Fatty acid hydroxylase-associated neurodegeneration

Alternate names

FAHN; Spastic paraplegia 35, autosomal recessive; SPG35

Definition

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.

Summary

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).

Epidemiology

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

Cause

• 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.

Gene mutations

• 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

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptomd

• 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Falls
• Mental deterioration(Cognitive decline)
• Progressive gait ataxia
• Progressive spastic paraplegia

30%-79% of people have these symptoms

• Anarthria(Loss of articulate speech)
• Atrophy of the spinal cord(Degeneration of the spinal cord)
• Bilateral tonic-clonic seizure(Grand mal seizures)
• Cerebellar atrophy(Degeneration of cerebellum)
• Cerebellar vermis atrophy
• Color vision test abnormality
• Dysarthria(Difficulty articulating speech)
• Generalized dystonia
• Horizontal nystagmus
• Hypoplasia of the corpus callosum(Underdevelopment of part of brain called corpus callosum)
• Loss of ability to walk
• Motor aphasia(Loss of expressive speech)
• Optic atrophy
• Progressive extrapyramidal movement disorder
• Progressive spastic paraparesis
• Progressive spastic quadriplegia
• Slow decrease in visual acuity(Slow decrease in sharpness of vision)
• Supranuclear gaze palsy
• Visual field defect(Partial loss of field of vision)

5%-29% of people have these symptoms

• Ankle clonus(Abnormal rhythmic movements of ankle)
• External ophthalmoplegia(Paralysis or weakness of muscles within or surrounding outer part of eye)
• Focal-onset seizure(Seizure affecting one half of brain)
• Strabismus(Cross-eyed)
• Urinary incontinence(Loss of bladder control)

1%-4% of people have these symptoms

• Anxiety(Excessive, persistent worry and fear)
• Bipolar affective disorder(Bipolar disorder)
• Depressivity(Depression)
• Dysphagia(Poor swallowing)
• Peripheral neuropathy

Diagnosis

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

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).

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

The diagnosis of FAHN is established in a proband with suggestive findings and biallelic FA2H pathogenic variants on molecular genetic testing

Treatment

• 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).

[1].

NIH genetic and rare disease info

• NIH info on Fatty acid hydroxylase-associated neurodegeneration

Fatty acid hydroxylase-associated neurodegeneration is a rare disease.

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