Sphingolipids are a type of lipids that play diverse roles in cellular processes. Several different types of sphingolipids exist, with differing functions. The major difference between these different types of sphingolipids is due to modifications in their cerebroside moiety. The FA2H (Fatty Acid 2 Hydroxylase) protein is an enzyme that catalyzes one such modification (2-hydroxylation of the N-acyl chain in sphingolipids), thereby forming 2-hydroxysphingolipids. These 2-hydroxysphingolipids serve several functions, mostly in the brain.
Mutations in the FA2H gene have been found to cause leukodystrophy dysmyelinating with spastic paraparesis with or without dystonia (DLDSP). The disorder is characterized by progressive neurologic disease manifested by spasticity, disordered tonicity of muscle, and white matter degeneration. In addition, recently, mutations in the same gene have been found to be the cause of an autosomal recessive form of spastic paraplegia associated with a progressive course and features of leukodystrophy (SPG35).
The FA2H gene is approximately 62Kb in length, and is situated on the long arm of chromosome 16. The protein itself is a multi pass microsomal membrane protein that weighs about 43 kDa and consists of 372 amino acids. Structurally the protein contains an N-terminal cytochrome b5 domain, four potential transmembrane domains, and an iron-binding histidine motif that is conserved among membrane bound desaturases and hydroxylases. This protein is expressed in several tissues including keratinocytes. However, the major tissues of expression are the brain and colon.
Dick et al. (2010) studied a large consanguineous Omani family with an autosomal recessive form of HSP (SPG35). The disease had a progressive course in this family, and was associated with intellectual disability, and radiological features of leukodystrophy. In addition, two affected individuals also had seizures. Homozygous mutations in the FA2H gene (p.Arg235Cys) were detected in the affected patients. In the affected patients, there was a significantly reduced function of the F2H enzyme.