Fatty acid hydroxylase-associated neurodegeneration (FAHN) - FA2H gene

Fatty acid hydroxylase-associated neurodegeneration (FAHN), also known as demyelinating leukodystrophy and spastic paraparesis, is a progressive disease of the nervous system characterized by problems with movement and vision that begin in childhood or adolescence

Signs related to the disease include changes in gait and frequent falls, spasticity, exaggerated reflexes, dystonia and/or ataxia; eye problems that include atrophy of the optic nerves, decreased acuity and visual field, impaired color perception, strabismus, nystagmus or difficulty moving the eyes, and supranuclear visual paralysis. In addition, people with FAHN may develop dysarthria and, in some cases, may lose the ability to speak. People with this disease may also have dysphagia, which in severe cases can lead to malnutrition and require a feeding tube. Swallowing difficulties can lead to aspiration pneumonia, which can be potentially fatal. As the disease progresses, some affected individuals manifest seizures and a decrease in intellectual function.

MRI of the brain in people with FAHN shows signs of iron accumulation, especially in the pale nucleus, which is involved in the regulation of movement. Some similar patterns of iron accumulation are seen in other neurological processes such as infantile neuroaxonal dystrophy (INAD) and pantothenate kinase-associated neurodegeneration (PKAN). All these diseases belong to a class of processes called neurodegeneration with iron accumulation in the brain (NBIA).

This entity is due to mutations in the FA2H (fatty acid 2-hydroxylase) gene, located on the long arm of chromosome 16 (16q23.1). This gene encodes the synthesis of the enzyme 2-hydroxylase fatty acid, responsible for modifying fatty acids. Specifically, the 2-hydroxylase fatty acid adds a single oxygen atom to a hydrogen atom at a particular point in a fatty acid, to create a 2-hydroxylated fatty acid. Certain 2-hydroxylated fatty acids are important in the formation of myelin, the protective covering that insulates nerves and ensures rapid transmission of nerve impulses. The part of the brain and spinal cord that contains myelin is the white substance.

At least nine mutations in the FA2H gene have been identified in people with FAHN. These genetic changes reduce or eliminate the function of the fatty acid 2-hydroxylase enzyme. A reduction in the function of this enzyme can lead to demyelination, which leads to leukodystrophy, which is likely to participate in the development of movement problems and other neurological abnormalities that occur in FAHN. The accumulation of iron in the brain is likely to also participate, although it is not clear how FA2H genetic mutations give rise to this accumulation of iron.

People with FA2H genetic mutations and some of the movement problems observed in FAHN were diagnosed with an entity called spastic paraplegia 35 at the time. People with mutations in this gene that manifest intellectual decline and optic nerve atrophy are said to have leukodystrophy related to FA2H. However, these entities are now generally considered as forms of neurodegeneration associated with fatty acid hydroxylase (FAHN).

This disease is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually don’t show signs and symptoms of the disease.

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with fatty acid hydroxylase-associated neurodegeneration (FAHN), by means of the complete PCR amplification of the exons of the FA2H gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leukocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).