NORD gratefully acknowledges Rayssa Leal Borges-Medeiros and Laura Durão Ferreira, Graduate Program/LIKA-UFPE, and João Ricardo Mendes de Oliveira, MD, PhD, Keizo Asami Laboratory (LIKA)-Universidade Federal de Pernambuco, Recife-PE, Brazil, for assistance in the preparation of this report.
Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by the presence of abnormal calcium/hydroxyapatite deposits (calcifications) in the brain. The clinical presentations generally attributed to these brain calcifications are highly variable, ranging from asymptomatic patients, to severely affected patients with progressive neuropsychiatric features. To date, pathogenic mutations in five genes have been associated with PFBC: SLC20A2, PDGFB, PDGFRB, XPR1 and, just recently, MYORG.
Primary familial brain calcification (PFBC) has recently become the preferred name for this condition because mutations in specific genes are now known to cause the disease. Previously, familial idiopathic basal ganglia calcification was the preferred name, and Fahr's disease is often used for either familial or sporadic brain calcification. It is unknown if these are the same or different diseases.
PFBC is characterized by symmetric and bilateral brain calcifications mainly in the basal nuclei, but also seen in the cerebellum (dentate nucleus), thalami and/or cerebral white matter. These calcium deposits are commonly found in the fourth to fifth decade of life, while neuropsychiatric symptoms (when present) usually begin in the third to fifth decade of life. Additionally, some individuals with PFBC may be clinically asymptomatic for several decades.
Early symptoms may include clumsiness, fatigue, slow or slurred speech and difficulty swallowing (dysphagia). Progressive deterioration of mental/cognitive abilities (dementia) and loss of previous motor development are accompanied by spastic paralysis and in some patients, twisting movements of the hands and feet (athetosis). Features of Parkinson disease found in this disorder may include tremors and rigidity (Parkinsonism), 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.
Associated symptoms include 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.
A recent study indicated that Parkinsonism was the most frequent symptom in a group of 44 PFBC patients, followed by cognitive impairment, psychiatric symptoms and cerebellar signs (Ramos et al., 2018). Other analyses have also suggested 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 caused by mutations in several different genes, and it can either be inherited or develop spontaneously. In inherited cases, the vast majority follow autosomal dominant inheritance, but autosomal recessive inheritance and new gene mutations in an affected person have also been reported.
Autosomal dominant genetic disorders occur when a single copy of an abnormal gene is necessary to cause a disease. The abnormal gene can be inherited from either parent, and the risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy, and is the same for males and females. Four different genes have been described to cause PFBC in an autosomal dominant fashion: SLC20A2, PDGFB, PDGFRB and XPR1.
Wang and colleagues (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). In the following years, more than 50 mutations in this gene have been identified, and mutations in this gene are the most common cause of PFBC (Lemos et al., 2015).
Since then, three other genes have been linked to autosomal dominant forms of PFBC: the beta subunit of platelet-derived growth factor (PDGFB) and its receptor (PDGFRB), which are involved in the blood brain barrier integrity (Nicolas et al., 2013; Keller et al., 2013); and more recently, the xenotropic and polytropic retrovirus receptor 1 (XPR1) gene, which is involved in intracellular phosphate homeostasis (Legati et al., 2015).
Autosomal recessive genetic disorders occur when two copies of an abnormal gene are necessary to cause a disease. The abnormal gene then has to be inherited from both parents in order to cause the disease in the offspring. So far, the only gene reported to be involved with an autosomal recessive form of PFBC was the MYORG gene (previously known as KIAA1161 or NET37) on chromosome 9, affecting 6 unrelated Chinese families (Yao et al., 2018).
Lastly, in some individuals the disorder is due to spontaneous (de novo) genetic mutations that may occur in the egg or sperm cell. It is not known how many people have PFBC as a result of new gene mutations. In such situations, the disorder is not inherited from the parents, but can still be passed on to the offspring (with a 50% chance).
The prevalence of PFBC is unknown, but more people are being diagnosed probably due to the growing availability of neuroimaging screening and genetic testing.
A recent study indicates that the prevalence of PFBC may be higher than what was initially thought. Through a population-based genomic analysis, the authors estimated that the prevalence of the condition ranges from 4.5/10,000 to 2.1/1,000 (Nicolas et al., 2018).
Neuroimaging techniques such as computed tomography (CT) of the brain (the most sensitive technique) and magnetic resonance imaging (MRI) are used to diagnose the calcium deposits in the brain. Although not necessary, the combination of these findings with a progressive movement disorder, neuropsychiatric problems beginning in the 40’s or 50’s, and a lack of biochemical abnormalities or other known causes (infection, toxic exposure, trauma) makes the diagnosis very likely.
Additionally, genetic screening for mutations on PFBC-causative genes SLC20A2, PDGFB, PDGFRB, XPR1 and MYORG should be performed, as it is currently the best way to determine with certainty if an individual has PFBC or not. This screening requires molecular diagnostic tests on DNA and can usually be performed by either private diagnostic laboratories or PFBC research groups. The molecular assays may be a simple DNA sequencing or any high-throughput DNA sequencing technologies, such as whole exome sequencing (WES) or whole genome sequencing (WGS).
Genetic counseling is recommended for affected individuals and their relatives, especially for those with mutations in PFBC-associated genes.
To date, no specific treatment for PFBC is known. 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 patients (Loeb et al., 1998, 2006, Oliveira & Oliveira, 2017).
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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