Neuroferritinopathy: symptoms, genetics and research

Ferritin is a protein that stores iron inside cells and releases it when needed. MedlinePlus Genetics explains that each ferritin molecule can hold as many as 4,500 iron atoms, which lets ferritin regulate the amount of iron in cells and tissues. In neuroferritinopathy, changes in the FTL gene, which makes the ferritin light chain, are believed to reduce ferritin's ability to store iron, so that excess iron is released in nerve cells of the brain.

The cells may respond by making more ferritin, and the excess iron and ferritin accumulate in the brain, particularly in the basal ganglia, resulting in the movement problems and other neurological changes. Because of this, the condition is classed with the group of disorders called neurodegeneration with brain iron accumulation, where it is sometimes called NBIA3.

This is different from conditions of general iron overload in the body, such as haemochromatosis. In neuroferritinopathy the problem lies in how iron is handled and stored within the brain.

MedlinePlus Genetics lists progressive problems with movement that begin at about age 40, which can include involuntary jerking movements (chorea), rhythmic shaking (tremor), difficulty coordinating movements (ataxia) or uncontrolled muscle tensing (dystonia). Symptoms may be more obvious on one side of the body than the other. Affected individuals may also have difficulty swallowing (dysphagia) and speaking (dysarthria).

Intelligence is unaffected in most people, but some develop a gradual decline in thinking and reasoning abilities (dementia). Personality changes such as reduced inhibitions and difficulty controlling emotions may also occur as the disorder progresses. LifeArc similarly describes severe motor and speech difficulties, ultimately leading to loss of essential functions such as swallowing.

• Involuntary jerking movements (chorea) or tremor.

• Muscle tensing and abnormal postures (dystonia).

• Poor coordination (ataxia).

• Slurred speech and swallowing difficulties.

• Sometimes changes in behaviour or thinking.

New involuntary movements, clumsiness, slurred speech or swallowing problems should be assessed by a GP, who can refer to a neurologist. Sudden weakness, facial droop, speech disturbance or loss of vision is a different matter and needs 999, as these can be signs of a stroke. If swallowing becomes unsafe, with frequent coughing or choking on food or drink, ask for an urgent referral to a speech and language therapist.

For someone already diagnosed, unexpected chest infections, weight loss or falls are worth raising early with the neurology team, as they can signal that swallowing or balance is changing.

The pages read for this guide do not describe a UK diagnostic pathway, so this is explained in general terms. Doctors usually begin with a neurological assessment and a brain MRI, which can show iron accumulation in the basal ganglia. Blood tests, including a ferritin level, are often done to look at iron status and other causes of movement disorders.

The diagnosis is confirmed by genetic testing for variants in the FTL gene, usually arranged through a clinical genetics service. Because the condition is autosomal dominant, genetic counselling is typically offered to family members, who can decide whether they wish to know their status.

MedlinePlus Genetics explains that the condition is inherited in an autosomal dominant pattern, meaning one copy of the altered gene in each cell is sufficient to cause it. In most cases an affected person inherits the variant from one affected parent. Other cases may result from new variants in people with no family history. Because symptoms usually begin in mid-life, many people have already had children before they know they carry the variant, which is one reason genetic counselling is valuable.

LifeArc says that neuroferritinopathy currently has no effective treatments. Management is therefore supportive and led by neurology with input from physiotherapy, occupational therapy, speech and language therapy and dietetics, depending on symptoms. Medicines used for other movement disorders are sometimes tried for specific symptoms, but this is individual and should be guided by a specialist.

LifeArc describes the DefINe trial, launched by the University of Cambridge and led by Professor Patrick Chinnery, which seeks to repurpose deferiprone, an oral medicine already licensed in the UK for blood disorders such as thalassaemia, to reduce brain iron accumulation. It is a placebo-controlled trial involving 40 patients taking deferiprone or placebo for a year, using 7T MRI to monitor iron levels, and it is funded by LifeArc. Data are intended to support an application for licensing under exceptional circumstances if successful. Recruitment status changes, so check with a specialist centre rather than assuming eligibility.

A rare progressive diagnosis affects families as well as individuals. Practical measures include early involvement of speech and language therapy for communication aids and safe swallowing strategies, physiotherapy for mobility and falls prevention, occupational therapy for home adaptations, and mental health support. In the NHS, these are arranged through neurology and community teams. Sources specific to UK support groups for neuroferritinopathy were not found; neurology teams and wider neurological charities can signpost support.