- Tools
- Downloads
- Links
- Community
- About
- Help
FB2026_01
,
released March 12, 2026
This report describes spastic paraplegia 35 (SPG35), more descriptively known as spastic paraplegia 35, autosomal recessive, with or without neurodegeneration. The human gene implicated in SPG35 is FA2H, which encodes an enzyme involved in sphingolipid metabolism. There is a single Drosophila ortholog, Dmel\Fa2h, for which multiple genetic reagents have been generated including loss-of-function alleles caused any insertional mutagenesis, RNAi-targeting constructs, and an over-expression construct.
The human Hsap\FA2H gene has been introduced into flies. Heterologous rescue (functional complementation) has been demonstrated for loss-of-function phenotypes of Dmel\Fa2h.
Animals homozygous for loss-of-function mutations (or compound heterozygotes for loss-of-function mutations) of Dmel\Fa2h exhibit reduced lifespan and motor impairments, analogous to phenotypes observed for SPG35. Cellular phenotypes including mitochondrial changes and altered autophagy have been characterized in the fly system and subsequently in patient-derived fibroblasts.
[updated Mar. 2023 by FlyBase; FBrf0222196]
The hereditary spastic paraplegias (SPG, HSP) are a large group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'). [from MIM:182600; 15.06.29]
[SPASTIC PARAPLEGIA 35, AUTOSOMAL RECESSIVE, WITH OR WITHOUT NEURODEGENERATION; SPG35](https://omim.org/entry/612319)
[FATTY ACID 2-HYDROXYLASE; FA2H](https://omim.org/entry/611026)
Autosomal recessive spastic paraplegia-35 is a complicated form of SPG characterized by childhood onset of gait difficulties due to progressive spastic paraparesis, dysarthria, and mild cognitive decline associated with leukodystrophy on brain imaging. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur (summary by Dick et al., 2010; pubmed:20104589). In addition, some patients with mutations in the FA2H gene have radiographic evidence of neurodegeneration with brain iron accumulation (NBIA), thus expanding the phenotype. [from MIM:612319; 2023.03.14]
spastic paraplegia 35, autosomal recessive, with or without neurodegeneration is caused by homozygous mutation in the gene encoding fatty acid 2-hydroxylase (FA2H). [from MIM:612319; 2023.03.14]
FA2H encodes an enzyme involved in sphingolipid metabolism; it catalyzes the hydroxylation of free fatty acids at the C-2 position to produce 2-hydroxy fatty acids, which are building blocks of sphingolipids and glycosphingolipids common in neural tissue and epidermis. [Gene Cards, FA2H; 2023.03.14]
One to one: 1 human gene to 1 Drosophila gene.
High-scoring ortholog of human FA2H (1
Drosophila to 1 human).