Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a progressive disorder of the nervous system (neurodegeneration) characterized by problems with movement and vision that begin during childhood or adolescence.

Changes in the way a person walks (gait) and frequent falls are usually the first noticeable signs of FAHN. Affected individuals gradually develop extreme muscle stiffness (spasticity) and exaggerated reflexes. They typically have involuntary muscle cramping (dystonia), problems with coordination and balance (ataxia), or both. The movement problems worsen over time, and some people with this condition eventually require wheelchair assistance.

People with FAHN often develop vision problems, which occur due to deterioration (atrophy) of the nerves that carry information from the eyes to the brain (the optic nerves) and difficulties with the muscles that control eye movement. Affected individuals may have a loss of sharp vision (reduced visual acuity), decreased field of vision, impaired color perception, eyes that do not look in the same direction (strabismus), rapid involuntary eye movements (nystagmus), or difficulty moving the eyes intentionally (supranuclear gaze palsy).

Speech impairment (dysarthria) also occurs in FAHN, and severely affected individuals may lose the ability to speak. People with this disorder may also have difficulty chewing or swallowing (dysphagia). In severe cases, they may develop malnutrition and require a feeding tube. The swallowing difficulties can lead to a bacterial lung infection called aspiration pneumonia, which can be life-threatening. As the disorder progresses, some affected individuals experience seizures and a decline in intellectual function.

Magnetic resonance imaging (MRI) of the brain in people with FAHN shows signs of iron accumulation, especially in an area of the brain called the globus pallidus, which is involved in regulating movement. Similar patterns of iron accumulation are seen in certain other neurological disorders such as infantile neuroaxonal dystrophy and pantothenate kinase-associated neurodegeneration. All these conditions belong to a class of disorders called neurodegeneration with brain iron accumulation (NBIA).

FAHN is a rare disorder; only a few dozen cases have been reported.

Mutations in the FA2H gene cause FAHN. The FA2H gene provides instructions for making an enzyme called fatty acid 2-hydroxylase. This enzyme modifies fatty acids, which are building blocks used to make fats (lipids). Specifically, fatty acid 2-hydroxylase adds a single oxygen atom to a hydrogen atom at a particular point on a fatty acid to create a 2-hydroxylated fatty acid. Certain 2-hydroxylated fatty acids are important in forming normal myelin; myelin is the protective covering that insulates nerves and ensures the rapid transmission of nerve impulses. The part of the brain and spinal cord that contains myelin is called white matter.

The FA2H gene mutations that cause FAHN reduce or eliminate the function of the fatty acid 2-hydroxylase enzyme. Reduction of this enzyme's function may result in abnormal myelin that is prone to deterioration (demyelination), leading to a loss of white matter (leukodystrophy). Leukodystrophy is likely involved in the development of the movement problems and other neurological abnormalities that occur in FAHN. Iron accumulation in the brain is probably also involved, although it is unclear how FA2H gene mutations lead to the buildup of iron.

People with FA2H gene mutations and some of the movement problems seen in FAHN were once classified as having a separate disorder called spastic paraplegia 35. People with mutations in this gene resulting in intellectual decline and optic nerve atrophy were said to have a disorder called FA2H-related leukodystrophy. However, these conditions are now generally considered to be forms of FAHN.

Genetic Testing Information

• Genetic Testing Registry: Hereditary spastic paraplegia 35

Genetic and Rare Diseases Information Center

• Fatty acid hydroxylase-associated neurodegeneration

Patient Support and Advocacy Resources

• National Organization for Rare Disorders (NORD)

Clinical Trials

• ClinicalTrials.gov

Catalog of Genes and Diseases from OMIM

• SPASTIC PARAPLEGIA 35, AUTOSOMAL RECESSIVE, WITH OR WITHOUT NEURODEGENERATION; SPG35

Scientific Articles on PubMed

• PubMed

• Arber CE, Li A, Houlden H, Wray S. Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories. Neuropathol Appl Neurobiol. 2016 Apr;42(3):220-41. doi: 10.1111/nan.12242. Epub 2015 Jun 2. Citation on PubMed or Free article on PubMed Central
• Dick KJ, Eckhardt M, Paisan-Ruiz C, Alshehhi AA, Proukakis C, Sibtain NA, Maier H, Sharifi R, Patton MA, Bashir W, Koul R, Raeburn S, Gieselmann V, Houlden H, Crosby AH. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia (SPG35). Hum Mutat. 2010 Apr;31(4):E1251-60. doi: 10.1002/humu.21205. Citation on PubMed
• Edvardson S, Hama H, Shaag A, Gomori JM, Berger I, Soffer D, Korman SH, Taustein I, Saada A, Elpeleg O. Mutations in the fatty acid 2-hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am J Hum Genet. 2008 Nov;83(5):643-8. doi: 10.1016/j.ajhg.2008.10.010. Citation on PubMed or Free article on PubMed Central
• Gregory A, Hayflick SJ. Genetics of neurodegeneration with brain iron accumulation. Curr Neurol Neurosci Rep. 2011 Jun;11(3):254-61. doi: 10.1007/s11910-011-0181-3. Citation on PubMed
• Gregory A, Venkateswaran S, Hayflick SJ. Fatty Acid Hydroxylase-Associated Neurodegeneration. 2011 Jun 28 [updated 2018 Sep 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK56080/ Citation on PubMed
• Hayflick SJ, Kurian MA, Hogarth P. Neurodegeneration with brain iron accumulation. Handb Clin Neurol. 2018;147:293-305. doi: 10.1016/B978-0-444-63233-3.00019-1. Citation on PubMed
• Kruer MC, Paisan-Ruiz C, Boddaert N, Yoon MY, Hama H, Gregory A, Malandrini A, Woltjer RL, Munnich A, Gobin S, Polster BJ, Palmeri S, Edvardson S, Hardy J, Houlden H, Hayflick SJ. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol. 2010 Nov;68(5):611-8. doi: 10.1002/ana.22122. Citation on PubMed
• Schipper HM. Neurodegeneration with brain iron accumulation - clinical syndromes and neuroimaging. Biochim Biophys Acta. 2012 Mar;1822(3):350-60. doi: 10.1016/j.bbadis.2011.06.016. Epub 2011 Jul 13. Citation on PubMed
• Schneider SA, Bhatia KP. Excess iron harms the brain: the syndromes of neurodegeneration with brain iron accumulation (NBIA). J Neural Transm (Vienna). 2013 Apr;120(4):695-703. doi: 10.1007/s00702-012-0922-8. Epub 2012 Dec 2. Citation on PubMed
• Schneider SA, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation. Semin Pediatr Neurol. 2012 Jun;19(2):57-66. doi: 10.1016/j.spen.2012.03.005. Citation on PubMed
• Schneider SA, Bhatia KP. Three faces of the same gene: FA2H links neurodegeneration with brain iron accumulation, leukodystrophies, and hereditary spastic paraplegias. Ann Neurol. 2010 Nov;68(5):575-7. doi: 10.1002/ana.22211. No abstract available. Citation on PubMed