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Neuroferritinopathy

Neuroferritinopathy is the only genetically dominant form of NBIA identified so far. Although the prevalence is unknown, only about 100 cases have been reported and most of these share the same gene change, suggesting they have descended from a common ancestor. It is caused by mutations in the FTL gene, which stands for ferritin light. This refers to one of two protein subunits that make up ferritin, a protein in the body that helps store and detoxify iron. MRIs are different from those of other NBIA patients.

Clinical Diagnosis

T2-weighted MRI views of the brain showing excess iron accumulation and cystic degeneration in advanced cases, along with an adult-onset progressive movement disorder (either chorea or dystonia) and a family history consistent with autosomal dominant transmission are indicative of this disorder.

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.

Serum ferritin concentration may be low. Eye movements are well preserved throughout the disease course. Axonal swellings (neuroaxonal spheroids) may be present.

Evaluations Following Initial Diagnosis

Psychometric, physiotherapy, speech therapy and dietary assessments should be made.

Management

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.

Genetics

Neuroferritinopathy is inherited in an autosomal dominant manner. In this case, a person affected with neuroferritinopathy has one working copy and one copy of the gene that has a change or mutation. This single mutation 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.

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.

 

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