Neuroferritinopathy

Neuroferritinopathy is a genetically dominant form of NBIA. That means it can be inherited if only one parent has the mutated gene. Although the prevalence is unknown, only about 100 cases have been reported, and most share the same gene change, suggesting a common ancestor. It is caused by mutations in the FTL gene, which stands for ferritin light. This is one of two sub-proteins 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

The effects of neuroferritinopathy typically begin around age 40, although onset in the early teenage years and in the sixth decade have been recorded. A family history consistent with autosomal dominant transmission are indicative of this disorder.

Individuals with neuroferritinopathy typically present with either dystonia or chorea. Dystonia is a movement disorder in which involuntary sustained or intermittent muscle contractions cause twisting and repetitive movements, abnormal postures, or both. Chorea is an ongoing random-appearing sequence of one or more discrete involuntary movements or movement fragments. This usually affects one or two limbs. Mild changes in thinking (cognitive effects) can also occur at this time.

Within 20 years of onset, neuroferritinopathy usually begins to affect movement in all the limbs. It also causes difficulty speaking and resembles Huntington’s disease. Cognitive deficits and behavioral issues worsen over time.

Serum ferritin concentration may be low. Eye movements are usually not affected throughout the disease course. Axonal swellings (neuroaxonal spheroids) may be present.

From the onset, all affected individuals have evidence of excess brain iron accumulation on T2-weighted MRI views of the brain. Later stages are associated with high signal on T2-weighted MRI in the caudate, globus pallidus, putamen, substantia nigra and red nuclei. This is followed by cystic degeneration in the caudate and putamen.

a. Non-contrast brain CT symmetric low signal in the putamina

b. T2-weighted MRI image showing cystic change involving the putamina and globus pallidi and with increased signal in the heads of the caudate nuclei [Crompton et al 2005]

Table taken from Neuroferritinopathy - GeneReviews® - NCBI Bookshelf

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 records show some patients have responded to 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.

Dietary assessment is helpful. Affected individuals should be evaluated to ensure that they maintain caloric intake. Physiotherapy can help maintain mobility and prevent tightening of muscles, ligaments or skin.

Genetics

Because neuroferritinopathy is inherited in an autosomal dominant manner, a person affected with neuroferritinopathy has one working copy of the affected gene and one copy 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 his or her children. Most individuals diagnosed with neuroferritinopathy have one affected parent. 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.

Note

A main resource for this clinical information is Neuroferritinopathy - GeneReviews® - NCBI Bookshelf. GeneReviews is primarily used by genetics professionals so the terminology and information may be difficult for the general public to understand.

TIRCON International NBIA Registry

The TIRCON International NBIA Registry is housed at Ludwig Maximilian University of Munich, Germany, and was created under an EU grant from 2011-2015 called Treat Iron-Related Childhood-Onset Neurodegeneration.

The NBIA Alliance and other sources have provided funding since 2015. Clinical centers from 16 countries have provided patient clinical data. There are over 750 entries consisting of NBIA patients and controls as of September 2015. Clinical centers seeing at least five NBIA patients are eligible to participate. Clinical and natural history data are available to researchers studying NBIA disorders. Contact Anna Baur-Ulatowska at Anna.Baur@med.uni.muenchen.de for more information on this registry.