FA2H – Hereditary Spastic Paraplegia Type 35

Hereditary Spastic Paraplegia type 35 (SPG35) is an autosomal recessive neurodegenerative disorder caused by biallelic mutations in the FA2H gene, which encodes fatty acid 2-hydroxylase critical for myelin lipid synthesis. Clinically, SPG35 presents with early-onset progressive spastic paraparesis, dysarthria, and characteristic leukodystrophy on brain MRI, often accompanied by urinary urgency and intellectual disability.

Genetic studies have identified multiple unrelated families with bi-allelic FA2H variants. In a Chinese non‐consanguineous pedigree, two siblings harbored triple heterozygous missense variants (n=2 probands) (PMID:23566484). A Turkish patient carried a novel homozygous frameshift c.160_169dup (p.Asp57GlyfsTer48) (n=1) (PMID:29376581). In a Malian consanguineous family, four siblings exhibited a homozygous splice-donor mutation c.786+1G>A (n=4) (PMID:31087769). A Czech case revealed a homozygous missense p.Pro44Ser (n=1) (PMID:30446360). Overall, at least 8 probands across 4 unrelated families support autosomal recessive inheritance.

The FA2H variant spectrum in SPG35 includes missense changes (p.Glu230Lys, p.Gly326Ser, p.Pro323Gln, p.Pro44Ser) and loss-of-function alleles such as c.160_169dup (p.Asp57GlyfsTer48) and splice-site c.786+1G>A. The recurrence of c.786+1G>A in distinct ethnic groups suggests a potential founder effect (PMID:31087769).

Functional assays demonstrate that patient-derived FA2H mutants p.Leu77Arg and p.Leu130Phe have markedly reduced enzymatic activity, confirming a loss-of-function mechanism (PMID:24359114). FA2H‐deficient mouse models exhibit central demyelination and axon loss paralleling human SPG35 pathology, further validating the disease mechanism (PMID:31135052).

Heterozygous FA2H variants have been reported in autism spectrum disorder cohorts, but in vitro assays showed no significant effect on enzymatic activity, and no firm association with disease was established, indicating that biallelic loss-of-function is required for SPG35 manifestation (PMID:24299421).

Taken together, robust genetic and functional evidence supports a strong association between biallelic FA2H mutations and autosomal recessive SPG35. Genetic testing of FA2H should be considered in patients with early-onset spastic paraplegia and leukodystrophy to confirm diagnosis, inform prognosis, and guide genetic counseling.

References

• Journal of the neurological sciences | 2013 | A rare family with Hereditary Spastic Paraplegia Type 35 due to novel FA2H mutations: a case report with literature review. PMID:23566484
• The Turkish journal of pediatrics | 2017 | Hereditary spastic paraplegia type 35 caused by a novel FA2H mutation. PMID:29376581
• American journal of medical genetics. Part A | 2019 | Hereditary spastic paraplegia type 35 in a family from Mali. PMID:31087769
• Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2019 | Autosomal recessive hereditary spastic paraplegia type SPG35 due to a novel variant in the FA2H gene in a Czech patient. PMID:30446360
• Clinical Genetics | 2015 | SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations. PMID:24359114
• Brain : a journal of neurology | 2019 | FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. PMID:31135052
• BMC medical genetics | 2013 | Heterozygous FA2H mutations in autism spectrum disorders. PMID:24299421

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