Primary familial brain calcification

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Primary familial brain calcification is a condition characterized by abnormal deposits of calcium (calcification) in blood vessels within the brain. These calcium deposits are visible only on medical imaging and typically occur in the basal ganglia, which are structures deep within the brain that help start and control movement of the body. Other brain regions may also be affected.

The main signs and symptoms of primary familial brain calcification are movement disorders and psychiatric or behavioral problems. These difficulties usually begin in mid-adulthood, and worsen over time. Most affected individuals have a group of movement abnormalities called parkinsonism, which include unusually slow movement (bradykinesia), muscle rigidity, and tremors. Other movement problems common in people with primary familial brain calcification include involuntary tensing of various muscles (dystonia), uncontrollable movements of the limbs (choreoathetosis), and an unsteady walking style (gait).

Psychiatric and behavioral problems occur in 20 to 30 percent of people with primary familial brain calcification. These problems can include difficulty concentrating, memory loss, changes in personality, a distorted view of reality (psychosis), and decline in intellectual function (dementia). Affected individuals may also have difficulty swallowing (dysphagia), impaired speech, headache, episodes of extreme dizziness (vertigo), seizures, or urinary problems.

The severity of primary familial brain calcification varies among affected individuals; some people have no symptoms related to the condition, whereas others have significant movement and psychiatric problems.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Primary familial brain calcification is caused by mutations in one of several genes. The most commonly mutated gene is called SLC20A2, and accounts for an estimated 40 percent of cases, followed by the PDGFRB gene, which is mutated in about 10 percent of cases. Changes in other genes each account for a small percentage of cases. In about half of individuals with primary familial brain calcification the genetic cause is unknown. These individuals are thought to have mutations in genes that have not yet been linked to the condition.

The SLC20A2 gene provides instructions for making a protein called sodium-dependent phosphate transporter 2 (PiT-2). This protein is highly active in nerve cells (neurons) in the brain where it plays a major role in regulating phosphate levels (phosphate homeostasis) by transporting phosphate across cell membranes. SLC20A2 gene mutations lead to the production of a PiT-2 protein that cannot effectively transport phosphate into cells. As a result, phosphate levels in the bloodstream rise. In the brain, the excess phosphate combines with calcium and forms deposits within blood vessels in the brain.

The PDGFRB gene provides instructions for making a protein that transmits signals from the cell surface into the cell. These signals control a variety of cell processes. PDGFRB gene mutations result in a protein with impaired signaling ability. However, it is unclear how the mutations cause primary familial brain calcification. The altered signaling may result in an abnormally large amount of calcium entering the cells that line blood vessels in the brain, leading to calcification of these blood vessels. Alternatively, changes in PDGFRB signaling could disrupt processes that regulate levels of phosphate and calcium in brain cells, leading to the formation of calcium deposits. Other genes known to be associated with primary familial brain calcification also have roles in cell signaling and phosphate homeostasis.

Researchers suggest that calcium deposits lead to the features of primary familial brain calcification by disrupting the connections between the basal ganglia and other areas of the brain, particularly the frontal lobes. These areas at the front of the brain are involved in reasoning, planning, judgment, and problem-solving. The regions of the brain that regulate social behavior, mood, and motivation may also be affected.

Research has shown that people with significant calcification tend to have more signs and symptoms of primary familial brain calcification than people with little or no calcification. However, this association does not apply to all people with primary familial brain calcification.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

In most cases, primary familial brain calcification 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 has one parent with the condition.

Less commonly, primary familial brain calcification is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Primary familial brain calcification was thought to be a rare disorder; however, because brain imaging tests are needed to see the calcium deposits, this condition is believed to be underdiagnosed. Recent research has indicated that primary familial brain calcification may occur in 2 to 6 per 1,000 people, with many affected individuals not showing signs and symptoms of the condition.

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.

Anxiety · Frequent (79-30%)

Intense feelings of nervousness, tension, or panic often arise in response to interpersonal stresses. There is worry about the negative effects of past unpleasant experiences and future negative possibilities. Individuals may feel fearful, apprehensive, or threatened by uncertainty, and they may also have fears of falling apart or losing control.

Basal ganglia calcification · Frequent (79-30%)

The presence of calcium deposition affecting one or more structures of the basal ganglia.

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).

Choreoathetosis · Frequent (79-30%)

Involuntary movements characterized by both athetosis (inability to sustain muscles in a fixed position) and chorea (widespread jerky arrhythmic movements).

Dementia · Frequent (79-30%)

A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.

Headache · Frequent (79-30%)

Cephalgia, or pain sensed in various parts of the head, not confined to the area of distribution of any nerve.

Mask-like facies · Frequent (79-30%)

A lack of facial expression often with staring eyes and a slightly open mouth.

Personality changes · Frequent (79-30%)

An abnormal shift in patterns of thinking, acting, or feeling.

Other findings in the same source

From: Orphanet

Additional reported features include Psychosis (Frequent (79-30%)); Rigidity (Frequent (79-30%)); Seizure (Frequent (79-30%)); Tremor (Frequent (79-30%)); Vertigo (Frequent (79-30%)); Bilateral basal ganglia lesions (Frequent (79-30%)); Progressive neurologic deterioration (Frequent (79-30%)); Abnormal pyramidal sign (Occasional (29-5%)); Clumsiness (Occasional (29-5%)); Diminished ability to concentrate (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Primary familial brain calcification 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 Primary familial brain calcification. 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.