Clinical characteristics.

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), and eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. With disease progression, dystonia and spasticity compromise the ability to ambulate, leading to wheelchair dependence. Life expectancy is variable. FAHN is considered to be a subtype of neurodegeneration with brain iron accumulation (NBIA).

Diagnosis/testing.

The diagnosis of FAHN is established in a proband with suggestive findings and typically by identification of biallelic FA2H pathogenic variants on molecular genetic testing; however, on occasion uniparental disomy (UDP) is causative.

Management.

Treatment of manifestations: Symptomatic treatment focuses primarily on the dystonia, which can be debilitating. Therapies used with varying success include the oral medications baclofen, tizanidine, dantrolene, and anticholinergics; injection of botulinum toxin targeting abnormal co-contraction of selected muscle groups; and ablative pallidotomy or thalamotomy. Attention should be given to nutritional status and feeding.

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, special education).

Surveillance: Regular assessment of nutritional status and swallowing, vision, mobility and environmental adaptations, speech, and communication needs.

Genetic counseling.

Genetic counseling for fatty acid hydroxylase-associated neurodegeneration (FAHN) depends on the causative genetic mechanism: FAHN caused by transmission of one pathogenic variant from each parent is inherited in an autosomal recessive manner; FAHN caused by transmission of two pathogenic variants from one parent (as the result of uniparental disomy [UPD] for chromosome 16) is a de novo event and is unlikely to recur.

Autosomal recessive inheritance: 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, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible.

Suggestive Findings

Fatty acid hydroxylase-associated neurodegeneration (FAHN) should be considered in individuals with the following clinical findings, neuroimaging findings, and family history (see Figure 1).

Figure 1.

Neuroimaging features of FAHN (A) vs PKAN (B) The two forms of NBIA share T_2-weighted / gradient-echo hypointensity. Distinguishing features include diffuse cerebral atrophy (seen in FAHN) and central globus pallidus T_2-weighted hyperintensity (seen in (more...)

Clinical findings

• Onset within the first or second decade of life
• Corticospinal tract involvement:
  • Spastic paraplegia or quadriplegia (commonly given a clinical diagnosis of hereditary spastic paraplegia)
  • Pyramidal tract signs (hypereflexia, clonus, Babinski sign, Hoffmann sign)
• Movement disorder including one or both of the following:
  • Dystonia
  • Ataxia
• Dysarthria
• Dysphagia
• Eye findings:
  • Optic atrophy manifest as progressive loss of visual acuity, sectoral visual field loss, and impaired color vision
  • In some individuals: strabismus, lateral-beating nystagmus, and supranuclear gaze palsy
• Epilepsy
• Cognitive decline

Neuroimaging findings. Brain MRI findings typically may include (in order of likelihood):

• On T₂-weighted images: variable unilateral or bilateral symmetric white matter hyperintensity that may affect both periventricular and subcortical white matter, and may become confluent with time. 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
• Optic atrophy
• T₂-weighted hypointensity of the globus pallidus (may display blooming on T₂*-weighted images).
  Note: T₂-weighted hypointensity coupled with an extrapyramidal movement disorder and intellectual decline is suggestive of a neurodegeneration with brain iron accumulation (NBIA) disorder (see Differential Diagnosis). The "eye of the tiger" sign, pathognomonic for pantothenate kinase-associated neurodegeneration (PKAN), another form of NBIA, is not seen in FAHN.

Family history is consistent with autosomal recessive inheritance, including parental consanguinity.

Establishing the Diagnosis

The diagnosis of FAHN is established in a proband with suggestive findings and biallelic FA2H pathogenic variants on molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with findings indistinguishable from other neurodegenerative disorders with pyramidal and extrapyramidal involvement are more likely to be diagnosed with comprehensive genomic testing (see Option 2).

Clinical Description

Fatty acid hydroxylase-associated neurodegeneration (FAHN) is characterized early in the disease course by central nervous system involvement including corticospinal tract involvement (spasticity), mixed movement disorder (ataxia/dystonia), eye findings (optic atrophy, oculomotor abnormalities), and later in the disease course by progressive intellectual impairment and seizures. FAHN is a subtype of neurodegeneration with brain iron accumulation (NBIA) but is also included under the classifications of leukodystrophies and hereditary spastic paraplegias.

Of note, leukodystrophy and hereditary spastic paraplegia 35 (HSP35), two phenotypes previously considered distinct disorders based on clinical findings [Dick et al 2008, Edvardson et al 2008], are now included in the phenotypic spectrum of FAHN based on molecular genetic findings [Dick et al 2010, Kruer et al 2010].

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 can 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.

A few individuals with FAHN and peripheral neuropathy have been reported [Donkervoort et al 2014, Zaki et al 2015].

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

While progressive intellectual impairment occurs in most persons with FAHN, more information on the cognitive phenotype and natural history are needed. Serial assessments have documented cognitive decline in two individuals [Tonelli et al 2012]. One report suggests a psychiatric component to FAHN based on findings of anxiety, depression, and bipolar disorder in affected sibs [Magariello et al 2017].

Although the neurodegeneration in 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.

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

Neuropathologic features for FAHN have not yet been reported. Bone marrow biopsy, although not necessary for diagnosis, may demonstrate accumulation of granular histiocytes.

Genotype-Phenotype Correlations

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

Nomenclature

Historically, the FA2H-related phenotype has been classified as either a genetic leukodystrophy [Vanderver et al 2015] or a hereditary spastic paraplegia (SPG35) (see OMIM 612319) [Dick et al 2008, Soehn et al 2016].

The authors prefer to refer to the FA2H-related phenotype as fatty acid hydroxylase-associated neurodegeneration because this term refers to the genetic basis of the disorder and encompasses all clinical classifications.

Prevalence

No reliable prevalence data are available. However, the prevalence is estimated to be lower than one in 1,000,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with fatty acid hydroxylase-associated neurodegeneration (FAHN), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations