Familial Idiopathic Basal Ganglia Calcification Research Articles

Teaching Neuro Images : Fahr syndrome caused by hypoparathyroidism

A 57-year-old woman with a remote history of thyroidectomy but no prior neurologic symptoms developed seizures, fever, and coma. Limited evaluation at her local hospital in rural Haiti demonstrated serum hypocalcemia (4 mg/dL) and extensive bilateral subcortical calcification in the cerebral and cerebellar hemispheres on CT (figure). This pattern of calcification can occur in inherited conditions such as familial idiopathic basal ganglia calcification (Fahr disease) and acquired conditions (referred to as Fahr syndrome) including parathyroid dysfunction and intrauterine infection.1,2 Given our patient's severe hypocalcemia, Fahr syndrome was attributed to presumed hypoparathyroidism related to prior thyroidectomy in her case.

Familial Idiopathic Basal Ganglia Calcification: A Father-Son Dyad Demonstrate Heterogeneity of Presentation and Disease Progression.

Familial idiopathic basal ganglia calcification (FIBGC) is a rare, heritable disease characterized by calcium deposition in the basal ganglia and other brain regions. Clinical presentations are diverse, featuring an array of neurologic, psychiatric, and/or cognitive symptoms. This dyad report presents neurogenetic, neuroimaging, neurological, and serial neuropsychological data from a father (S1) and son (S2) with FIBGC. The SLC20A2 genetic mutation c.1828-1831delTCCC was identified for each patient, both of whom evidenced similar patterns of brain calcification mainly in the basal ganglia and cerebellum on neuroimaging. S1's onset was in his late 60s with primary motor abnormalities followed by cognitive decline; S2's younger onset (late 30s) was characterized by predominant psychiatric symptoms and mild cognitive changes. Our unique, detailed longitudinal study revealed that both subjects demonstrated largely stable performance across most neuropsychological domains assessed. The subjects' differences in presentation demonstrate the variable expressivity in FIBGC even with the same pathogenic variant within a single family. Distinct phenotypes may be associated with age of onset even in persons with the same mutation, consistent with past research. Disease progression may feature an initial period of notable change from baseline followed by relative stability, as seen both on imaging and neuropsychological evaluation.

A case of Fahr’s disease presenting as epilepsy

Fahr’s disease refers to sporadic or familial idiopathic basal ganglia calcification that is associated with many neurological, psychiatric and cognitive abnormalities. We report a case of Fahrs disease in a 25year old man who presented to us with generalized tonic clonic seizure and behavioral abnormalities. Clinical examination did not show any abnormal physical findings. The CT scan of brain showed multiple, symmetric and extensive calcifications in the basal ganglia, thalamus, and dentate nucleus, subcortical white matter of cerebral and cerebellar areas. Presently the patient is under follow up with good seizure control with phenytoin and sodium valproate. Keywords: Basal ganglia, Calcification, Fahr’s disease, Seizure.

A rare consortium of functional neurological disorder and Fahr’s disease - a herald of extensive calcification

Fahr’s disease is also known as familial idiopathic basal ganglia calcification affecting the cerebral microvessels and presenting with numerous neuropsychiatric manifestations. Functional neurological disorder (FND), a pure neuropsychiatric phenomenon occurs rarely in Fahr’s disease. Herein, we have presented a case of 17 year old female presenting neuropsychiatric symptoms like pseudoseizure, left sensorineural deficit and mild headache for last 4 months. Mental status examination revealed impaired attention and concentration. Laboratory examinations were within normal limits except CT scan and MRI Brain which revealed bilateral and symmetrical basal ganglia calcification. This is a rare case of FND associated with Fahr’s Disease, never reported in the literature. This case highlights the need for evaluating the biological factors in causation of FND where psychological factors were not assessed.

Fahr’s disease: familial idiopathic basal ganglia calcification with and without extrapyramidal disorders

Fahr’s disease (FD), also known as familial idiopathic basal ganglia calcification, is a neurodegenerative disease affecting cerebral micro vessels, mainly in the basal ganglia. It mostly presents with movement disorders, dementia and behavioral abnormalities. It is considered hereditary with an autosomal dominant transmission. Fahr’s disease is often underestimated and under diagnosed. We reported the clinical differences found in two patients with Fahr’s Disease. In particular, we described a case of Fahr’s disease with behavioral alteration with extrapyramidal movement disorders, and a rare case of Fahr’s disease with cognitive and behavioral alterations in absence of extrapyramidal movement disorders.

Fahr's disease: idiopathic abnormal basal ganglia calcifications in the brain

A 56-year-old diabetic man complains for isolated chronic headaches for many years. He denied any seizure, involuntary limb movements or blurring of vision. Physical examination was unremarkable for any focal neurological deficits. Cranial Computed tomography (CT) scan showed extensive symmetrical calcifications of the bilateral basal ganglia and over the lateral periventricular areas (figure). Laboratory studies including serum calcium, phosphate, parathormone, thyroid hormones and vitamins were within normal range. There was no other obvious etiology or family history of similar illness. Based on these findings, the patient was diagnosed with Fahr´s disease and was managed conservatively. Fahr´s disease (FAD), also known as “familial idiopathic basal ganglia calcification”, is a rare neurological disorder characterized by abnormal calcified deposits in the basal ganglia, cerebellum and subcortical white matter. FAD differs from Fahr´s syndrome in which there is an underlying cause for brain calcifications. Neurological and psychiatric symptoms are variable and may include deterioration of motor function, parkinsonism, seizures, headache, dysarthria, spasticity, visual disturbances, dementia, psychosis, and affective disorders. FAD could be easily confused with other more common neurological and psychiatric disorders. It is particularly important to not miss the treatable etiologies of Fahr´s syndrome. The diagnosis is based on the CT scan because it is difficult to identify calcifications by routine magnetic resonance imaging. Treatment is essentially symptomatic.

Partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of idiopathic basal ganglia calcification

Idiopathic basal ganglia calcification (IBGC) is a rare intractable disease characterized by abnormal mineral deposits, including mostly calcium in the basal ganglia, thalamus, and cerebellum. SLC20A2 is encoding the phosphate transporter PiT-2 and was identified in 2012 as the causative gene of familial IBGC. In this study, we investigated functionally two novel SLC20A2 variants (c.680C > T, c.1487G > A) and two SLC20A2 variants (c.82G > A, c.358G > C) previously reported from patients with IBGC. We evaluated the function of variant PiT-2 using stable cell lines. While inorganic phosphate (Pi) transport activity was abolished in the cells with c.82G > A, c.358G > C, and c.1487G > A variants, activity was maintained at 27.8% of the reference level in cells with the c.680C > T variant. Surprisingly, the c.680C > T variant had been discovered by chance in healthy members of an IBGC family, suggesting that partial preservation of Pi transport activity may avoid the onset of IBGC. In addition, we confirmed that PiT-2 variants could be translocated into the cell membrane to the same extent as PiT-2 wild type. In conclusion, we investigated the PiT-2 dysfunction of four SLC20A2 variants and suggested that a partial reduced Pi transport function of PiT-2 might not be sufficient to induce brain calcification of IBGC.

Primary familial brain calcification: a clinical case

Primary familial brain calcification (familial idiopathic basal ganglia calcification, Fahr’s disease) is a rare neurodegenerative syndrome characterised by a symmetrical bilateral calcification in the basal ganglia, dentate nucleus, cerebral cortex, and other regions of the brain. The widespread use of multislice computed tomography and magnetic resonance imaging increased the number of diagnosed cases, yet neither causes nor efficient treatment of this disease are known to date. Due to variable symptoms, primary familial brain calcification can resemble multiple neurological, mental, and endocrine disorders. Here we describe a case of a 38-year-old woman where timely multislice computed tomography led to the proper diagnosis and successful treatment.

Commentary on "Basal Ganglia Calcification: A Case Report of Fahr Disease With Pure Psychiatric Symptoms".

Fahr disease, also known as familial idiopathic basal ganglia calcification, is a rare neurodegenerative disorder, the etiology of which remains unknown. Given its various presentations, Fahr disease is presumed to be underdiagnosed and its prevalence underestimated. We present a case of Fahr disease that presented mainly with pure psychiatric symptoms. Isolated psychiatric symptoms without neurological manifestations are rarely seen in patients diagnosed with Fahr disease. Psychiatrists should consider Fahr disease as a differential diagnosis in the evaluation of psychiatric illness.

A Novel SLC20A2 Mutation Associated with Familial Idiopathic Basal Ganglia Calcification and Analysis of the Genotype-Phenotype Association in Chinese Patients.

Background:Idiopathic basal ganglia calcification (IBGC) is a genetic disorder characterized by bilateral basal ganglia calcification and neural degeneration. In this study, we reported a new SLC2OA2 mutation of IBGC and reviewed relevant literature to explore the association between phenotypes and genotypes in Chinese IBGC patients.Methods:Clinical information of the proband and her relatives were collected comprehensively. Blood samples of both the patient and her father were obtained, and genetic screening related to IBGC was performed using second generation sequencing with their consent. Findings were confirmed by Sanger sequencing. Polyphen-2 was used to predict the potential association between mutations and disease. Then, we retrieved literatures of Chinese IBGC patients and explored the association between phenotype and genotype.Results:A novel mutation was identified through genetic testing, and it is suggested to be a damage mutation predicted by Polyphen-2. Through literature review, we found that SLC20A2 mutation is the most common cause for IBGC in China. Its hot spot regions are mainly on the 1st and 8th exons; the second common one is PDGFB where the hot spot covered a length of 220–230 bp localized on the 2nd exon; moreover, Chinese IBGC patients featured early-onset, more severe movement disorder and relatively mild cognitive impairment compared with those in other countries.Conclusions:There is significant heterogeneity both in phenotype and genotype in Chinese IBGC patients. Further research of pathogenic mechanism of IBGC is required to eventually develop precise treatment for individuals who suffered this disease.

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.

Teaching NeuroImages: Fahr syndrome caused by hypoparathyroidism.

A 57-year-old woman with a remote history of thyroidectomy but no prior neurologic symptoms developed seizures, fever, and coma. Limited evaluation at her local hospital in rural Haiti demonstrated serum hypocalcemia (4 mg/dL) and extensive bilateral subcortical calcification in the cerebral and cerebellar hemispheres on CT (figure). This pattern of calcification can occur in inherited conditions such as familial idiopathic basal ganglia calcification (Fahr disease) and acquired conditions (referred to as Fahr syndrome) including parathyroid dysfunction and intrauterine infection.1,2 Given our patient's severe hypocalcemia, Fahr syndrome was attributed to presumed hypoparathyroidism related to prior thyroidectomy in her case.

A new SLC20A2 mutation identified in southern Italy family with primary familial brain calcification

BackgroundPrimary familial brain calcification (PFBC) is a rare neurodegenerative disease characterized by bilateral calcifications mostly located in the basal ganglia and in the thalami, cerebellum and subcortical white matter. Clinical manifestations of this disease include a large spectrum of movement disorders and neuropsychiatric disturbances. PFBC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. Three causative genes have been reported: SLC20A2, PDGFRB and PDGFB. ObjectiveWe screened three PFBC Italian families for mutations in the SLC20A2, PDGFRB and PDGFB genes. MethodsPhenotypic data were obtained by neurologic examination, CT scan and magnetic resonance imaging. Mutation screening of SLC20A2, PDGFRB and PDGFB was performed by sequencing. ResultsWe identified a new heterozygous deletion c.21_21delG (p.L7Ffs*10) in SLC20A2 gene in one of these families. No mutations were detected in the other two families. ConclusionsOur data confirm that mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

Clinical features of familial idiopathic basal ganglia calcification caused by a novel mutation in the SLC20A2 gene

To describe clinical and genetic feature in a Chinese family with familial idiopathic basal ganglia calcification 3 (IBGC-3) caused by a novel mutation in the SLC20A2 gene. Clinical data was collected from a family with familial IBGC-3. All of the family members underwent cerebral CT. Potential mutation of the SLC20A2 gene were screened in the proband, 5 symptomatic patients, 5 asymptomatic family members, and 100 healthy Chinese controls. Exon 8 of the SLC20A2 gene was cloned into plasmid and sequenced. There were 6 symptomatic patients (3 males and 3 females) in an autosomal dominant pedigree. The patients manifested as juvenile-onset paroxysmal kinesigenic dyskinesia, in addition to pyramidal signs in proband. 5 patients alive had calcification in bilateral basal ganglia and subcortical areas. One asymptomatic member also had calcification in the brain; and 2 cases of asymptomatic young members had bilateral globus pallidus calcification. A novel c.1086delC mutation in SLC20A2 gene has been identified in proband and 7 family members with intracranial calcification. The deletion mutation was not found in 2 family members without intracranial calcification and healthy controls members. There is no clear relationship between clinical symptoms and the severity of calcification in cerebral CT. Familial idiopathic basal ganglia calcification caused by the SLC20A2 gene mutation can manifest as juvenile onset paroxysmal kinesigenic dyskinesia. Further study should be done to validate the unrelated relationships between the severity of calcification in IBGC 3 cranial CT and clinical symptoms.

Familial idiopathic basal ganglia calcification (Fahr's disease) and diabetes mellitus: A review of literature

Familial idiopathic basal ganglia calcification (Fahr's disease) and diabetes mellitus: A review of literature

Fahr's Disease Linked to a Novel SLC20A2 Gene Mutation Manifesting with Dynamic Aphasia

Background: Idiopathic basal ganglia calcification (IBGC), also known as Fahr's disease, is a rare disorder characterized by widespread cerebral calcifications, an autosomal dominant pattern of inheritance and clinical and genetic heterogeneity. The recently identified IBGC gene, SLC20A2, encodes for type III sodium-dependent phosphate transporter 2 and its loss-of-function mutations may lead to the regional accumulation of inorganic phosphate in the brain, causing calcium phosphate deposition. Objective: To describe the clinical, neuroimaging and genetic findings in an Italian family with IBGC. Methods: The family members underwent clinical and radiological examination in order to diagnose IBGC according to standard criteria and screening for SLC20A2 gene mutations. The affected subjects also underwent neuropsychological longitudinal assessments and functional neuroimaging investigations. Results: The 2 affected family members harbored a novel missense mutation, G1618A, in the SLC20A2 gene, leading to gly540-to-arg (G540R) substitution in a highly conserved residue. This is the first SLC20A2 gene mutation associated with familial IBGC reported in the Italian population and is damaging according to all prediction programs. In the index case we observed a fair correlation between cortical areas with no calcifications but with significant hypometabolism at [18F]FDG-PET (inferior frontal premotor cortex) and the neuropsychological picture dominated by dynamic aphasia and buccofacial apraxia. Conclusion: These findings expand the catalog of SLC20A2 mutations identified to date and add dynamic aphasia to the spectrum of neuropsychological deficits reported in IBGC, supporting the use of functional neuroimaging studies for better investigation of genotype-phenotype correlations.

PDGF, pericytes and the pathogenesis of idiopathic basal ganglia calcification (IBGC).

Platelet-derived growth factors (PDGFs) are important mitogens for various types of mesenchymal cells, and as such, they exert critical functions during organogenesis in mammalian embryonic and early postnatal development. Increased or ectopic PDGF activity may also cause or contribute to diseases such as cancer and tissue fibrosis. Until recently, no loss-of-function (LOF) mutations in PDGF or PDGF receptor genes were reported as causally linked to a human disease. This changed in 2013 when reports appeared on presumed LOF mutations in the genes encoding PDGF-B and its receptor PDGF receptor-beta (PDGF-Rβ) in familial idiopathic basal ganglia calcification (IBGC), a brain disease characterized by anatomically localized calcifications in or near the blood microvessels. Here, we review PDGF-B and PDGF-Rβ biology with special reference to their functions in brain-blood vessel development, pericyte recruitment and the regulation of the blood-brain barrier. We also discuss various scenarios for IBGC pathogenesis suggested by observations in patients and genetically engineered animal models of the disease.

Evaluation of SLC20A2 mutations that cause idiopathic basal ganglia calcification in Japan

To investigate the clinical, genetic, and neuroradiologic presentations of idiopathic basal ganglia calcification (IBGC) in a nationwide study in Japan. We documented clinical and neuroimaging data of a total of 69 subjects including 23 subjects from 10 families and 46 subjects in sporadic cases of IBGC in Japan. Mutational analysis of SLC20A2 was performed. Six new mutations in SLC20A2 were found in patients with IBGC: 4 missense mutations, 1 nonsense mutation, and 1 frameshift mutation. Four of them were familial cases and 2 were sporadic cases in our survey. The frequency of families with mutations in SLC20A2 in Japan was 50%, which was as high as in a previous report on other regions. The clinical features varied widely among the patients with SLC20A2 mutations. However, 2 distinct families have the same mutation of S637R in SLC20A2 and they have similar characteristics in the clinical course, symptoms, neurologic findings, and neuroimaging. In our study, all the patients with SLC20A2 mutations showed calcification. In familial cases, there were symptomatic and asymptomatic patients in the same family. SLC20A2 mutations are a major cause of familial IBGC in Japan. The members in the families with the same mutation had similar patterns of calcification in the brain and the affected members showed similar clinical manifestations.

Loss of Function of Slc20a2 Associated with Familial Idiopathic Basal Ganglia Calcification in Humans Causes Brain Calcifications in Mice

Familial idiopathic basal ganglia calcification (FIBGC) is a neurodegenerative disorder with neuropsychiatric and motor symptoms. Deleterious mutations in SLC20A2, encoding the type III sodium-dependent phosphate transporter 2 (PiT2), were recently linked to FIBGC in almost 50 % of the families reported worldwide. Here, we show that knockout of Slc20a2 in mice causes calcifications in the thalamus, basal ganglia, and cortex, demonstrating that reduced PiT2 expression alone can cause brain calcifications.

Novel SLC20A2 mutations identified in southern Chinese patients with idiopathic basal ganglia calcification

Idiopathic basal ganglia calcification (IBGC) is a rare neuropsychiatric disorder characterized by bilateral and symmetric cerebral calcifications. Recently, SLC20A2 was identified as a causative gene for familial IBGC, and three mutations were reported in a northern Chinese population. Here, we aimed to explore the mutation spectrum of SLC20A2 in a southern Chinese population. Sanger sequencing was employed to screen mutations within SLC20A2 in two IBGC families and 14 sporadic IBGC cases from a southern Han Chinese population. Four novel mutations (c.82G>A p.D28N, c.185T>C p.L62P, c.1470_1478delGCAGGTCCT p.Q491_L493del and c.935-1G>A) were identified in two families and two sporadic cases, respectively; none were detected in 200 unrelated controls. No mutation was found in the remaining 12 patients. Different mutations may result in varied phenotypes, including brain calcification and clinical manifestations. Our study supports the hypothesis that SLC20A2 is a causative gene of IBGC and expands the mutation spectrum of SLC20A2, which facilitates the understanding of the genotype–phenotype correlation of IBGC.