Fahr's Disease Research Articles

Fahr’s Disease Presenting with Manic Symptoms

Bilateral striopallidodentate calcinosis, commonly known as Fahr's disease, is a rare syndrome characterised by symmetrical calcification over the basal ganglion and dentate nucleus. No case of Fahr's disease with associated manic symptoms has been described in the literature to date. We report an unusual case of Fahr's Disease in a 18 year old unmarried male who presented to the emergency department of Universal College of Medical Sciences - Teaching Hospital, Nepal with symptoms of mania. Computed tomographic scan of the patient demonstrated extensive symmetrical calcification over the basal ganglia and dentate nuclei. No underlying cause for the bilateral calcification was found. This rare case of Fahr's disease, which has never been reported in Indian literature has been reported to highlight this unusual condition and its differentiation from the commoner Fahr's syndrome.

MRI Cannot Detect Calcification for the Diagnosis of Fahr's Syndrome.

MRI Cannot Detect Calcification for the Diagnosis of Fahr's Syndrome.

Refractory focal epilepsy in a paediatric patient with primary familial brain calcification

Primary familial brain calcification (PFBC), otherwise known as Fahr’s disease, is a rare autosomal dominant condition with manifestations of movement disorders, neuropsychiatric symptoms, and epilepsy in a minority of PFBC patients. The clinical presentation of epilepsy in PFBC has not been described in detail. We present a paediatric patient with PFBC and refractory focal epilepsy based on seizure semiology and ictal EEG, but with generalized interictal EEG abnormalities. The patient was found to have a SLC20A2 mutation known to be pathogenic in PFBC, as well as a variant of unknown significance in SCN2A. This case demonstrates that the ictal EEG is important for accurately classifying epilepsy in affected subjects with PFBC. Further, epilepsy in PFBC may be a polygenic disorder.

Cerebrovascular disorders and Fahr's disease: Report of two cases and literature review

Fahr's disease is a rare idiopathic nosological entity, characterized by calcification of the basal ganglia and dentate nuclei of the cerebellum. Sometimes it may be associated to other diseases like cerebrovascular disorders. However, this link remains unclear and it needs to be further validated. We report two cases of patients with cerebrovascular disorders and Fahr's disease. In the first case, a 69-years-old woman with right internal capsule-basal ganglia haemorrhage. In the second case, a 72-years-old woman with ischemic stroke and pericallosal artery aneurysm. The physiopathology is discussed and concerning literature is reviewed.

Chapter 20 - Primary familial brain calcifications

Primary familial brain calcification (PFBC) is a neurodegenerative disease with characteristic calcium deposits in the basal ganglia and other brain regions. The disease usually presents as a combination of abnormal movements, cognitive and psychiatric manifestations, clinically indistinguishable from other adult-onset neurodegenerative disorders. The differential diagnosis must be established with genetic and nongenetic disorders that can also lead to calcium deposits in encephalic structures. In the past years PFBC causal mutations have been discovered in genes related to calcium phosphate homeostasis (SLC20A2, XPR1) and in genes involved with endothelial function and integrity (PDGFB, PDGFRB). The most frequently mutated gene is SLC20A2, where mutations can affect any domain of the protein. There is no clearcut relationship between the specific mutation/gene, onset age, neuroimaging pattern, and severity of clinical manifestations. The discovery of the genetic basis of PFBC provides not only a diagnostic tool, but also an insight into the pathomechanisms and potential therapeutic trials for this rare disease.

Anesthesia Management in Patient With Fahr Syndrome: A Case Report

Fahr sendromu, serebellum, bazal gangliyonlar gibi alanlarda simetrik intrakraniyal kalsifikasyonlarla karakterize norodejeneratif bir hastaliktir. Kalsiyum ve fosfor metabolizmasinin bozuk oldugu bu hastalikta hipokalseminin tespit ve tedavisi anestezi uygulamasi acisindan onem tasimaktadir. Olgu sunumunda 64 yasinda hipoparatiroidi ile iliskili Fahr Sendromu tanisi olan hastanin genel anestezi yonetimi irdelenmistir.

A Unique Presentation Of Fahr Syndrome Secondary To Chronic Hypoparathyroidism: A Case Report

Idiopathic basal ganglia calcification, or Fahr Syndrome, often presents in middle-aged patients presenting with parkinsonian symptoms. Unique presentation of young patient presenting with a seizure, and without the presence of parkinsonian symptoms. Imaging revealed near complete calcification of bilateral basal ganglia. Most common etiology of basal ganglia calcification is idiopathic or familial, but may also be secondary to metabolic derangements.

CT Diagnosis of Fahr disease, a case report

CT Diagnosis of Fahr disease, a case report

Serum Fetuin-A Levels in Patients with Bilateral Basal Ganglia Calcification

Background and PurposeThe idiopathic basal ganglia calcification (Fahr syndrome) may occur due to senility. Fetuin-A is a negative acute phase reactant which inhibits calcium-phosphorus precipitation and vascular calcification. In this study, we aimed to evaluate whether serum fetuin-A levels correlate with bilateral basal ganglia calcification. MethodForty-five patients who had bilateral basal ganglia calcification on brain CT were selected according to the inclusion and exclusion criteria, and 45 age and gender-matched subjects without basal ganglia calcification were included for the control group. Serum fetuin-A levels were measured from venous blood samples. All participants were divided into two groups; with and without basal ganglia calcification. These groups were divided into subgroups regarding age (18–32 and 33–45 years of age) and gender (male, female). ResultsWe detected lower levels of serum fetuin-A in patients with basal ganglia calcification compared with the subjects without basal ganglia calcification. In all subgroups (female, male, 18–32 years and 33–45 years), mean fetuin-A levels were significantly lower in patients with basal ganglia calcification (p = 0.017, p = 0.014, p = 0.024, p = 0.026, p = 0.01 respectively). And statistically significantly lower levels of fetuin-A was found to be correlated with the increasing densities of calcification in the calcified basal ganglia group (p-value: <0.001). ConclusionConsidering the role of fetuin-A in tissue calcification and inflammation, higher serum fetuin-A levels should be measured in patients with basal ganglia calcification. We believe that the measurement of serum fetuin-A may play a role in the prediction of basal ganglia calcification as a biomarker.

Calcitriol Reverses the Down-Regulation Pattern of Tuberous Sclerosis Complex Genes in an In Vitro Calcification Model.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with autosomal dominant inheritance, and most of the cases are related to loss of function of the TSC1 and TSC2 genes. TSC may occur with a wide range of clinical findings and skin, kidney, brain, and heart are the most commonly affected organs. Brain calcifications in TSC are also described and reported as diffuse and without pattern of symmetry or bilaterality. Recently, a new discovery opened the possibility of using vitamin D (VitD) for treating cerebral calcifications. Calcitriol, the active form of VitD, was able to reduce the calcification in an in vitro model, increasing expression of a gene related to primary familial brain calcification. We show that in the same experimental model, calcitriol was also able to restore and even increase expression of genes related to TSC. This article discusses the use of calcitriol supplementation in patients with TSC, which can be a very interesting strategy due to its low cost and because it is already used in various therapies.

Bilateral striopallidodentate calcinosis associated with Sjögren's syndrome and IgDλ monoclonal gammopathy of undetermined significance

We presented the first case of bilateral striopallidodentate calcinosis secondary to Sjögren's syndrome. Further consideration should be given to the association between Sjögren's syndrome and bilateral striopallidodentate calcinosis, because Sjögren's syndrome is latent, but more frequent than other autoimmune diseases.

Estimation of minimal disease prevalence from population genomic data: Application to primary familial brain calcification.

Primary Familial Brain Calcification (PFBC) is a rare calcifying disorder of the brain with autosomal dominant inheritance, of unknown prevalence. Four causal genes have been identified so far: SLC20A2, PDGFB, PDGFRB, and XPR1, with pathogenic, probably pathogenic or missense variants of unknown significance found in 27.7% probands in the French PFBC series. Estimating PFBC prevalence from a clinical input is arduous due to a large diversity of symptoms and ages of onset and to incomplete clinical penetrance. Abnormal calcifications on CT scan can be used as a reliable diagnostic biomarker whatever the clinical status, but differential diagnoses should be ruled out including the challenging exclusion of common basal ganglia calcifications. Our primary aim was to estimate the minimal prevalence of PFBC due to a variant in one of the known genes. We extracted variants from the four known genes present in the gnomAD database gathering genomic data from 138,632 individuals. We interpreted all variants based on their predicted effect, their frequency, and previous studies on PFBC patients. Using the most conservative estimate, the minimal prevalence of PFBC related to a variant in one of the four known genes was 4.5 p. 10,000 (95%CI [3.4-5.5] p. 10,000). We then used variant detection rates in patients to extrapolate an overall minimal prevalence of PFBC to 2.1 p. 1,000 (95%CI [1.9-2.4] p. 1,000). The population-based genomic analysis indicates that PFBC is not an exceptionally rare disorder, still underestimated and underdiagnosed.

Fahr's disease with Epilepsy: A Case Report

Fahr's disease with Epilepsy: A Case Report

Clinical and radiological diversity in genetically confirmed primary familial brain calcification

Primary familial brain calcification (PFBC) is a rare neuropsychiatric disorder with characteristic symmetrical brain calcifications. Patients with PFBC may have a variety of symptoms, although they also may be clinically asymptomatic. Parkinsonism is one of the most common movement disorders; however, the underlying mechanism remains unclear. This condition is typically transmitted in an autosomal dominant fashion. To date, mutations in SLC20A2, PDGFRB, PDGFB, and XPR1 have been reported to cause PFBC. The aim of the study was to identify the genetic cause of brain calcification in probands from three PFBC families and in 8 sporadic patients and to perform clinical and radiological assessments focusing on parkinsonism in mutation carriers. Three familial PFBC probands and their relatives and eight sporadic patients affected with brain calcifications were enrolled in this study. Whole-exome sequencing identified three novel mutations: c.269G > T, p.(Gly90Val) and c.516+1G > A in SLC20A2 in familial cases, and c.602-1G > T in PDGFB in a sporadic patient. The c.516+1G > A mutation resulted in exon 4 skipping in SLC20A2 (p.Val144Glyfs*85). Dopamine transporter single photon emission computed tomography using 123I-ioflupane and 123I-metaiodobenzylguanidine cardiac scintigraphy revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in two SLC20A2-related PFBC patients with parkinsonism.

Primary familial brain calcification with a novel SLC20A2 mutation: Analysis of PiT-2 expression and localization.

Primary familial brain calcification (PFBC) is an autosomal dominant rare disorder characterized by bilateral and symmetric brain calcifications, and neuropsychiatric manifestations. Four genes have been linked to PFBC: SLC20A2, PDGFRB, PDGFB, and XPR1. In this study, we report molecular and clinical data of a PFBC patient carrying a novel SLC20A2 mutation and we investigate the impact of the mutation on PiT-2 expression and function. Sanger sequencing of SLC20A2, PDGFRB, PDGFB, XPR1 led to the identification of a novel duplication of twelve nucleotides (c.1876_1887dup/ p.Trp626_Thr629dup) in SLC20A2 gene. SLC20A2 encodes for a cell membrane transporter (PiT-2) involved in maintenance of inorganic phosphate homeostasis. We performed an analysis of expression and functionality of PiT-2 protein in patient primary cultured fibroblasts. In patient fibroblasts, the mutation does not affect PiT-2 expression but alter sub-cellular localization. The Pi-uptake assay revealed a less Pi depletion in patient than in control fibroblasts, suggesting that SLC20A2 duplication may impair Pi internalization. This is the first study reporting sub-cellular expression analysis of mutant PiT-2 in primary cultured fibroblasts from a PFBC patient, showing that p.Trp626_Thr629dup in SLC20A2 alters PiT-2 sub-cellular localization and reduces Pi-uptake, leading to onset of PFBC in our patient.

FAHR'S Sy ndrome: A rare Neurodegenerative Disorder

Idiopathic Basal Ganglia Calcification, also known as Fahr disease or Fahr's Syndrome or Bilateral StriatoPallidoDentate Calcinosis (BSPDC) is a rare, genetically dominant, inherited neurological disorder characterized by abnormal deposits of calcium in areas of the brain that control movement, including the basal ganglia and the cerebral cortex. A rare idiopathic disease which manifests in middle age characterized by punctate areas of non-arteriosclerotic calcination in parts of the gray and dentate nuclei, particularly of smaller brain vessels. The symptoms include mental and growth retardation, dystonic movements, and athetosis. May be caused by a malfunction of the glandula parathyreoidea. The term Fahr triad consists of symmetrical calcification of the basal ganglia, neuropsychiatric symptoms, and hypofunction of the parathyroid gland. Treatment is directed toward minimizing symptoms. The prognosis for any individual with Fahr's Syndrome is variable and hard to predict. Progressive neurological deterioration generally results in disability and death.Medicine Today 2017 Vol.29(1): 39-41

Fahr's Syndrom e: A rare case- Presented as Acute Ischaemic Stroke

Fahr's syndrome refers to a rare syndrome characterized by symmetrical and bilateral intracranial calcification. We present a 65-year-old female with Fahr disease, presenting with headache with acute ischaemic stroke with left sided hemiplegia. CT scan of brain reveals irregular variable size hyperdense areas are noted in both basal ganglia regions and in both cerebellar hemisphere.Medicine Today 2017 Vol.29(1): 45-46

Analysis of gene expression and functional characterization of XPR1: a pathogenic gene for primary familial brain calcification.

Primary familial brain calcification (PFBC) is a neuropsychiatric disorder characterized by bilateral cerebral calcification with diverse neurologic or psychiatric symptoms. Recently, XPR1 variation has accounted for PFBC as another new causative gene. However, little is known about the distribution and basic function of XPR1 and its interaction with the other three pathogenic genes for PFBC (SLC20A2, PDGFRB and PDGFB). The aim of this study was to further clarify the role of XPR1 in PFBC brain pathology. As a result, gene expression profiles showed that XPR1 mRNA was widely expressed throughout the mouse brain. Cerebellum and striatum, most commonly affected in PFBC, contained a higher level of XPR1 protein than other brain regions. Additionally, XPR1 deficiency seriously affected Pi efflux and XPR1 mutations seemed to have an effect through haploinsufficiency mechanism. The immunoprecipitation and immunohistochemical studies demonstrated that XPR1 could interact with PDGFRB and might form a complex on the cell membrane. These results suggested that XPR1 played a fundamental role in the maintenance of cellular phosphate balance in the brain. This provided us with a novel perspective on understanding the pathophysiology of PFBC. The expression networks and interaction with the known pathogenic genes could shed new light on additional candidate genes for PFBC.

Induced pluripotent stem cells derived from a patient with familial idiopathic basal ganglia calcification (IBGC) caused by a mutation in SLC20A2 gene

Idiopathic basal ganglia calcification (IBGC), also known as Fahr disease or primary familial brain calcifications (PFBC), is a rare neurodegenerative disorder characterized by calcium deposits in basal ganglia and other brain regions, causing neuropsychiatric and motor symptoms. We established human induced pluripotent stem cells (iPSCs) from an IBGC patient. The established IBGC-iPSCs carried SLC20A2 c.1848G>A mutation (p.W616* of translated protein PiT2), and also showed typical iPSC morphology, pluripotency markers, normal karyotype, and the ability of in vitro differentiation into three-germ layers. The iPSC line will be useful for further elucidating the pathomechanism and/or drug development for IBGC.

Brain calcifications and PCDH12 variants.

Objective:To assess the potential connection between PCDH12 and brain calcifications in a patient carrying a homozygous nonsense variant in PCDH12 and in adult patients with brain calcifications.Methods:We performed a CT scan in 1 child with a homozygous PCDH12 nonsense variant. We screened DNA samples from 53 patients with primary familial brain calcification (PFBC) and 26 patients with brain calcification of unknown cause (BCUC).Results:We identified brain calcifications in subcortical and perithalamic regions in the patient with a homozygous PCDH12 nonsense variant. The calcification pattern was different from what has been observed in PFBC and more similar to what is described in in utero infections. In patients with PFBC or BCUC, we found no protein-truncating variant and 3 rare (minor allele frequency <0.001) PCDH12 predicted damaging missense heterozygous variants in 3 unrelated patients, albeit with no segregation data available.Conclusions:Brain calcifications should be added to the phenotypic spectrum associated with PCDH12 biallelic loss of function, in the context of severe cerebral developmental abnormalities. A putative role for PCDH12 variants remains to be determined in PFBC.