Fatty acid hydroxylase-associated neurodegeneration

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

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).

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

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.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

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

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Mental deterioration · Very frequent (99-80%)

Loss of previously present mental abilities, generally in adults.

Progressive gait ataxia · Very frequent (99-80%)

A type of gait ataxia displaying progression of clinical severity.

Falls · Very frequent (99-80%)

Progressive spastic paraplegia · Very frequent (99-80%)

Anarthria · Frequent (79-30%)

A defect in the motor ability that enables speech.

Bilateral tonic-clonic seizure · Frequent (79-30%)

A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.

Cerebellar atrophy · Frequent (79-30%)

Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.

Cerebellar vermis atrophy · Frequent (79-30%)

Wasting (atrophy) of the vermis of cerebellum.

Other findings in the same source

From: Orphanet

Additional reported features include Dysarthria (Frequent (79-30%)); Generalized dystonia (Frequent (79-30%)); Horizontal nystagmus (Frequent (79-30%)); Hypoplasia of the corpus callosum (Frequent (79-30%)); Loss of ambulation (Frequent (79-30%)); Motor aphasia (Frequent (79-30%)); Optic atrophy (Frequent (79-30%)); Supranuclear gaze palsy (Frequent (79-30%)); Upper motor neuron dysfunction (Frequent (79-30%)); Atrophy of the spinal cord (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Fatty acid hydroxylase-associated neurodegeneration is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Fatty acid hydroxylase-associated neurodegeneration. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.