NORD gratefully acknowledges Dr Joao Ricardo Mendes de Oliveira, MD, PhD, Department of Neuropsychiatry, Federal University of Pernambuco, Brazil, for assistance in the preparation of this report.
Primary familial brain calcification (PFBC) is a rare neurological disorder characterized by the presence of abnormal calcium deposits (calcifications) of unknown cause. Associated symptoms include progressive deterioration of cognitive abilities (dementia), loss of contact with reality (psychosis), mood swings and loss of acquired motor skills. As the condition progresses, paralysis may develop that is associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Additional abnormalities may include relatively slow, involuntary, continual writhing movements (athetosis) or chorea, a related condition characterized by irregular, rapid, jerky movements.Introduction
Primary familial brain calcification has recently become the preferred name for this condition because mutations in specific genes are now known to be the cause. Previously, familial idiopathic basal ganglia calcification was the preferred name. Fahr's disease is often used for either familial or sporadic basal ganglia calcification, and it is unknown if these are the same or different diseases.
PFBC is characterized by abnormal calcium deposits in the basal ganglia, dentate nucleus, thalami and cerebral white matter of the brain and may be found as early as the first decade of life. Neuropsychiatric symptoms usually begin in the third to fifth decade. Early symptoms may include clumsiness, fatigue, slow or slurred speech and difficulty swallowing (dysphagia). Some individuals with PFBC remain free of symptoms for several decades. Progressive deterioration of mental abilities (dementia) and loss of previous motor development are accompanied by spastic paralysis and in some cases, twisting movements of the hands and feet (athetosis). Features of Parkinson disease found in this disorder may include tremors and rigidity, a masklike facial expression, shuffling walk, and a pill rolling motion of the fingers. Muscle cramping (dystonia), uncontrollable spasmodic irregular movements (chorea), and seizures can also occur. Occasional symptoms include sensory changes, headaches and urinary incontinence.
Wang et al. (2012) reported 7 families with PFBC from China, Spain and Brazil, with different mutations in the SLC20A2 gene on chromosome 8, encoding for a phosphate inorganic transporter (PIT-2). More than 50 mutations in this gene have been identified (Lemos et al, 2015).
More recently, three other genes have been linked to PFBC: the beta subunit of platelet-derived growth factor (PDGFB) and its receptor (PDGFRB), which are involved in the blood brain barrier integrity and in the rate of inorganic phosphate incorporation by the PIT-1 molecule (Nicolas et al., 2013; Keller et al., 2013); and most recently, the XPR1 gene, which is involved in intracellular phosphate homeostasis (Legati et al., 2015).
A recent analysis suggests that males are more severely affected than females, especially those who have SLC20A2 gene mutations, followed by those with PDGFB and PDGFRB gene mutations (Nicolas et al, 2015).
PFBC is inherited as an autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. It is not known how many people have PFBC as a result of a new gene mutation. In such situations, the disorder is not inherited from the parents.
The prevalence of PFBC is unknown but more people are being diagnosed, probably due to the growing availability of neuroimaging screening.
Neuroimaging techniques such as computed tomography (CT) of the brain (the most sensitive technique), magnetic resonance imaging (MRI) and skull X-rays are used to diagnose calcification of the basal ganglia. This finding in combination with a progressive movement disorder, neuropsychiatric problems beginning in the 40’s or 50’s, a lack of biochemical abnormalities or other known causes (infection, toxic exposure, trauma) make the diagnosis very likely.
No specific treatment is known for PFBC. Medications can be used to treat symptoms associated with this condition, such as movement disorders, seizures, anxiety, depression, psychosis and urinary incontinence. Off label prescription of biphosphanates have been reported in few cases (Loeb et al, 1998, 2006).
Genetic counseling is recommended for affected individuals and their families, especially for those with mutations in SLC20A2, PDGFB, PDGFRB or XPR1 genes.
Speech and gait were improved in one patient treated with disodium etidronate, but other neurologic symptoms and calcification were unchanged.
Levodopa therapy was found to be effective in treating parkinsonian features in one individual who had PFBC and Parkinson disease.
The anticonvulsant oxcarbazepine was effective in treating a Turkish patient with basal ganglia calcification and dyskinesia.
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Contact for additional information about primary familial brain calcification :
João Ricardo Mendes de Oliveira, MD, PhD
Federal University of Pernambuco
Av. Prof. Moraes Rego, 1235
Cidade Universitária, Recife
PE, 50670-901, Brazil
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