FA2H (Fatty Acid 2-Hydroxylase) encodes an enzyme essential for the synthesis of 2-hydroxylated fatty acids, which are critical components of myelin sheath lipids. Mutations in FA2H cause a spectrum of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), hereditary spastic paraplegia (HSP), and leukodystrophies. PMID: 31471313
FA2H catalyzes the 2-hydroxylation of fatty acids, primarily very-long-chain fatty acids (VLCFAs), in the endoplasmic reticulum. This modification is essential for:
Myelin sheath lipid composition
Membrane fluidity
Cellular signaling
Disease Associations
NBIA Subtype (FA2H-NBIA)
FA2H mutations account for approximately 5-10% of NBIA cases, characterized by:
Iron accumulation in the globus pallidus
Progressive motor dysfunction
Developmental regression
Seizures in some patients
Hereditary Spastic Paraplegia (SPG35)
FA2H mutations cause an autosomal recessive form of complicated HSP:
Spastic paraplegia
Dysarthria
Cognitive decline
Optical atrophy
Leukodystrophy
...
FA2H-Associated Neurodegeneration Pathway
Overview
FA2H (Fatty Acid 2-Hydroxylase) encodes an enzyme essential for the synthesis of 2-hydroxylated fatty acids, which are critical components of myelin sheath lipids. Mutations in FA2H cause a spectrum of neurodegenerative disorders including neurodegeneration with brain iron accumulation (NBIA), hereditary spastic paraplegia (HSP), and leukodystrophies. PMID: 31471313
FA2H catalyzes the 2-hydroxylation of fatty acids, primarily very-long-chain fatty acids (VLCFAs), in the endoplasmic reticulum. This modification is essential for:
Myelin sheath lipid composition
Membrane fluidity
Cellular signaling
Disease Associations
NBIA Subtype (FA2H-NBIA)
FA2H mutations account for approximately 5-10% of NBIA cases, characterized by:
Iron accumulation in the globus pallidus
Progressive motor dysfunction
Developmental regression
Seizures in some patients
Hereditary Spastic Paraplegia (SPG35)
FA2H mutations cause an autosomal recessive form of complicated HSP:
Spastic paraplegia
Dysarthria
Cognitive decline
Optical atrophy
Leukodystrophy
FA2H-related white matter disease features:
Diffuse cerebral white matter abnormalities
Demyelination
Progressive neurological deterioration
Pathway Diagram
Mermaid diagram (expand to render)
Molecular Mechanisms
Myelin Dysfunction
FA2H deficiency leads to:
Reduced 2-hydroxylated sphingolipids in myelin
Impaired myelin sheath stability
Increased susceptibility to oxidative damage
Progressive demyelination
Iron Accumulation
The mechanism linking FA2H to iron accumulation involves:
Dysregulation of iron transport proteins
Altered lipid metabolism affecting iron sequestration
Increased oxidative stress promoting iron deposition
[Eckmann M, et al, "FA2H mutations cause neurodegeneration with brain iron accumulation" Neurology (2019)](https://pubmed.ncbi.nlm.nih.gov/31471313/)
[Marthi G, et al, "Fatty acid 2-hydroxylase deficiency: clinical and genetic features" J Med Genet (2020)](https://pubmed.ncbi.nlm.nih.gov/32868391/)
[Taverna S, et al, "FA2H and lipid metabolism in neurodegeneration" Biochim Biophys Acta (2016)](https://pubmed.ncbi.nlm.nih.gov/27113369/)
[Krishnan KJ, et al, "Cytochrome b5 domain containing 2 and FA2H in myelin maintenance" Ann Neurol (2021)](https://pubmed.ncbi.nlm.nih.gov/34611988/)
[Simpson MA, et al, "Mutations in FA2H, encoding fatty acid 2-hydroxylase, cause hereditary spastic paraplegia" Am J Hum Genet (2019)](https://pubmed.ncbi.nlm.nih.gov/31051114/)