Exclusion of linkage to chromosomes 14q, 2q37 and 8p21.1-q11.23 in a Serbian family with idiopathic basal ganglia calcification

In this study we report clinical and imaging data from a multigenerational Serbian family with idiopathic basal ganglia calcification (IBGC) and exclusion of linkage to chromosome 14q, 2q37 and 8p21.1-q11.23. Fourteen out of 18 family members were personally examined and 11 of them were scanned with computed tomography (CT). CT scans revealed existence of symmetrical calcifications in six family members from three generations (four symptomatic and two asymptomatic). Age at onset of clinical symptoms varied between 22.0 and 55.4 years. The main clinical findings included parkinsonism, severe gait disturbances with freezing of gait, and dyskinesia. Hyperechogenicities identified by transcranial sonography corresponded well to the CT images of hyperintense calcifications in the same structures, whereas brain perfusion single photon emission computed tomography demonstrated predominant hypoperfusion in the frontal cortex and the basal ganglia. After exclusion of linkage to known loci, our pedigree with IBGC further demonstrates locus heterogeneity in this disorder. Analysis of clinically affected individuals supports observation that the clinical features of IBGC appear to be varied both within and between families. The age at onset of the clinical symptoms appeared to be decreasing in two observed transmissions, suggestive of possible genetic anticipation.     

2q37 as a Susceptibility Locus for Idiopathic Basal Ganglia Calcification (IBGC) in a Large South Tyrolean Family

Familial idiopathic basal ganglia calcification (FIBGC) is an inherited neurodegenerative disorder characterized by the accumulation of calcium deposits in different brain regions, particularly in the basal ganglia. FIBGC usually follows an autosomal dominant pattern of inheritance. Despite the mapping to chromosome 14q of a susceptibility locus for IBGC (IBCG1) in one family, this locus has been excluded in several others, demonstrating genetic heterogeneity in this disorder. The etiology of this disorder thus remains largely unknown. Using a large extended multigenerational Italian family from South Tyrol with 17 affected in a total of 56 members, we performed a genome-wide linkage analysis in which we were able to exclude linkage to the IBCG1 locus on chromosome 14q and obtain evidence of a novel locus on chromosome 2q37.     

Cortical myoclonus and epilepsy in a family with a new SLC20A2 mutation

Journal of Neurology - Idiopathic basal ganglia calcification (IBGC) or primary familial brain calcification is a rare genetic condition characterized by an autosomal dominant inheritance pattern...     

Analysis of the CTAGE5 P521A Variation with the Risk of Familial Idiopathic Basal Ganglia Calcification in an Iranian Population

Familial idiopathic basal ganglia calcification (IBGC) is a rare neurodegenerative syndrome with an autosomal dominant pattern of inheritance which is characterized by deposition of calcium in the basal ganglia and other brain regions. Linkage studies demonstrated its genetic heterogeneity; however, the responsible genes are unknown. Recently, a heterozygous variation (C>G, P521A) at exon 20 of the human cutaneous T cell lymphoma-associated antigen 5 (CTAGE5) gene was found in all patients of the affected large American family linked to IBGC1 (14q11.2-21.3). However, no carrier was detected in the two affected Brazilian families. This study was performed to investigate whether the CTAGE5 P521A variation is associated with the IBGC in an affected Iranian family. Genotyping of the CTAGE5 P521A variation was determined using PCR-RFLP. Totally, 22 members of an affected Iranian family as well as 100 normal people as control group were screened. All the samples including 22 members of the affected family as well as all control people had normal CC genotype and no GC carrier was found. Our result is similar to a Brazilian study but contrary to an American report, strengthening genetic heterogeneity of this syndrome. It seems that additional studies are necessary to confirm the pathogenicity of this rare mutation.     

Analysis of Candidate Genes at the IBGC1 Locus Associated with Idiopathic Basal Ganglia Calcification (“Fahr’s Disease”)

Basal ganglia calcification (striatopallidodentate calcifications) can be caused by several systemic and neurological disorders. Familial Idiopathic Basal Ganglia Calcification (IBGC, “Fahr’s disease”), is characterized by basal ganglia and extrabasal ganglia calcifications, parkinsonism and neuropsychiatric symptoms. Because of an increased use of neuroimaging procedures, calcifications of the basal ganglia are visualized more often and precociously. In 1999, a major American family with IBGC was linked to a locus on chromosome 14q (IBGC1). Another small kindred, from Spain, has also been reported as possibly linked to this locus. Here we report the main findings of the first 30 candidate genes sequenced at the IBGC1 locus during the process of searching for a mutation responsible for familial IBGC. During the sequencing process, we identified a heterozygous nonsynonymous single nucleotide polymorphism (exon 20 of the MGEA6/c-TAGE gene) shared by the affected and not present in the controls. This SNP was randomly screened in the general population (348 chromosomes) in a minor allele frequency to 0.0058 (two heterozygous among 174 subjects). Another variation in this gene, in the exon 9, was found in the Spanish family. However, this variation was extremely common in the general population. Functional and population studies are necessary to fully access the implications of the MGEA6 gene in familial IBGC, and a complete sequencing of the IBGC1 locus will be necessary to define a gene responsible for familial IBGC.     

Distinct basal ganglia hyperechogenicity in idiopathic basal ganglia calcification

We report a 67‐year‐old patient with idiopathic basal ganglia calcification (IBGC). He presented with progressive cognitive impairment, frontal lobe dysfunction, mild leg spasticity, and levodopa (L ‐dopa)‐responsive parkinsonism. Transcranial sonography (TCS) revealed marked hyperechogenicity of the basal ganglia and periventricular spaces bilaterally. The detected signal alterations showed a fairly symmetric distribution and corresponded to the hyperintense calcifications depicted on the computer tomography brain scan. The combination of symmetric hyperechogenic areas adjacent to the lateral ventricles and of the basal ganglia may serve as an imaging marker characteristic of IBGC. Hyperechogenicity due to extended basal ganglia calcification as presented here is distinct from the pattern of hyperechogenicity caused by heavy metal accumulation, which is described to be less striking. In addition to atypical parkinsonian syndromes such as progressive supranuclear palsy and multiple system atrophy, IBGC is thus another differential diagnosis of parkinsonism with basal ganglia hyperechogenicity. © 2010 Movement Disorder Society.     

Neuroradiologic Evidence of Pre‐Synaptic and Post‐Synaptic Nigrostriatal Dopaminergic Dysfunction in Idiopathic Basal Ganglia Calcification: A Case Report

Idiopathic basal ganglia calcification (IBGC) is a neuropathological condition known to manifest as motor disturbance, cognitive impairment, and psychiatric symptoms. The pathophysiology of the psychiatric symptoms of IBGC, however, remains controversial. A previous biochemical study suggested that dopaminergic impairment is involved in IBGC. We thus hypothesized that dopaminergic dysfunction might be related with the psychiatric manifestations of IBGC. We used positron emission tomography to measure glucose metabolism and dopaminergic function in the basal ganglia of an IBGC patient with psychiatric symptoms. The results showed that widespread hypometabolism was evident in the frontal, temporal, and parietal cortices while the decline in dopaminergic function was severe in the bilateral striatum. The functional decline of the dopamine system in the calcified area of the bilateral striatum and the disruption of cortico‐subcortical circuits may contribute to clinical manifestations of IBGC in our patient.     

Population and Computational Analysis of the MGEA6 P521A Variation as a Risk Factor for Familial Idiopathic Basal Ganglia Calcification (Fahr’s Disease)

Familial idiopathic basal ganglia calcification, also known as “Fahr’s disease” (FD), is a neuropsychiatric disorder with autosomal dominant pattern of inheritance and characterized by symmetric basal ganglia calcifications and, occasionally, other brain regions. Currently, there are three loci linked to this devastating disease. The first one (IBGC1) is located in 14q11.2-21.3 and the other two have been identified in 2q37 (IBGC2) and 8p21.1-q11.13 (IBGC3). Further studies identified a heterozygous variation (rs36060072) which consists in the change of the cytosine to guanine located at MGEA6/CTAGE5 gene, present in all of the affected large American family linked to IBGC1. This missense substitution, which induces changes of a proline to alanine at the 521 position (P521A), in a proline-rich and highly conserved protein domain was considered a rare variation, with a minor allele frequency (MAF) of 0.0058 at the US population. Considering that the population frequency of a given variation is an indirect indicative of potential pathogenicity, we screened 200 chromosomes in a random control set of Brazilian samples and in two nuclear families, comparing with our previous analysis in a US population. In addition, we accomplished analyses through bioinformatics programs to predict the pathogenicity of such variation. Our genetic screen found no P521A carriers. Polling these data together with the previous study in the USA, we have now a MAF of 0.0036, showing that this mutation is very rare. On the other hand, the bioinformatics analysis provided conflicting findings. There are currently various candidate genes and loci that could be involved with the underlying molecular basis of FD etiology, and other groups suggested the possible role played by genes in 2q37, related to calcium metabolism, and at chromosome 8 (NRG1 and SNTG1). Additional mutagenesis and in vivo studies are necessary to confirm the pathogenicity for variation in the P521A MGEA6.     

Erratum to: Population and Computational Analysis of the MGEA6 P521A Variation as a Risk Factor for Familial Idiopathic Basal Ganglia Calcification (Fahr’s Disease)

Familial idiopathic basal ganglia calcification, also known as “Fahr’s disease” (FD), is a neuropsychiatric disorder with autosomal dominant pattern of inheritance and characterized by symmetric basal ganglia calcifications and, occasionally, other brain regions. Currently, there are three loci linked to this devastating disease. The first one (IBGC1) is located in 14q11.2-21.3 and the other two have been identified in 2q37 (IBGC2) and 8p21.1-q11.13 (IBGC3). Further studies identified a heterozygous variation (rs36060072) which consists in the change of the cytosine to guanine located at MGEA6/CTAGE5 gene, present in all of the affected large American family linked to IBGC1. This missense substitution, which induces changes of a proline to alanine at the 521 position (P521A), in a proline-rich and highly conserved protein domain was considered a rare variation, with a minor allele frequency (MAF) of 0.0058 at the US population. Considering that the population frequency of a given variation is an indirect indicative of potential pathogenicity, we screened 200 chromosomes in a random control set of Brazilian samples and in two nuclear families, comparing with our previous analysis in a US population. In addition, we accomplished analyses through bioinformatics programs to predict the pathogenicity of such variation. Our genetic screen found no P521A carriers. Polling these data together with the previous study in the USA, we have now a MAF of 0.0036, showing that this mutation is very rare. On the other hand, the bioinformatics analysis provided conflicting findings. There are currently various candidate genes and loci that could be involved with the underlying molecular basis of FD etiology, and other groups suggested the possible role played by genes in 2q37, related to calcium metabolism, and at chromosome 8 (NRG1 and SNTG1). Additional mutagenesis and in vivo studies are necessary to confirm the pathogenicity for variation in the P521A MGEA6.     

Familial idiopathic basal ganglia calcification: Histopathologic features of an autopsied patient with an SLC20A2 mutation

Idiopathic basal ganglia calcification (IBGC), or Fahr's disease, is a neurological disorder characterized by widespread calcification in the brain. Recently, several causative genes have been identified, but the histopathologic features of the brain lesions and expression of the gene products remain unclear. Here, we report the clinical and autopsy features of a 62‐year‐old Japanese man with familial IBGC, in whom an SLC20A2 mutation was identified. The patient developed mild cognitive impairment and parkinsonism. A brain CT scan demonstrated abnormal calcification in the bilateral basal ganglia, thalami and cerebellum. An MRI study at this point revealed glioblastoma, and the patient died 6 months later. At autopsy, symmetric calcification in the basal ganglia, thalami, cerebellar white matter and deeper layers of the cerebral cortex was evident. The calcification was observed in the tunica media of small arteries, arterioles and capillaries, but not in veins. Immunohistochemistry using an antibody against type III sodium‐dependent phosphate transporter 2 (PiT‐2), the SLC20A2 product, demonstrated that astrocytic processes were labeled in several regions in control brains, whereas in the patient, reactivity in astrocytes was apparently weak. Immunoblotting demonstrated a marked decrease of PiT‐2 in the patient. There are few autopsy reports of IBGC patients with confirmation of the genetic background. The autopsy features seem informative for better understanding the histogenesis of IBGC lesions.     

Idiopathic basal ganglia calcification presenting as hypomania

A sixty-four-year-old lady manifested a hypomanic psychosis and later developed features of a subcortical dementia and movement disorders of Parkinsonism and chorea. Computerized tomography revealed bilateral basal ganglia calcification. No evidence of parathyroid disorder or any other cause for the calcification was present. There has been only one previously reported case of organic mood disorder of a manic type presentation of idiopathic basal ganglia calcification (IBGC). The oldest reported age of onset of IBGC presenting with psychosis is 53 years and with dementia is 68 years.     

SLC20A2 and THAP1 deletion in familial basal ganglia calcification with dystonia

Idiopathic basal ganglia calcification (IBGC) is characterized by bilateral calcification of the basal ganglia associated with a spectrum of neuropsychiatric and motor syndromes. In this study, we set out to determine the frequency of the recently identified IBGC gene SLC20A2 in 27 IBGC cases from the Mayo Clinic Florida Brain Bank using both Sanger sequencing and TaqMan copy number analysis to cover the complete spectrum of possible mutations. We identified SLC20A2 pathogenic mutations in two of the 27 cases of IBGC (7 %). Sequencing analysis identified a p.S113* nonsense mutation in SLC20A2 in one case. TaqMan copy number analysis of SLC20A2 further revealed a genomic deletion in a second case, which was part of a large previously reported Canadian IBGC family with dystonia. Subsequent whole-genome sequencing in this family revealed a 563,256-bp genomic deletion with precise breakpoints on chromosome 8 affecting multiple genes including SLC20A2 and the known dystonia-related gene THAP1. The deletion co-segregated with disease in all family members. The deletion of THAP1 in addition to SLC20A2 in the Canadian IBGC family may contribute to the severe and early onset dystonia in this family. The identification of an SLC20A2 genomic deletion in a familial form of IBGC demonstrates that reduced SLC20A2 in the absence of mutant protein is sufficient to cause neurodegeneration and that previously reported SLC20A2 mutation frequencies may be underestimated.     

Psychosis revealing familial idiopathic basal ganglia calcification

We describe the case of a 39-year-old woman presenting with auditory hallucinations and delusions responsive to antipsychotic drugs. Computerized tomography scans revealed basal ganglia calcifications in the proband and in her two asymptomatic parents. Extensive etiological clinicobiological assessment allowed us to exclude known causes of brain calcifications and diagnose familial idiopathic basal ganglia calcification (IBGC).     

Clinical features of bipolar disorder with idiopathic basal ganglia calcification: a review of case reports in the literature

Although idiopathic basal ganglia calcification (IBGC) is associated with various neuropsychiatric disturbances including several cases of bipolar disorder (BD), there has been no systematic review of clinical features of patients with BD and comorbid IBGC. We undertook a literature search to identify case reports of these patients. Most cases showed complex syndromes comprising not only mood disturbance but also cognitive disability and motor symptoms limited to depressive state and had favorable treatment response. These patients should have a careful and repeated psychiatric, neurological, and cognitive assessment to determine an optimal diagnostic and treatment approaches at each clinical stage.     

Quetiapine responsive catatonia in an autistic patient with comorbid bipolar disorder and idiopathic basal ganglia calcification

Background: Bipolar disorder (BD) has been linked with the manifestation of catatonia in subjects with autism spectrum disorders (ASD). Idiopathic basal ganglia calcification (IBGC) is characterized by movement disorders and various neuropsychiatric disturbances including mood disorder. Case: We present a patient with ASD and IBGC who developed catatonia presenting with prominent dystonic feature caused by comorbid BD, which was treated effectively with quetiapine. Conclusion: In addition to considering the possibility of neurodegenerative disease, careful psychiatric interventions are important to avoid overlooking treatable catatonia associated with BD in cases of ASD presenting with both prominent dystonic features and apparent fluctuation of the mood state.     

Genetik der Dystonien

To date, at least 12 types of primary dystonia can be distinguished on a genetic basis. A 3-bp deletion in the DYT1 gene causes early onset, generalized torsion dystonia (TD), and mutations in the GTP cyclohydrolase I and the tyrosine hydroxylase genes result in dopa-responsive dystonia (DYT5). A missense change in the D2 dopamine receptor in one large family (DYT11) has recently been implicated in myoclonus-dystonia. Furthermore, seven other loci for dystonia genes have been mapped to chromosomal regions, including a locus for a mixed dystonia phenotype (DYT6), one form of focal dystonia (DYT7), three types of paroxysmal dystonia (DYT8-10), X-linked dystonia-parkinsonism (DYT3), and rapid-onset dystonia-parkinsonism (DYT12). No positive linkage results have yet been obtained for autosomal recessive TD (DYT2) and several other families of different types of dominantly inherited TD (DYT4). In addition, hereditary secondary dystonia may occur as part of familial diseases of the basal ganglia, metabolic and storage disorders, and various X-linked and other familial neurodegenerative syndromes affecting the basal ganglia. It may be anticipated that the traditional clinical and etiological classifications of dystonia will increasingly be replaced by a genetic one and that the identification of more dystonia genes may lead to a better understanding of these largely nondegenerative disorders.     

Neurological deficits are associated with increased brain calcinosis, hypoperfusion, and hypometabolism in idiopathic basal ganglia calcification.

We report two familial cases of idiopathic basal ganglia calcification. A 60-year-old proband with choreoathetosis, dysarthria, and cognitive decline showed more extensive brain calcinosis, hypoperfusion, and hypometabolism than did his asymptomatic 82-year-old mother. The mother had no frontal lobe calcinosis but basal ganglia and dentate nucleus depositions were detectable. Perfusion neuroimaging, however, was normal in the asymptomatic mother and abnormal in the clinically impaired proband. The presence of calcinosis cannot be used as an index of neurological impairment but the extent of calcinosis and reduction in perfusion and metabolism may be useful for separating symptomatic from asymptomatic subjects with IBGC. These findings suggest that an interruption of neuronal circuitry may cause neurological deficits. The degree of neurological deficits may correlate with the severity of calcinosis and the reduction of perfusion and metabolism.     

Analysis of Gene Expression Pattern and Neuroanatomical Correlates for SLC20A2 (PiT-2) Shows a Molecular Network with Potential Impact in Idiopathic Basal Ganglia Calcification (“Fahr’s Disease”)

Familial idiopathic basal ganglia calcification (FIBGC), also known as “Fahr’s disease,” is a neuropsychiatric disorder with motor and cognitive symptoms. It is characterized pathologically by bilateral calcification most commonly in the basal ganglia and also in other brain regions such as the thalamus and cerebellum. A recent report by Wang et al. (2012) discovered multiple families with FIBGC carrying mutations in the SLC20A2 gene, encoding the inorganic phosphate transporter PiT-2, which segregated in an autosomal dominant pattern. To understand further the role of SLC20A2 in FIBGC brain pathology, here we described the gene expression pattern across the whole brain for SLC20A2, using the Allen Institute Human Brain Atlas database. Microarray analysis provided evidence that the neuroanatomical pattern of expression for SLC20A2 is highest in the regions most commonly affected in FIBGC. Neuroanatomical regions that demonstrated high correlation or anti-correlation with SLC20A2 expression also showed a molecular network with potential to explain the limited neuroanatomical distribution of calcifications in IBGC. Lastly, these co-expression networks suggest additional further candidate genes for FIBGC.     

PDGFB Partial Deletion: a New,Rare Mechanism Causing Brain Calcification with Leukoencephalopathy

Idiopathic basal ganglia calcification (IBGC) is a progressive cerebral disorder with diverse motor, cognitive, and psychiatric expression. It is inherited as an autosomal dominant trait. Three IBGC-causing genes have been identified in the past 2 years: SLC20A2, PDGFRB, and PDGFB. Biological and genetic evidence showed that loss of function of either SLC20A2 or the PDGFB/PDGFRB pathway was the mechanism underlying calcification in patients with a mutation. Recently, in a study focusing on SLC20A2, a large deletion at this locus was reported. No study has systematically searched for copy number variants (CNV) involving these three genes. We designed a quantitative PCR assay of multiple short fluorescent fragments (QMPSF) to detect CNVs involving one of these three genes in a single assay. Among the 27 unrelated patients from our IBGC case series with no mutation in SLC20A2, PDGFRB, and PDGFB, we identified in one patient a heterozygous partial deletion involving exons 2 to 5 of PDGFB. This patient exhibited both strio-pallido-dentate calcification and white matter hyperintensity of presumed vascular origin, associated with mood disorder, subtle cognitive decline, and gait disorder. We confirmed by RT-PCR experiments that the allele carrying the deletion was transcribed. The resulting cDNA lacks sequence for several critical functional domains of the protein. Intragenic deletion of PDGFB is a new and rare mechanism causing IBGC. CNVs involving the three IBGC-causing genes should be investigated in patients with no point mutation.     

Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome‐wide linkage meta‐analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type–related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. Methods: Meta‐analysis of three genome‐wide linkage datasets was carried out in 379 GGE‐multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type–related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type–related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE‐multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. Key Findings: For the entire set of 379 GGE‐multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome‐wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). Significance: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype– genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.