Clinical characteristics: Primary familial brain calcification (PFBC) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with a gradually progressive movement disorder and neuropsychiatric symptoms. The movement disorder first manifests as clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia. Seizures of various types occur frequently, some individuals experience chronic headache and vertigo; urinary urgency or incontinence may be present.
Diagnosis/testing: The diagnosis of PFBC relies on: visualization of bilateral calcification of the basal ganglia on neuroimaging; presence of progressive neurologic dysfunction; and absence of metabolic, infectious, toxic, or traumatic cause. A family history consistent with autosomal dominant inheritance is often found as well. Thus, the diagnosis of PFBC should be left for those cases where other neurologic or systemic disorders potentially associated with ectopic calcium deposits have not been identified after appropriate examinations. A heterozygous pathogenic variant in PDGFB, PDGFRB, SLC20A2, or XPR1 has been identified in a little more than half of those individuals with a clinical diagnosis of PFBC.
Management: Treatment of manifestations: Pharmacologic treatment to improve anxiety, depression, obsessive-compulsive behaviors, as well as for movement disorders (e.g., tremors) or dystonia; anticholinergics for urinary incontinence; anti-seizure medication for seizures.
Surveillance: Annual neurologic and neuropsychiatric assessments.
Agents/circumstances to avoid: Cautious use of neuroleptic medications as they may exacerbate extrapyramidal symptoms.
Genetic counseling: PFBC is inherited in an autosomal dominant manner. Most individuals diagnosed with PFBC have an affected parent identified either clinically or by brain CT scan. However, the transmitting parent may be clinically asymptomatic throughout life or may develop disease manifestations that are later in onset or less severe than those in the proband. If a parent of the proband is affected and/or is known to be heterozygous for a PFBC-related pathogenic variant, sibs of a proband are at a 50% risk of inheriting the pathogenic variant; however, the risk to sibs of being clinically affected may be slightly lower due to reduced penetrance. Offspring of an affected individual have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.
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