Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease)

Familial idiopathic basal ganglia calcification (IBGC, Fahr disease) is an inherited neurologic condition characterized by basal ganglia and extra-basal ganglia brain calcifications, parkinsonism, and neuropsychiatric symptoms. The authors examined six families for linkage to the previously identified genetic locus (IBGC1) located on chromosome 14q. The authors found evidence against linkage to IBGC1 in five of the six families supporting previous preliminary studies demonstrating genetic heterogeneity in familial IBGC.     

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.     

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.     

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).     

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.     

Clinical significance of basal ganglia calcifications detected by CT: A retrospective study of 33 cases

In a retrospective study 2015 CT scans were studied for the presence of basal ganglia calcifications. These were discovered in 33 cases. No abnormalities in serum calcium or phosphate levels or any other specific clinical symptoms related to these calcifications were found. It is concluded that basal ganglia calcifications casually detected by CT generally have no clinical significance.     

Familial temporal lobe epilepsy with aphasic seizures and linkage to chromosome 10q22-q24

PURPOSE: To describe the phenotypic expression of a new family with familial lateral temporal lobe epilepsy with aphasic seizures, and to compare the findings with the clinical features of previously reported families linked to chromosome 10q22-q24. METHODS: Medical records were collected from 12 living affected members. The patients underwent a personal interview and a clinical neurologic examination. Results from interictal scalp EEGs and neuroimaging examinations were obtained. RESULTS: The cardinal ictal symptom was a brief sensory aphasia in eight of the patients. In four, this was accompanied by auditory symptoms, usually in the form of monotonous unformed sounds. Simple partial seizures with psychic or somatosensory seizures also were present. Visual ictal symptoms and complex partial seizures were absent. All patients had generalized tonic-clonic seizures. Magnetic resonance imaging (MRI) or computed tomography (CT) did not reveal morphologic correlates. Improvement with age seemed to occur in many patients. Significant linkage to chromosome 10q22-q24 was established by testing 17 polymorphic microsatellite markers. CONCLUSIONS: The epilepsy of this family appears to represent a variety of autosomal dominant lateral temporal lobe epilepsy. Aphasic seizures and a peculiar seizure-precipitating effect of the activation of speech (initiation or perception) may serve as markers for identifying further families with this phenotype.     

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.     

Familial partial epilepsy with variable foci in a Dutch family: clinical characteristics and confirmation of linkage to chromosome 22q

PURPOSE: Three forms of idiopathic partial epilepsy with autosomal dominant inheritance have been described: (a) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); (b) autosomal dominant lateral temporal epilepsy (ADLTE) or partial epilepsy with auditory features (ADPEAF); and (c) familial partial epilepsy with variable foci (FPEVF). Here we describe linkage analysis in a Dutch four-generation family with epilepsy fulfilling criteria of both ADNFLE and FPEVF. METHODS: Clinical characteristics and results of EEG, computed tomography (CT), and magnetic resonance imaging (MRI) were evaluated in a family with autosomal dominantly inherited partial epilepsy with apparent incomplete penetrance. Linkage analysis was performed with markers of the ADNFLE (1p21, 15q24, 20q13.3) and FPEVF (2q, 22q11-q12) loci. RESULTS: Epilepsy was diagnosed in 10 relatives. Age at onset ranged from 3 months to 24 years. Seizures were mostly tonic, tonic-clonic, or hyperkinetic, with a wide variety in symptoms and severity. Most interictal EEGs showed no abnormalities, but some showed frontal, central, and/or temporal spikes and spike-wave complexes. From two patients, an ictal EEG was available, showing frontotemporal abnormalities in one and frontal and central abnormalities in the other. Linkage analysis with the known loci for ADNFLE and FPEVF revealed linkage to chromosome 22q in this family. CONCLUSIONS: The clinical characteristics of this family fulfilled criteria of both ADNFLE and FPEVF. The frequent occurrence of seizures during daytime and the observation of interictal EEG abnormalities originating from different cortical areas were more in agreement with FPEVF. The observed linkage to chromosome 22q supported the diagnosis of FPEVF and confirmed that this locus is responsible for this syndrome.     

Linkage to chromosome 13q11-12 of an autosomal recessive cerebellar ataxia in a Tunisian family

OBJECTIVE: To report the clinical findings and the genetic linkage mapping of an autosomal recessive cerebellar ataxia associated to peripheral neuropathy, showing an early onset cerebellar ataxia with retained tendon reflexes (EOCA) phenotype. BACKGROUND: EOCA is a clinical syndrome delimited by Harding distinguished from Friedreich's ataxia (FA) mainly by the preservation of tendon reflexes. Molecular genetic study of patients with EOCA has demonstrated genetic heterogeneity. A form of autosomal recessive spastic ataxia has been described in Charlevoix Saguenay area in Quebec (ARSACS); the gene responsible has been mapped to chromosome 13q. METHODS: Genetic linkage analysis was performed on 18 members of a large family including 8 of 9 members with EOCA. After exclusion of FA and ataxia with vitamin E deficiency loci as well as loci of autosomal dominant cerebellar ataxias, we performed a linkage analysis to markers of 13q11-12 region. RESULTS: The 9 affected members of this family showed stereotyped clinical features with cerebellar ataxia, pyramidal syndrome, and a variable degree of axonal peripheral neuropathy. Linkage was detected between the disease locus and the microsatellite marker D13S232. Surrounding markers to D13S232 confirmed the linkage and showed the homozygosity of the affected members. CONCLUSION: The family reported here showed the same locus as autosomal recessive spastic ataxia Charlevoix Saguenay disease.     

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.     

Basal ganglia calcification and psychosis in 22q11.2 deletion syndrome

Intracerebral calcifications are a facultative symptom of hypoparathyreoidism in 22q11.2 deletion syndrome (22qDS). We describe a patient with 22qDS, basal ganglia calcification (BGC) and psychotic symptoms and discuss the etiological connection of BGC with psychiatric symptoms. Future work needs to determine the prevalence of BGC in 22qDS and psychiatric disorders.     

Two cases of familial idiopathic basal ganglia calcifications (BCG) with non-symptomatic family members

We reported two families each propositus of which exhibited extrapyramidal signs and dementia with bilateral basal ganglia calcifications (BGC), while some of the other non-symptomatic family members showed BCG on brain CT by further examinations. Family 1) A 49-year-old woman was normal until her mid 40s when her memory began to fail. At age 40, dementia, finger-tremor and rigidity were observed and with brain CT and Magnetic Resonance Imaging, BCG and dentate calcifications were found. Her two daughters (20 years old and 26 years old) were free of any neuropsychiatric symptoms, but with CT examinations disclosed BCG. Family 2) A 40-year-old man. His symptoms started at 33 years old. He noticed gradually increasing finger-tremor, rigidity and dysarthria. At 40 years he showed mild dementia and BCG on Brain CT. His mother (64 years old) was non-symptomatic but CT showed that she had BCG. In the two families the calcium, phosphorous and parathyroid hormone levels, and Ellsworth-Howard test were normal. Other specific etiology including infections and somatic abnormalities was not discovered. Familial idiopathic basal ganglia calcification was considered to be rare. But the main purpose of this report is to point out that we must pay attention to the possibility of BCG of non-symptomatic family members if one showed dementia and extrapyramidal signs, and BCG on Brain CT in middle age.     

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.     

A young woman with visual hallucinations,delusions of persecution and a history of performing arson with possible three‐generation Fahr disease

Objective: Fahr disease (FD) is a rare neurological and psychiatric disorder. The disease is classified by intracranial calcification of the basal ganglia with the globus pallidus region being particularly affected. We examined a young woman with visual hallucinations, delusions of persecution and a history of performing arson with possible third‐generation FD. Method: Case report of third‐generation FD. Results: A 23‐year‐old woman was arrested for two arsons: i) The patient exhibited progressive psychotic symptoms, including visual hallucinations, delusion of injury, irritability, lability of mood, mental retardation and visual disorders and ii) Computed tomography (CT) imaging demonstrated bilateral calcifications of the basal ganglia (globus pallidus) in the patient, her mother and her grandmother. Conclusion: We found a family with a three‐generation history of FD who exhibited calcification in the brain and mental retardation. Compared to her mother, the patient described here displayed anticipation of disease onset.     

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.     

Hereditary frontotemporal dementia is linked to chromosome 17q21—q22: A genetic and clinicopathological study of three dutch families

Hereditary frontotemporal dementia (HFTD) is a rare autosomal dominant form of presenile dementia characterized by behavioral changes and reduced speech. Three multigeneration kindreds with this condition, in the Netherlands, were investigated for clinicopathological comparison and linkage analysis. Frontotemporal atrophy on computed tomographic scanning and/or magnetic resonance imaging was usually present. Single-photon emission computed tomography (SPECT) showed frontal hypoperfusion in the early phase of the disease. Brain tissue showed moderate to severe atrophy of frontal and temporal cortex with neuronal loss, gliosis, and spongiosis. Pick bodies were lacking in all cases of the 3 families. The mean age of onset varied significantly between families. We report here evidence for linkage to chromosome 17q21–q22 with a maximum lod score of 4.70 at Θ = 0.05 with the marker D17S946 and D17S791. Three other neurodenegenerative disorders with a strong clinical and pathological resemblance have recently been mapped to the same chromosomal region, suggesting that a group of clinically related neurodegenerative disorders may originate from mutations in the same gene.     

Four cases of Cockayne syndrome

The evaluation of four patients with Cockayne syndrome (CS) by computed tomography (CT) and magnetic resonance imaging (MRI) is reported. All patients had characteristic clinical manifestations of CS. In a special respect, we found hyperopia in two patients and previous habitual abortions in two maternal histories. Extrapyramidal signs were seen in one patient. Three patients are type 1 CS (case 1, 3, 4) and one patient (case 2) is type 2 CS (congenital form). The cranial CT in two patients (case 1, 2) revealed prominent calcifications in basal ganglia, dentate nucleus and hemispheric white matter. While CT showed vagal calcifications in basal ganglia in other two patients (case 3, 4), T2-weighted MRI revealed obvious low intensity area in putamen and caudate nucleus, and high intensity area in the white matter. Sagittal section revealed atrophic changes of cerebellar vermis and brain stem. Thus it seems that MRI may be useful diagnostic adjunct in CS patients.     

Autosomal dominant lateral temporal epilepsy: clinical spectrum, new epitempin mutations, and genetic heterogeneity in seven European families

PURPSOE: To describe the clinical and genetic findings of seven additional pedigrees with autosomal dominant lateral temporal epilepsy (ADLTE). METHODS: A personal and family history was obtained from each affected and unaffected member, along with a physical and neurologic examination. Routine and sleep EEGs, computed tomography (CT), or magnetic resonance imaging (MRI) were performed in almost all the patients. DNAs from family members were typed with several microsatellite markers localized on either side of LGI1 at 10q24 and screened for LGI1 mutations. RESULTS: The seven families included a total of 34 affected individuals (10 deceased). The age at onset ranged between 8 and 50 years (average, 22 years). Twenty-six patients had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Less frequent ictal symptoms were visual, psychic, or aphasic seizures, the latter occurring in isolation in one family. The attacks were rare and well controlled by antiepileptic drug treatment but recurred after drug discontinuation. Interictal EEGs were usually unrevealing. MRI or CT scans were negative. Analysis of LGI1/Epitempin exons failed to show mutations in three pedigrees. Linkage analysis strongly suggested exclusion of linkage in one of these families. We found two novel missense mutations, a T-->C substitution in exon 6 at position 598, and a T-->A transition in exon 8 at position 1295, the latter being detected in a family with aphasic seizures. CONCLUSIONS: Our data confirm the inclusion of aphasic seizures within the ADLTE clinical spectrum, suggest the existence of locus heterogeneity in ADLTE, and provide new familial cases with LGI1 missense mutations associated with the disease.