Primary Familial Brain Calcification

Alternate names

FIBGC (formerly); Idiopathic basal ganglia calcification 1; Fahr's Syndrome (formerly); Bilateral striopallidodentate calcinosis; BSPDC; Cerebral calcification nonarteriosclerotic idiopathic adult-onset; Striopallidodentate calcinosis autosomal dominant adult-onset; Ferrocalcinosis, cerebrovascular; Fahr disease, familial (formerly); Primary familial brain calcification; Familial idiopathic basal ganglia calcification (formerly)

Definition

Primary familial brain calcification (PFBC) is a neurodegenerative disorder characterized by calcium deposits in the basal ganglia, a part of the brain that helps start and control movement.

Cause

PFBC is a genetic condition. Mutations in the SLC20A2 gene are thought to cause about half of the cases of PFBC. Mutations in the PDGFRB and PDGFB genes have also been shown to cause PFBC. In some cases, the genes responsible have not yet been found. 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.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

PFBC is inherited in an autosomal dominant manner.[1].

Onset

Symptoms typically start in an individual's 30's to 40's but may begin at any age. The neuropsychiatric symptoms and movement disorders worsen over time.

Signs and symptoms

• The first symptoms often include clumsiness, fatigue, unsteady walking (gait), slow or slurred speech, difficulty swallowing (dysphagia) and dementia.
• Migraines and seizures frequently occur.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Abnormality of neuronal migration
• Cerebral calcification(Abnormal deposits of calcium in the brain)
• Hepatomegaly(Enlarged liver)
• Intrauterine growth retardation(Prenatal growth deficiency)
• Microcephaly(Abnormally small skull)
• Seizure
• Subcutaneous hemorrhage(Bleeding below the skin)
• Thrombocytopenia(Low platelet count)
• Ventriculomegaly

30%-79% of people have these symptoms

• Corneal opacity

5%-29% of people have these symptoms

• Abnormal pyramidal sign

Diagnosis

The diagnosis of PFBC relies upon: 1) visualization of bilateral (on both sides) calcification of the basal ganglia on neuroimaging, 2) presence of progressive neurological dysfunction, 3) absence of a metabolic, infectious, toxic, or traumatic cause, and 4) a family history consistent with autosomal dominant inheritance (a person must inherit one copy of the altered gene from one parent to have the condition). Molecular genetic testing can help confirm the diagnosis.

• Genetic testing may help to confirm the diagnosis.
• For individuals in who a diagnosis of PFBC is being considered, other causes of brain calcification should be eliminated prior to pursuing genetic testing, particularly in simplex cases.
• Testing that might be done includes biochemical analysis of blood and urine, as well as analysis of cerebrospinal fluid.
• If no other primary cause for brain calcification is detected or if the family history is suggestive of autosomal dominant inheritance, molecular genetic testing should be considered.
• Sequencing of SLC20A2 should be pursued first.
• If no mutation is identified, deletion/duplication analysis of SLC20A2 may be considered.
• If no identifiable mutation or deletion in SLC20A2 is found, sequence analysis of PDGFRB and PDGFB may be considered.

Treatment

• There is no standard course of treatment for PFBC.
• Treatment typically addresses symptoms on an individual basis.
• Medications may be used to improve anxiety, depression, obsessive-compulsive behaviors, and dystonia.
• Antiepileptic drugs (AEDs) can be prescribed for seizures.
• Oxybutynin may be prescribed for urinary incontinence (loss of bladder control).
• Surveillance typically includes yearly neurologic and neuropsychiatric assessments.

Prognosis

The prognosis for any individual with PFBC is variable and hard to predict. There is no reliable correlation between age, extent of calcium deposits in the brain, and neurological deficit.

NIH genetic and rare disease info

• NIH info on Primary Familial Brain Calcification

Primary Familial Brain Calcification is a rare disease.

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