Fatty Acid
Hydroxylase-Associated
Neurodegeneration (FAHN)
FAHN
Fatty Acid Hydroxylase-associated Neurodegeneration (also known as HSP35), is caused by a mutation in the fatty acid 2-hydroxylase (FA2H) gene found on chromosome 16.
FAHN is ultra-rare; with approximately 5% of NBIA Individuals having the diagnosis. Onset usually occurs in childhood, or within the first or second decade of life. FAHN affects the central nervous system (brain and spinal cord) and causes problems with the corticospinal tract, which is the path of communication between the brain and limbs. This communication problem results in spasticity of the limbs.
Ataxia is also common, which is impaired coordination, balance and speech, Ataxia and spasticity share some of the same symptoms. Individuals with spasticity can have difficulty walking and doing other tasks because of muscle stiffness, spasms and contractions. Often, these individuals also experience dystonia, which are involuntary movements and prolonged muscle contractions that result in twisting body motions, tremors and abnormal posture.
Affected FAHN individuals also experience optic atrophy, profound cerebellar atrophy and white matter changes in the brain, in addition to high iron levels in the brain. Later in the disease course, individuals experience progressive intellectual impairment and seizures. Life expectancy varies among individuals.
Clinical Diagnosis
FAHN is diagnosed through an MRI of the brain. A common type of MRI known as a T2-weighted scan will show abnormalities in FAHN individuals: hypointensity (darkness) of the globus pallidus and possibly variable unilateral or bilateral symmetric white matter hyperintensity (brightness). There may be progressive atrophy (wasting away or diminution) of various regions of the brain and spinal cord, as well as thinning of the corpus callosum, which is the thin separation between the brain’s two hemispheres. Bone marrow biopsy, although not necessary for diagnosis, may demonstrate accumulation of granular histiocytes, which are immune cells.
The diagnosis of FAHN may be suspected in individuals with the onset of hallmark features in the first or second decade: spasticity, ataxia, dystonia, optic atrophy, eye movement abnormalities early in the disease course and progressive intellectual impairment and seizures later in the disease course. Other features are spastic paraplegia or quadriplegia and pyramidal tract signs (problems, such as spasticity, caused by dysfunction of the motor neurons that originate in the cerebral cortex and terminate in the spinal cord); dysarthria (difficulty pronouncing words); and dysphagia (difficulty swallowing).
Note: Because very few individuals with FAHN have been documented, the phenotype (disease characteristics) is likely to expand as more cases are ascertained, and thus the designation of any phenotypic feature as ‘hallmark’ may be premature.
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with 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 developmental delay is observed or suspected
- Assessment for physical therapy, occupational therapy, and/or speech therapy and appropriate assistive devices
Management
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; intrathecal baclofen; and deep brain stimulation.
More information on these therapies can be found in the Medical Information section of our website.
Attention should be given to diet and swallowing to prevent aspiration. Children with FAHN should have regular measurement of height and weight to assure adequate nutrition, with gastrostomy tube placement as needed. Assessment of ambulation and speech and communication needs, and ophthalmologic examination also are recommended.
Since most individuals with FAHN lose the ability to walk and speak, independence should be encouraged when possible. Adaptive equipment and devices that can help include walkers or wheelchairs and augmentative communication aids.
Genetics
FAHN is inherited in an autosomal recessive manner. Because most of our genes exist in pairs (one coming from the mother and one coming from the father), we normally carry two working copies of each gene. When one copy of a recessive gene has a change, or mutation, the person should still have normal health. That person is called a carrier.
Recessive diseases only occur when both parents are carriers for the same condition and then pass their mutated genes onto their child. Statistically, there is a one in four chance that two carriers would have an affected child. There is a two in four chance the parents will have a child who is also a carrier. The chances are one in four that the child will not have the gene mutation. Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are suggested if both disease-causing mutations have been identified in an affected family member.
Prenatal Testing
If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk can be done. In one test, DNA is extracted from fetal cells obtained by amniocentesis, usually at 15 to 18 weeks’ gestation, and analyzed. Or, sampling is done of the chorionic villus, the tiny finger-like projections on the edge of the placenta, usually at 10 to 12 weeks’ gestation.
Embryo screening, known as preimplantation genetic diagnosis, may be an option for some families in which the disease-causing mutations have been identified.
Note
A main resource for the clinical information provided here is FAHN - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult to understand for the general public.
Research
Research grants have been awarded to various studies to help understand the disease. A focus of the research has been creating disease models which will allow scientists to perform studies testing possible drug therapies to see if effective in the disease models. It is important that the model mimic the condition seen in patients with FAHN.
A successful mouse model has been created to study the disease and research is underway to create a stem cell model. To develop these stem cells in the lab, cells will be taken from the connective tissue of FAHN patients. Researchers will then use a gene editing technology, CRISPR/Cas9, to add copies of certain genes to the cells, endowing them with a stem cell’s special characteristics. They can develop into central nervous system cells that may be affected by FAHN.
As research moves forward, these disease models could provide scientists important clues on the cause of disease as well as help develop and test potential treatments through drug screeningthat can be later used in clinical trials. trials.
Researchers are also gathering data to create a natural history of FAHN and are analyzing clinical, genetic and imaging data.
Natural History Studies
TIRCON International NBIA Registry
The TIRCON International NBIA Registry was created under a European Union grant called Treat Iron-Related Childhood-Onset Neurodegeneration. Grant funding ran from 2011 to 2015, and the project is housed at Ludwig Maximilian University of Munich, Germany. The NBIA Alliance and other sources have provided registry funding since 2015. Clinical centers from 12 countries take part in the registry by entering their patient data. There were over 750 entries consisting of NBIA patients and controls as of September 2021. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data is available to researchers studying NBIA disorders. For more information on the registry, contact Anna Baur-Ulatowska at Anna.Baur@med.uni-muenchen.de
Research Publications and Articles
Following is a list of some recent research articles. Others can be found at Pub Med Central.
2019 - FAHN/SPG35: a narrow phenotypic spectrum across disease classifications
2018 - Defective FA2H Leads to a Novel Form of Neurodegeneration with Brain Iron Accumulation (NBIA)
