A genetically dominant form of NBIA caused by mutations in the FTL gene which encodes the light subunit of the ferritin protein. Ferritin is responsible for iron storage and its release.
Neuroferritinopathy is a NBIA disorder characterized by symptoms that are similar to Huntington disease with adult-onset chorea or dystonia and cognitive (mental) changes.
Movement problems typically affect one or two limbs in the beginning, eventually progress to all the limbs within 5-10 years and can become more generalized within 20 years. Over time, mental decline and behavioral issues become significant problems for individuals with neuroferritinopathy.
The average lifespan varies for individuals with neuroferritinopathy, but due to improvements in medical care, more affected individuals are now living well into late adulthood.
Psychometric, physiotherapy, speech therapy and dietary assessments should be made.
The prevalence is unknown. About 100 cases have been reported and most of these share the same gene change, suggesting they have descended from a common ancestor.
Symptoms of neuroferritinopathy typically start to appear around age 40, but can range from the early teenage years to age 60. It typically starts during adulthood around age 40 with dystonia, jerky movements (chorea), and mild changes in thinking (cognitive effects). Within 20 years it usually begins to affect movement in all the limbs and causes difficulty speaking and resembles Huntington’s disease. Cognitive deficits and behavioral issues become major problems with time.
- Chorea (brief, repetitive, jerky, uncontrolled movements)
- Dystonia (involuntarily muscle contraction and spasms) affects one or two limbs in the beginning and progresses to other limbs within 5-10 years. Onset is often asymmetrical (occurs differently in bilateral limbs or muscles). If asymmetry occurs, it will remain throughout the course of the disease
- Parkinsonism (symptoms similar to Parkinson’s disease) Bradykinesia (slow movements). Increased tendon reflexes
- Speech problems
- Dysarthria, difficulty using or controlling the muscles of the mouth, tongue, larynx or vocal cords, which are used to make speech. This can make a person’s speech difficult to understand in several different ways, including stuttering, slurring, or soft or raspy speech
- Dysphonia (movement of the vocal cords is forced and strained), results in a jerky, quivery, hoarse, tight, or groaning voice
- Orolingual dyskinesia (difficulty performing voluntary movements of the mouth and tongue, like chewing)
- Dysphagia (difficulty swallowing)
- Eye problems Abnormal EOM (extraocular movement) Movement of the eye in one or more directions is abnormal Abnormal fundi (the retina and optic nerve)
- Subtle cognitive decline (mental)
MRIs are different from those of other NBIA patients.
- Hypointensity (darkness) on T2-weighted MRI, caudate, globus pallidus, putamen, substantia nigra, and red nuclei. The dark patches indicate excess of iron accumulation.
- Hyperintensity (brightness) on T2-weighted MRI, cystic degeneration and cavitation in the caudate and putamen in advanced cases.
- Mild cortical and cerebellar atrophy (decrease in cerebellum size)
- Adult-onset progressive movement disorder (either chorea or dystonia)
- family history consistent with autosomal dominant transmission
- Serum ferritin concentration may be low.
- Axonal swellings (neuroaxonal spheroids) may be present.
Eye movements are well preserved throughout the disease course.
Diagnosis of neuroferritinopathy can be confirmed through genetic testing of the FTL gene to find a gene change in ~80% of cases. Genetic testing is done through sequence analysis.
There is no standard treatment for neuroferritinopathy. A team of medical professionals recommends treatments based on current symptoms the diagnosed individuals.
The extent of the disease can be determined:
- Psychometric assessment
- Physiotherapy assessment
- Speech therapy assessment
- Dietary assessment
- Medical genetics consultation
- Parkinsonism, the symptoms similar to Parkinson disease can be treated with the same medications used in Parkinson. The movement disorder is particularly resistant to conventional therapy, but some response has been recorded with levodopa, tetrabenazine, orphenadrine, benzhexol, sulpiride, diazepam, clonazepam, and deanol in standard doses. [Chinnery et al 2007, Ondo et al 2010]. Botulinum toxin is helpful for painful focal dystonia.
- Regular assessment of nutrition and caloric intake
- Physiotherapy to maintain mobility and prevent contracture (permanent tightening of a muscle or joint).
The altered FTL gene inherited in an autosomal dominant manner is the cause of neuroferritinopathy. Autosomal” refers to the fact that the FTL gene is located on chromosome 19. “Dominant” refers to the fact that having a gene change in just one of the two gene copies is enough to cause the disease.
There is a one in two chance (50%) that an affected individual will pass the gene change on to any of his/her children. Most individuals diagnosed with neuroferritinopathy have one parent who is also affected.
The proportion of cases caused by de novo (new) mutations is unknown.
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.
Please see the link in the right hand column on this page for more detailed clinical information on Neuroferritinopathy at Gene Reviews, which was used as a source for some of the above information. Gene Reviews is primarily for the use of genetics professionals so the terminology and information may be difficult to understand for the general public.
Gene Reviews Author:
Patrick F Chinnery, MBBS, PhD, FRCP, FRCPath, FMedSci
Institute of Human Genetics
University of Newcastle upon Tyne
Newcastle upon Tyne, United Kingdom