SPG35 contributes to the second common subtype of AR‐HSP in China: frequency analysis and functional characterization of FA2H gene mutations

Abstract

Hereditary spastic paraplegias (HSPs) encompass a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, mutations in fatty acid 2-hydroxylase gene (FA2H) have been identified responsible for HSPs type 35 (SPG35). This study aims to define the contribution of FA2H to Chinese autosomal recessive HSP (AR-HSP) patients and provide insights into the enzymatic functions of the novel mutations. Direct sequencing of FA2H was conducted in 31 AR-HSP families and 55 sporadic cases without SPG11, SPG15, SPG5 and SPG7 gene mutations. Enzymatic activity of the mutated proteins was further examined. Three novel mutations were found in two Chinese families, including two compound heterozygous mutations (c.388C>T/p.L130F and c.506+6C>G) and one homozygous mutation (c.230T>G/p.L77R). The c.506+6C>G splice-site mutation led to the deletion of exon 3. Measurement of enzymatic functions revealed a significant reduction in the enzymatic activity of FA2H associated with p.L130F and p.L77R. Overall, our data widens the spectrum of the mutations on FA2H, and functional analyses indicate that these mutations severely impair the enzymatic activity of FA2H. Furthermore, frequency analysis shows that SPG35 is the second most common subtype of AR-HSP in China.

Update in Neurodegeneration with Brain Iron Accumulation: Advances in Molecular Diagnosis and Treatment Strategies

“…FAHN is a rare form of NBIA with few reported cases in the literature. [22][23][24][25][26][27] FAHN may present with a pyramidal motor phenotype, 23 typically with gait disturbance and frequent falls during the first or the second decade of life, and usually following previous normal development. While pyramidal signs dominate the clinical picture at onset, extrapyramidal findings and other neurologic features often manifest after initial presentation, including ataxia, dystonia, and dysphagia.…”

Hereditary spastic paraplegia type 35 with a novel mutation in fatty acid 2-hydroxylase gene and literature review of the clinical features

“…In the literature, a few cases have been reported with HSP type 35. [ 3 4 5 6 ] Here, we report HSP type 35 case of Turkish origin with a novel homozygous mutation in FA2H gene, presented with progressive gait disturbance and cognitive impairment.…”

“…[ 2 ] AR HSPs are more frequent in consanguineous populations with a prevalence of 0.6/100,000 in Norway and up to 5.75/100,000 in Tunisia. [ 2 3 ] HSP type 35 is an AR form of HSPs caused by mutations in the fatty acid 2-hydroxylase ( FA2H ) gene at 1'q21-q23 chromosome. [ 2 ]…”

“…Other variable neurologic features, such as dystonia, optic atrophy, and seizures, may also occur. [ 3 4 ]…”

“…In another case, Liao et al . [ 3 ] reported three novel FA2H gene mutations in two unrelated Chinese families with SPG35. Bektaş et al .…”