. A Drosophila FAHN model recapitulated motor impairment, reduced lifespan, mitochondrial and autophagy defects, and was rescued by human FA2H expression, confirming pathogenicity via loss of function ([PMID:36589738]).

No robust evidence disputes the FA2H–FAHN association, though heterozygous mutations appear insufficient to cause FAHN. Rare heterozygous variants were explored in autism without clear enzymatic impact ([PMID:24299421]).

Collectively, genetic and experimental data fulfill a strong ClinGen gene–disease validity framework. FA2H sequencing is recommended for early-onset spastic paraplegia and leukodystrophy phenotypes, guiding diagnosis, prognosis, and future therapeutic targeting of sphingolipid metabolism.

Key Take-home: Biallelic FA2H loss-of-function variants cause FAHN/SPG35 via autosomal recessive inheritance, presenting with progressive spasticity, ataxia, and characteristic imaging, with confirmatory functional assays enabling precise genetic diagnosis.

References

• Brain : a journal of neurology • 2019 • FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. PMID:31135052
• Brain & development • 2020 • Novel biallelic FA2H mutations in a Japanese boy with fatty acid hydroxylase-associated neurodegeneration. PMID:31837835
• Genes • 2023 • Novel Homozygous FA2H Variant Causing the Full Spectrum of Fatty Acid Hydroxylase-Associated Neurodegeneration (SPG35). PMID:38275596
• Frontiers in cell and developmental biology • 2022 • A new model for fatty acid hydroxylase-associated neurodegeneration reveals mitochondrial and autophagy abnormalities. PMID:36589738

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