Primary Familial Brain Calcification

Primary familial brain calcification is an inherited neurodegenerative disorder with bilateral, symmetrical calcium deposits in the basal ganglia, thalamus, dentate nuclei and subcortical white matter in the absence of a metabolic, infective or toxic cause. It was formerly called Fahr disease.

It is rare, with an estimated prevalence of about 1 in 20,000 to 1 in 1,000,000. Many carriers are asymptomatic. Symptoms usually start between 30 and 50 years.

Genetics. Autosomal dominant genes are SLC20A2 (most common, about 40%), PDGFB, PDGFRB and XPR1. MYORG and JAM2 cause autosomal recessive disease. About one third of patients have no variant identified.

Pathophysiology. The genes control phosphate transport and blood brain barrier integrity, and defects cause perivascular calcium phosphate deposition, with neurovascular unit damage.

Presentation is movement disorder (parkinsonism, dystonia, chorea, tremor, ataxia), cognitive decline (frontal and executive dysfunction), psychiatric symptoms (depression, psychosis, mood change, personality change), migraine, seizures and speech disorder. Features vary widely even within families.

CT head is the most sensitive test (bilateral calcification of the basal ganglia, thalamus and cerebellum). MRI is less sensitive for calcium. Exclude secondary causes: measure calcium, phosphate, magnesium, parathyroid hormone and vitamin D, and assess for pseudohypoparathyroidism, hypoparathyroidism, mitochondrial disease, infection (congenital infection, HIV), radiation, lead and carbon monoxide exposure, and Aicardi-Goutieres syndrome. Genetic testing confirms the cause.

Differential diagnosis.

• Physiological calcification of the globus pallidus in older adults.
• Hypoparathyroidism and pseudohypoparathyroidism, mitochondrial disease and Cockayne syndrome.
• Post-infectious and post-radiation calcification.

There is no treatment that removes calcium or changes the course. Care is symptomatic.

Movement disorders. Levodopa carbidopa 100/25 mg three times daily, increased gradually to 600 mg of levodopa daily as needed, with variable benefit. Botulinum toxin for focal dystonia, and trihexyphenidyl 1 mg daily increased cautiously for dystonia (avoid in older adults and in cognitive impairment). Tetrabenazine 12.5 mg daily increased to a maximum of 100 mg daily (monitor depression) for chorea.

Seizures. Levetiracetam 500 mg twice daily, increased to 1500 mg twice daily (adjust to eGFR) or other drugs.

Psychiatric and cognitive. Treat depression and psychosis with usual drugs, and avoid dopamine blocking drugs where possible. Cognitive rehabilitation and support.

Metabolic. Correct calcium, phosphate and parathyroid disorders when found.

Migraine. Usual preventive and acute treatment.

Family care. Genetic counselling and cascade testing with consent.

Monitoring. Annual neurological and cognitive review, with imaging only when clinically needed.

Referral and escalation. Refer to neurology and clinical genetics. Refer to psychiatry for psychosis or severe mood disorder.