Neuroferritinopathy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Neuroferritinopathy is a disorder in which iron gradually accumulates in the brain. Certain brain regions that help control movement (basal ganglia) are particularly affected. People with neuroferritinopathy have progressive problems with movement that begin at about age 40. These movement problems can include involuntary jerking motions (chorea), rhythmic shaking (tremor), difficulty coordinating movements (ataxia), or uncontrolled tensing of muscles (dystonia). Symptoms of the disorder may be more apparent on one side of the body than on the other. Affected individuals may also have difficulty swallowing (dysphagia) and speaking (dysarthria).

Intelligence is unaffected in most people with neuroferritinopathy, but some individuals 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.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the FTL gene cause neuroferritinopathy. The FTL gene provides instructions for making the ferritin light chain, which is one part (subunit) of a protein called ferritin. Ferritin stores and releases iron in cells. Each ferritin molecule can hold as many as 4,500 iron atoms. This storage capacity allows ferritin to regulate the amount of iron in the cells and tissues.

Mutations in the FTL gene that cause neuroferritinopathy are believed to reduce ferritin's ability to store iron, resulting in the release of excess iron in nerve cells (neurons) of the brain. The cells may respond by producing more ferritin in an attempt to handle the free iron. Excess iron and ferritin accumulate in the brain, particularly in the basal ganglia, resulting in the movement problems and other neurological changes seen in neuroferritinopathy.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

The prevalence of neuroferritinopathy is unknown. Fewer than 100 individuals with this disorder have been reported.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal basal ganglia morphology · Very frequent (99-80%)

Abnormality of the basal ganglia.

Cognitive impairment · Very frequent (99-80%)

Abnormal cognition is characterized by deficits in thinking, reasoning, or remembering.

Decreased serum ferritin · Very frequent (99-80%)

Abnormally reduced concentration of ferritin, a ubiquitous intracellular protein that stores iron, in the blood.

Dystonia · Very frequent (99-80%)

An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.

Iron accumulation in brain · Very frequent (99-80%)

An abnormal build up of iron (Fe) in brain tissue.

Abnormal caudate nucleus morphology · Frequent (79-30%)

Any structural abnormality of the caudate nucleus.

Abnormal putamen morphology · Frequent (79-30%)

Any structural anomaly of the putamen, a brain nucleus which together with the caudate nucleus and fundus striati makes up the striatum.

Abnormal thalamic MRI signal intensity · Frequent (79-30%)

A deviation from normal signal on magnetic resonance imaging (MRI) of the thalamus.

Abnormality of the dentate nucleus · Frequent (79-30%)

An abnormality of the dentate nucleus.

Bradykinesia · Frequent (79-30%)

Bradykinesia literally means slow movement, and is used clinically to denote a slowness in the execution of movement (in contrast to hypokinesia, which is used to refer to slowness in the initiation of movement).

Chorea · Frequent (79-30%)

Chorea (Greek for 'dance') refers to widespread arrhythmic involuntary movements of a forcible, jerky and restless fashion. It is a random-appearing sequence of one or more discrete involuntary movements or movement fragments. Movements appear random because of variability in timing, duration or location. Each movement may have a distinct start and end. However, movements may be strung together and thus may appear to flow randomly from one muscle group to another. Chorea can involve the trunk, neck, face, tongue, and extremities.

Dysarthria · Frequent (79-30%)

Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.

Dysphagia · Frequent (79-30%)

Difficulty in swallowing.

Dysphonia · Frequent (79-30%)

Difficulty in speaking due to a physical disorder of the mouth, tongue, throat, or vocal cords. Associated with a known physical or neurological cause.

Other findings in the same source

From: Orphanet

Additional reported features include Emotional lability (Frequent (79-30%)); Eye of the tiger anomaly of globus pallidus (Frequent (79-30%)); Focal dystonia (Frequent (79-30%)); Gait disturbance (Frequent (79-30%)); Hypomimic face (Frequent (79-30%)); Involuntary movements (Frequent (79-30%)); Iron accumulation in substantia nigra (Frequent (79-30%)); Leg dystonia (Frequent (79-30%)); T2 hypointense thalamus (Frequent (79-30%)); Orofacial dyskinesia (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Neuroferritinopathy is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Neuroferritinopathy. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.