Última actualización:
8/16/2023
Años publicados: 1989, 1996, 1999, 2000, 2009, 2012, 2015, 2018, 2023
NORD gratefully acknowledges Paula Vitória Macêdo de Barros and Ihgu Lucena, Graduate Program/LIKA-UFPE, and João Ricardo Mendes de Oliveira, MD, PhD, Keizo Asami Laboratory (LIKA) – Universidade Federal de Pernambuco and Medical Sciences Center, Recife-PE, Brazil, for assistance in the preparation of this report. Dr. Rayssa Leal Borges-Medeiros and Dr. Laura Durão Ferreira contributed to earlier versions 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 heterogeneous, ranging from asymptomatic patients to severe cases with progressive neuropsychiatric features. To date, disease-causing changes (pathogenic variants or mutations) in six genes have been associated with PFBC: SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM-2. PFBC has recently become the preferred name for this condition because variants in specific genes are now known to be the cause of the condition. Previously, familial idiopathic basal ganglia calcification was the preferred name, and Fahr’s disease is often used for either familial or sporadic brain calcification, and it is unknown if these are the same or different diseases.
PFBC is characterized by symmetric and bilateral brain calcifications mainly in the basal ganglia, but also seen in the cerebellum, thalami, cerebral white matter and/or pons. These calcium phosphate deposits are commonly found in the fourth to fifth decade of life, while symptoms usually begin in the third to fifth decade of life, even though some individuals with PFBC may be clinically asymptomatic for several decades. PFBC is rare among children but, when present, most of these children present with seizures. Neuropsychiatric and movement disorders are the main PFBC clinical presentations in adults.
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 characterized by irregular, rapid, jerky moves (chorea) and seizures can also occur. Occasional symptoms include sensory changes, headaches and urinary incontinence. Other associated symptoms include loss of contact with reality (psychosis), mood swings, depression and loss of acquired motor skills. As the condition progresses, paralysis may develop associated with increased muscle stiffness (rigidity) and restricted movements (spastic paralysis). Recently, stroke in young people with no risk factors has been related to MYORG gene variants (Yang et al, 2022).
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 variants, followed by those with PDGFB and PDGFRB gene variants (Nicolas et al., 2015).
PFBC is caused by variants 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 have also been reported.
As previously mentioned, 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, being the same for males and females. Variants in 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 variants in the SLC20A2 gene on chromosome 8, encoding for a phosphate inorganic transporter (PiT-2). In the following years, more than 50 variants in this gene have been identified, and variants 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 must be inherited from both parents in order to cause the disease in children. So far, two genes have been linked to a recessive pattern: MYORG and JAM-2 (Yao et al., 2018; Schottlaender et al, 2020). Patients with variants in these genes are generally more severely affected. Patients with MYORG gene variants often have calcification present in the pons as a very predictable finding.
Lastly, in some individuals the disorder is due to spontaneous (de novo) genetic variants that may occur in the egg or sperm cell. It is not known how many people have PFBC as a result of a new gene variant, but there is a case linked to SLC20A2 and twins linked to PDGFB pathogenic variants. In such situations, the disorder is not inherited from the parents, but can still be passed on to children (with a 50% chance for each child) (Keller et al, 2013; Ferreira et al, 2014).
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 by Nicolas and collaborators 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, which means the disease is much more common than previously considered (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.
Genetic testing for variants in genes that cause PFBC (SLC20A2, PDGFB, PDGFRB, XPR1, MYORG and JAM-2), should be performed, as this is currently the best way to determine with certainty if an individual has PFBC. The molecular genetic testing may be DNA sequencing, whole exome sequencing (WES) or whole genome sequencing (WGS).
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, headaches, depression, psychosis and urinary incontinence (Oliveira JRM, 2011). Medications established in psychiatric clinical practice are generally prescribed to control other disorders, such as mood stabilizers (mainly anticonvulsants) that may be useful in managing depressive symptoms, irritability, euphoria or agitation. Antipsychotics are also used to treat symptoms such as delusions and hallucinations, but they are also useful for managing psychomotor agitation.
Genetic counseling is recommended for affected individuals and their relatives, especially for those with mutations in PFBC-associated genes.
Biphosphanates have been prescribed to treat some patients, with variable clinical response including no response and positive improvements. (Loeb et al., 1998, 2006, Oliveira & Oliveira, 2016). These medications are not specifically approved by the U.S. Food and Drug Administration (FDA) to treat PFBC.
A large-scale study, named CALCIFADE, is under development and sponsored by University Medical Center Utrecht and the Netherlands Brain Foundation (clinicaltrials.gov/ct2/show/NCT05662111) to follow patients with brain calcification under treatment with a biphosphanate.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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
Phone: 55-81-987819856
[email protected]
TEXTBOOKS
Oliveira JRM. Managing Idiopathic Basal Ganglia Calcification (“Fahr’s Disease”). New York: Nova Publishing; 2011.
Manyam BV. Fahr Disease. In: The NORD Guide to Rare Disorders. Lippincott, Williams and Wilkins; 2003:532.
JOURNAL ARTICLES
Yang Q, Li J, Jiao B, Weng L. Primary familial brain calcification in a patient with a novel compound heterozygous mutation in MYORG presenting with an acute ischemic stroke: a case report. Ann Transl Med. 2022 Apr;10(7):423. doi: 10.21037/atm-21-4883. PMID: 35530931; PMCID: PMC9073774.
Schottlaender LV, Abeti R, Jaunmuktane Z, Macmillan C et al. Bi- allelic JAM2 variants lead to early-onset recessive primary familial brain calcification. Am J Hum Genet. 2020 Mar5;106(3):412-421.
Knowles JK, Santoro JD, Porter BE, Baumer FM. Refractory focal epilepsy in a paediatric patient with primary familial brain calcification. Seizure. 2018 Mar;56:50-52. doi: 10.1016/j.seizure.2018.02.001. Epub 2018 Feb 6. PMID: 29448117; PMCID: PMC5899664.
Ramos EM, Carecchio M, Lemos R, et al. Primary brain calcification: an international study reporting novel variants and associated phenotypes. Eur J Hum Genet. 2018; 26:1462-77.
Yao XP, Cheng X, Wang C, et al. Biallelic Mutations in MYORG Cause Autosomal Recessive Primary Familial Brain Calcification. Neuron. 2018;98:1116-23.
Oliveira JR, Oliveira MF. Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate. Sci Rep. 2016;6:22961. Published 2016 Mar 15. doi:10.1038/srep22961
Legati A, Giovannini D, Nicolas G, et al. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet. 2015;47:579-81.
Lemos RR, Ramos EM, Legati A, et al. Update and Mutational Analysis of SLC20A2: A Major Cause of Primary Familial Brain Calcification. Hum Mutat. 2015;36:489-95.
Nicolas G, Charbonnier C, de Lemos RR, et al. Brain calcification process and phenotypes according to age and sex: Lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers. Am J Med Genet B Neuropsychiatr Genet. 2015;168:586-94.
Ferreira JB, Pimentel L, Keasey MP, et al. First report of a de novo mutation at SLC20A2 in a patient with brain calcification. J Mol Neurosci. 2014;54:748-51.
Keller A, Westenberger A, Sobrido MJ, et al. Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet. 2013;45:1077-82.
Nicolas G, Pottier C, Maltête D, et al. Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology. 2013;80:181-7.
Wang C, Li Y, Shi L, et al. Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet. 2012;44:254-6.
Alemdar M, Selek A, Iseri P, et al. Fahr’s disease presenting with paroxysmal non-kinesigenic dyskinesia: a case report. Parkinsonism Relat Disord. 2008;14:69-71.
Weisman DC, Yaari R, Hansen LA, Thal LJ. Density of the brain, decline of the mind: an atypical case of Fahr disease. Arch Neurol. 2007;64:756-7.
Baba Y, Broderick DF, Uitti RJ, et al. Heredofamilial brain calcinosis syndrome. Mayo Clin Proc. 2005;80:641-51.
Manyam BV. What is and what is not ‘Fahr’s disease’. Parkinsonism Relat Disord. 2005;11:73-80.
Modrego PJ, Mojonero J, Serrano M, Fayed N. Fahr’s syndrome presenting with pure and progressive presenile dementia. Neurol Sci. 2005;26:367-9.
Manyam BV, Walters AS, Keller IA, Ghobrial M. Parkinsonism associated with autosomal dominant bilateral striopallidodentate calcinosis. Parkinsonism Relat Disord. 2001;7:289-95.
Manyam BV, Walters AS, Narla KR. Bilateral striopallidodentate calcinosis: clinical characteristics of patients seen in a registry. Mov Disord. 2001;16:258-64.
INTERNET
Ramos EM, Oliveira J, Sobrido MJ, et al. Primary Familial Brain Calcification. 2004 Apr 18 [Updated 2017 Aug 24]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1421/
Accessed August 15, 2023.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Basal Ganglia Calcification, Idiopathic,1; IBGC1. Entry No: 213600. Last Edited: 03/27/2020. Available at: https://omim.org/entry/213600 Accessed August 15, 2023.
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