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Fatty Acid Hydroxylase-Associated Neurodegeneration

, MD, , MS, and , MD.

Author Information

Initial Posting: ; Last Revision: September 20, 2012.


Clinical characteristics.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), eye findings (optic atrophy, oculomotor abnormalities) early in the disease course, and progressive intellectual impairment and seizures later in the disease course. FAHN is considered to be a subtype of neurodegeneration with brain iron accumulation (NBIA). To date, a total of 25 individuals from seven families of diverse ethnicity with FAHN have been described; much is yet to be learned about the clinical manifestations and natural history.


The diagnosis of FAHN may be suspected when characteristic neurologic findings are accompanied by supportive findings on brain MRI. FA2H is the only gene in which pathogenic variants are known to FAHN.


Treatment of manifestations: Symptomatic treatment is aimed primarily at the dystonia, which can be debilitating. Therapies used with varying success include the oral medications baclofen, anticholinergics, tizanidine, and dantrolene; focal injection of botulinum toxin targeting abnormal co-contraction of selected muscle groups; intrathecal baclofen; deep brain stimulation; and ablative pallidotomy or thalamotomy. Independence should be encouraged when possible through use of adaptive aids (e.g., walker or wheelchair for gait abnormalities; augmentative communication devices) and appropriate community resources (e.g., financial services, programs for the visually impaired, and special education).

Prevention of secondary complications: Attention to swallowing and diet to assure adequate nutrition and prevent aspiration; gastrostomy tube placement as needed.

Surveillance: Regular measurement of height and weight in children to assess nutritional status, ophthalmologic examination, and assessment of ambulation and environmental adaptations and swallowing, speech, and communication needs.

Genetic counseling.

FAHN is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If the pathogenic variants have been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

GeneReview Scope

Fatty Acid Hydroxylase-Associated Neurodegeneration: Included Phenotypes
  • Dysmyelinating leukodystrophy and spastic paraparesis with or without dystonia
  • Spastic paraplegia 35 (SPG35)

For synonyms and outdated names see Nomenclature.


Clinical Diagnosis

The diagnosis of fatty acid hydroxylase-associated neurodegeneration (FAHN) may be suspected in individuals with in the first- or second-decade onset of the hallmark features: corticospinal tract involvement, movement disorder, and suggestive neuroimaging findings. See Figure 1.

Figure 1. . Neuroimaging features of FAHN (A) vs PKAN (B) The two forms of NBIA share T2/GRE hypointensity.

Figure 1.

Neuroimaging features of FAHN (A) vs PKAN (B) The two forms of NBIA share T2/GRE hypointensity. Distinguishing features include diffuse cerebral atrophy (seen in FAHN) and central globus pallidus T2 hyperintensity (seen in PKAN), producing the characteristic (more...)

Hallmark Features

Note: Fewer than 30 individuals with FAHN have been reported; the phenotype is likely to expand as more cases are ascertained, and thus the designation of any phenotypic feature as ‘hallmark’ may be premature.

  • Onset within the first or second decade of life
  • Corticospinal tract involvement
    • Spastic paraplegia or quadriplegia
    • Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
  • Movement disorder including one or both of the following:
    • Dystonia
    • Ataxia
  • Dysarthria
  • Dysphagia
  • Brain magnetic resonance imaging (MRI) findings typically including:
    • T2 hypointensity of the globus pallidus (may display blooming on T2*-weighted images). T2 hypointensity coupled with an extrapyramidal movement disorder and intellectual decline is suggestive of a neurodegeneration with brain iron accumulation (NBIA) disorder (see Differential Diagnosis).
    • T2-weighted images may demonstrate variable unilateral or bilateral symmetric white matter hyperintensity. These findings can affect both periventricular and subcortical white matter and may become confluent with time. The U-fibers and cerebellar white matter appear to be affected to a lesser degree.
    • Progressive atrophy of the cerebellar hemispheres, vermis, pons, medulla and spinal cord
    • Thinning of the corpus callosum
      Note: The 'eye of the tiger' sign, pathognomonic for pantothenate kinase-associated neurodegeneration (PKAN), another form of NBIA, is not seen in FAHN.

Corroborative Features

  • Eye findings
    • Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision.
    • Other findings may include strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
  • Family history consistent with autosomal recessive inheritance, including parental consanguinity

Pathologic Diagnosis

Bone marrow biopsy, although not necessary for diagnosis, may demonstrate accumulation of granular histiocytes.

Neuropathologic features for FAHN have not yet been reported.

Molecular Genetic Testing

Gene. FA2H is the only gene in which pathogenic variants are known to cause fatty acid hydroxylase-associated neurodegeneration (FAHN).

Table 1.

Summary of Molecular Genetic Testing Used in Fatty Acid Hydroxylase-Associated Neurodegeneration

Gene 1Test MethodAllelic Variants Detected 2Variant Detection Frequency by Test Method 3
FA2HSequence analysis 4Sequence variants>95% 5
Deletion/duplication analysis 6Exon and whole-gene deletions/duplications 7Unknown

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Performed using primers spanning all seven exons and intron-exon boundaries of FA2H with comparison to reference sequence [Kruer et al 2010]


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Interpretation of test results. When only one pathogenic variant is identified in an individual with clinical and neuroimaging features of FAHN, a diagnosis of ‘suspected FAHN’ is appropriate.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of FAHN may be clinically suspected when the following are present:

  • A mixed movement disorder (ataxia/dystonia) and corticospinal tract findings
  • Corroborative ophthalmologic features: optic atrophy, strabismus, nystagmus, and supranuclear gaze palsy
  • Supportive findings on neuroimaging: T2 hypointensity of the globus pallidus, T2 subcortical white matter hyperintensity, and atrophy of the corpus callosum, brain stem, and cerebellum

On the basis of this constellation of features, molecular genetic testing of FA2H should be considered first using sequence analysis. If no or only one pathogenic variant is identified, deletion/duplication analysis should be considered.

Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.

Clinical Characteristics

Clinical Description

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is considered to represent a subtype of neurodegeneration with brain iron accumulation (NBIA), a class of disorders that also includes pantothenate kinase-associated neurodegeneration (PKAN) and neuroaxonal dystrophy (NAD; see Infantile Neroaxonal Dystrophy).

The signs and symptoms of FAHN are largely confined to the central nervous system and include corticospinal tract involvement, movement disorder, and eye findings. To date, a total of 25 individuals from seven families of diverse ethnicity with FAHN have been described [Dick et al 2008, Edvardson et al 2008, Dick et al 2010, Kruer et al 2010]; therefore, information on the extent of the phenotype and natural history are limited. (See Table 2.)

Table 2.

Clinical Features of FAHN in the 25 Individuals Reported to Date

HeritageAffected PersonsAge at Onset (yrs)SpasticityAtaxiaDystoniaOptic AtrophySeizuresIntellectual Decline
TOTAL25 (22 1)3-1122/229/1513/155/68/2213/20

ND = not determined


Only proband reported

The most frequent presenting finding is a subtle change in gait that may lead to increasingly frequent falls. This typically occurs in childhood or adolescence and may be the result of focal dystonia and/or corticospinal tract involvement.

The degree of spasticity resulting from corticospinal tract involvement may vary among persons with FAHN. Individuals affected to a lesser degree may develop spastic paraparesis but retain the ability to walk, while individuals with more severe disease may demonstrate a spastic quadriplegic pattern of disability and lose their ability to ambulate, instead relying on a wheelchair.

Dystonia may begin focally (e.g., affecting one foot) but typically spreads to assume a generalized pattern. The degree of dystonia seen in FAHN is generally milder than that in other forms of NBIA, such as PKAN, in which status dystonicus occurs.

Ataxia typically begins in childhood or adolescence and may emerge along with dystonia and/or spasticity. The ataxia that occurs in FAHN may affect both axial and appendicular function and, along with both dystonia and spasticity, can markedly impair gait.

Dysarthria may be prominent in FAHN. In some individuals, expressive speech can be impaired to the point of anarthria. Dysphagia, potentially necessitating gastrostomy tube placement, can also occur.

Optic atrophy in FAHN may begin as a subtle loss of visual acuity in childhood, but may progress to the point of functional blindness. The oculomotor abnormalities seen in FAHN may impair functional vision as well.

Seizures are not typically seen in the early stages of disease, but may occur later in the disease course. When present, seizures tend to be complex partial or generalized in nature but are typically infrequent and respond relatively well to anticonvulsants.

Progressive intellectual impairment is reported in most persons with FAHN, although more detailed data on the cognitive phenotype and natural history are needed.

Leukodystrophy and hereditary spastic paraplegia 35 (HSP35) are two phenotypes previously identified as distinct disorders but now included in the phenotypic spectrum of FAHN:

  • Pathogenic variants in FA2H were first identified in a family with progressive dystonia and intellectual decline [Edvardson et al 2008]. Neuroimaging revealed widespread T2 white matter hyperintensities consistent with a clinical diagnosis of leukodystrophy. Further review of neuroimaging revealed T2 hypointensities in the globus pallidus [Kruer et al 2010]. This phenotype likely represents a variant of FAHN.
  • Dick et al [2008] described spastic paraplegia and dystonia in a consanguineous Omani family. They mapped the disease-associated locus, which they designated SGP35, to 16q21-23. Subsequently, Dick et al [2010] identified pathogenic variants in FA2H in the index family as well as in an additional family from Pakistan. Affected individuals exhibited spastic paraplegia, dystonia, and optic atrophy, leading to the characterization of the SPG35-associated phenotype as a ‘complicated’ form of HSP.

Although FAHN is progressive, declines may be intermittent and punctuated by periods of relative clinical stability. However, lost skills are not usually regained. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence.

Although premature death often occurs in the 20s or 30s secondary to a combination of nutrition-related immunodeficiency and respiratory compromise, life span is variable.

Neuropathologic features for FAHN have not yet been reported.

Genotype-Phenotype Correlations

No clear genotype-phenotype correlations have been observed for pathogenic variants in FA2H.


FAHN was called ‘hereditary spastic paraplegia 35 (HSP35)’ by Dick et al [2008]. More recently Dick et al [2010] identified FA2H pathogenic variants in two families with HSP35 (see Clinical Description, Leukodystrophy and hereditary spastic paraplegia 35).


No reliable prevalence data on this rare disorder have been collected. However, the prevalence is estimated to be less than one in 1,000,000.

Differential Diagnosis

Clinical suspicion that an individual may have a form of neurodegeneration with brain iron accumulation (NBIA) typically arises in the context of a progressive extrapyramidal movement disorder, intellectual decline, and neuroimaging that demonstrates iron deposition in the globus pallidus.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a neurodegenerative disorder that clinically shows overlap with other early-onset neurodegenerative disorders. Disorders that may exhibit clinical and neuroimaging features similar to those seen in FAHN include the following.

Other forms of NBIA

Several disorders may feature symmetric T2-weighted hyperintense (‘MRI bright’) lesions in the globus pallidus, suggesting metabolic compromise. Examples include the following:

Conversely, although a small area of central hyperintensity within the otherwise hypointense globi pallidi can be seen as the ‘eye’ in the ‘eye of the tiger’ sign observed in pantothenate kinase-associated neurodegeneration (PKAN), other forms of NBIA, including FAHN, characteristically feature uniformly symmetric T2 hypointense (‘MRI dark’) globi pallidi (see PKAN, Figure 1).

The differential diagnosis of a neurodegenerative disorder associated with T2 hypointensity of the globus pallidus is largely limited to other mineral deposition disorders.

  • Striatonigral calcinosis likely represents a heterogeneous patient group that share a propensity to deposit calcium in the basal ganglia. Features of this disease may be similar to those of NBIA. However, the two disorders are readily distinguished by CT scan, on which calcium appears hyperdense, while iron appears isodense to the surrounding parenchyma.
  • An as-yet-unnamed hereditary metabolic disorder that results in similar findings has been described [Tuschl et al 2008].

Miners and persons with liver failure are at risk for brain manganese deposition associated with T1 hyperintense lesions of the globus pallidus which, on T2-weighted sequences, are typically indistinguishable from surrounding brain tissue.

Wilson disease, a disorder of copper metabolism that can present with hepatic, neurologic, or psychiatric disturbances, or a combination of these presenting between ages three years and more than 50 years, may feature mixed T2 hyperintensity and hypointensity on MRI. Neurologic findings include movement disorders (tremors, dystonia, chorea, poor coordination, loss of fine-motor control,) or rigidity/parkinsonism (mask-like facies, gait disturbance, pseudobulbar involvement). Diagnosis depends on the detection of low serum copper and ceruloplasmin concentrations; increased urinary copper excretion; and molecular genetic testing of ATP7B.

Other disorders to consider:


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with fatty acid hydroxylase-associated neurodegeneration (FAHN), the following evaluations may be useful:

  • Neurologic examination for dystonia, ataxia, and spasticity, including formal evaluation of ambulation, speech, and feeding
  • Ophthalmologic assessment for evidence of optic atrophy or eye movement abnormalities
  • Screening developmental assessment, with referral for more formal testing if delay is indicated
  • Assessment for physical therapy, occupational therapy, and/or speech therapy and appropriate assistive devices

Prevention of Primary Manifestations

Pharmacologic and surgical interventions have focused on palliation of symptoms.

Weighted gloves can sometimes be used to assist with dysmetria.

Symptomatic treatment is aimed primarily at the dystonia, which can be debilitating. Therapies to manage dystonia in affected individuals that have been used with varying success include the following:

  • Oral trihexyphenidyl, baclofen, tizanidine, benzodiazepines, and/or dantrolene
  • Intramuscular botulinum toxin targeting abnormal co-contraction of selected muscle groups
  • Ablative pallidotomy or thalamotomy. Dystonia may return despite this aggressive measure [Justesen et al 1999]. (For discussion of deep brain stimulation [DBS] see Therapies Under Investigation.)

It is important to help affected individuals to maintain independence whenever possible.

  • Affected individuals should be referred to appropriate community resources for financial services, services for the visually impaired (if optic atrophy is present), and special education.
  • As needed, individuals should be referred for adaptive aids such as a walker or wheelchair for gait abnormalities and augmentative communication devices.

Prevention of Secondary Complications

Swallowing evaluation and regular dietary assessments are indicated to assure adequate nutrition and prevent aspiration. Once the individual can no longer maintain an adequate diet orally, gastrostomy tube placement is indicated.


The following should be performed on a regular basis:

  • Monitoring of height and weight using appropriate growth curves to screen children for worsening nutritional status
  • Ophthalmologic assessment. Fundus photography may be helpful in characterizing changes in the optic nerve over time.
  • Assessment of ambulation, speech, and swallowing
  • Regular review of communication needs and environmental adaptations

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Deep brain stimulation (DBS). To the authors’ knowledge, DBS has not yet been employed in the treatment of dystonia secondary to FAHN. Ongoing studies in the use of DBS for the management of other forms of NBIA suggest that it does provide benefit to a subset of affected individuals [Timmermann et al 2010]. Future studies will be necessary to determine whether DBS may be similarly useful for dystonia in FAHN.

Intrathecal baclofen pump. The implantable intrathecal baclofen pump has shown efficacy in ameliorating dystonia in some forms of NBIA. The intraventricular baclofen pump has been used successfully in at least one person with NBIA among a cohort of individuals with refractory dystonia [Albright & Ferson 2009]. Additional experience is necessary to better define the optimal mode of drug delivery and risk/benefit ratio.

Iron chelation. Interest in iron chelation has reemerged as trials using deferiprone have been published in other disorders of brain iron accumulation, including Friedreich ataxia [Boddaert et al 2007] and superficial siderosis [Levy & Llinas 2011]. Deferiprone can cross the blood-brain barrier and remove intracellular iron.

  • A single case report suggests regression of symptoms in an adult with NBIA of unknown cause [Forni et al 2008].
  • A recently completed phase II deferiprone trial in Italy in persons with PKAN demonstrated after six months of treatment decreased T2 hypointensity but no detectable change in clinical symptom severity [Zorzi et al 2011]. No serious treatment-related adverse events occurred.

Long-term clinical trials of deferiprone in specific forms of NBIA will be necessary to further assess safety and efficacy.

Search for access to information on clinical studies for a wide range of diseases and conditions.


Riluzole, recently recommended for cerebellar ataxia [Ristori et al 2010], has not to the authors’ knowledge undergone a therapeutic trial in FAHN.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one mutated allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband

  • The offspring of an individual with FAHN are obligate heterozygotes (carriers) for a pathogenic variant in FA2H.
  • Unless an individual with FAHN has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in FA2H.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

If the pathogenic variants in the family have been identified, carrier testing for at-risk family members is possible through laboratories offering either testing for the gene of interest or custom testing.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the FA2H pathogenic variants have been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for FAHN are possible options.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • NBIA Disorders Association
    2082 Monaco Court
    El Cajon CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
  • NBIA Disorders Association Research Registry and Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON) Registry
    CA 92019-4235
    Phone: 619-588-2315
    Fax: 619-588-4093
  • Registry for NBIA and Related Disorders
    Oregon Health & Science University
    Phone: 503-494-4344
    Fax: 503-494-6886

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Fatty Acid Hydroxylase-Associated Neurodegeneration: Genes and Databases

GeneChromosome LocusProteinLocus SpecificHGMD
FA2H16q23​.1Fatty acid 2-hydroxylaseFA2H databaseFA2H

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Fatty Acid Hydroxylase-Associated Neurodegeneration (View All in OMIM)


Molecular Genetic Pathogenesis

Human FA2H encodes the fatty acid 2-hydroxylase, an enzyme that alpha-hydroxylates nascent fatty acids that are subsequently incorporated into several diverse lipid species. Pathogenic variants in FA2H are believed to lead to fatty acid hydroxylase-associated neurodegeneration (FAHN) through a loss-of-function mechanism. This is supported by the identification of variants that lead to premature truncation of the protein [Kruer et al 2010], as well as in vitro evidence of decreased α-hydroxylation activity [Dick et al 2010] and decreased protein abundance [Kruer et al 2010] secondary to pathogenic variants associated with clinical FAHN.

In the peripheral nervous system, there is evidence that a second fatty acid-hydroxylating enzyme (perhaps phytanoyl coA 2-hydroxylase) may compensate for loss of FA2H activity [Edvardson et al 2008]. However, in the central nervous system, this redundancy does not seem to exist. A decrease in 2-OH fatty acids may lead to abnormal white matter, as 2-OH sphingomyelin is an important myelin constituent [Eckhardt et al 2005]. Deficiency of 2-OH fatty acids may also lead to an abnormal increase in membrane fluidity [Guo et al 2010], with implications for the regulation of autophagy via the endosomal-lysosomal system. An important cell-cycle signaling role for FA2H has also been shown [Alderson & Hama 2009]. However, further investigation is needed to better characterize the mechanism(s) by which loss of functional FA2H may lead to FAHN.

Gene structure. The reference sequence NM_024306.4 has seven exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. No common sequence variants have been identified to date in persons with FAHN; all have been ‘private’ variants.

Normal gene product. FA2H encodes a 43-kd protein of 372 amino acid residues that is a functional fatty acid hydroxylase [Alderson et al 2004]. This protein is known to localize to the endoplasmic reticulum and to require iron as a cofactor. Hydroxy fatty acids have important structural and signal transduction roles.

Abnormal gene product. Pathogenic variants can generally be categorized into null or missense alleles. Pathogenic missense variants in FA2H have been detected, leading to decreased protein abundance or enzyme activity. Null alleles have been detected as well.


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Chapter Notes

Revision History

  • 20 September 2012 (cd) Revision: deletion/duplication analysis available clinically
  • 28 June 2011 (me) Review posted live
  • 3 January 2011 (mk) Original submission
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