Boeve B.F.,Mayo Medical School |
Dejesus-Hernandez M.,Neurogenetics Laboratory |
Knopman D.S.,Mayo Medical School |
Vemuri P.,Mayo Medical School |
And 22 more authors.
Brain | Year: 2012
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n=63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n=30), amyotrophic lateral sclerosis (n=18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n=12), and other various syndromes (n=3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings. © The Author (2012).
Fullston T.,Neurogenetics Laboratory |
Fullston T.,University of Adelaide |
Brueton L.,Birmingham Womens Hospital |
Willis T.,Birmingham Childrens Hospital |
And 6 more authors.
European Journal of Human Genetics | Year: 2010
Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81CG (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121-123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41-C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81CG mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations. © 2010 Macmillan Publishers Limited All rights reserved.
Brusa L.,SantEugenio Hospital |
Orlacchio A.,Neurogenetics Laboratory |
Orlacchio A.,University of Rome Tor Vergata |
Stefani A.,University of Rome Tor Vergata |
And 6 more authors.
Functional Neurology | Year: 2013
Since levodopa-induced peak dyskinesias (LIDs) may reflect, in part, a disproportionate phasic release of dopamine from synaptic vesicles, we examined the ability of the vesicular depletor tetrabenazine (TBZ) to reduce LIDs in 10 dyskinetic advanced Parkinson's disease (PD) patients. After basal evaluation, the patients received, through a slow titration, oral TBZ twice a day for six weeks (up to 50 mg daily) before being re-assessed after a challenge with levodopa. The primary outcome measure was the change in the Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia score (items 32 to 34). TBZ was well tolerated. A clear treatment effect on LIDs emerged (up to 45%, p<0.05). In two patients a little worsening of motor performance necessitated an increase of the antiparkinsonian therapy, which did not worsen peak-dose LIDs. The patients experienced a clear benefit in terms of their quality of life. In this open-label pilot study, orally administered TBZ resulted in objective and subjective improvements in LIDs. Larger pharmacological studies are in progress. © CIC Edizioni Internazionali.
Malik R.,Ludwig Maximilians University of Munich |
Freilinger T.,Ludwig Maximilians University of Munich |
Freilinger T.,University Hospital of Tuebingen |
Winsvold B.S.,University of Oslo |
And 68 more authors.
Neurology | Year: 2015
Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p 6.4 × 10-28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p 2.7 × 10-20 for the CE score in MO). Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype. © 2015 American Academy of Neurology.
PubMed | University of Turku, Ludwig Maximilians University of Munich, St George's, University of London, Max Planck Institute of Psychiatry and 20 more.
Type: Journal Article | Journal: Cephalalgia : an international journal of headache | Year: 2015
There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls.Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated (p<510(-8); thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs.Significant heterogeneity of SNP effects (p het<1.410(-3)) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genome-wide SNP effects to be in the same direction across the subgroups.Any differences in common genetic risk across these subgroups are outweighed by the similarities. Meta-analysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.
Kelley B.J.,Mayo Medical School |
Kelley B.J.,Robert H And Clarice Smith And Abigail Van Buren Alzheimers Disease Research Program |
Haidar W.,Mayo Medical School |
Haidar W.,Robert H And Clarice Smith And Abigail Van Buren Alzheimers Disease Research Program |
And 16 more authors.
Archives of Neurology | Year: 2010
Objective: To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), with emphasis on the unique clinical features in this kindred. Design: Antemortem and postmortem characterization of a kindred with a familial neurodegenerative disorder. Setting: Multispecialty group academic medical center. Patients: Affected members of a kindred with dementia with or without parkinsonism associated with a unique mutation in PGRN. Main Outcome Measure: Genotype-phenotype correlation. Results: Of 10 affected individuals identified, 6 presented with early amnestic symptoms which resulted in initial diagnoses of Alzheimer disease or amnestic mild cognitive impairment. Some individuals presented with features characteristic of frontotemporal dementia. Mean age at onset was substantially younger in generation III (75.8 years; range, 69-80 years) than in generation II (60.7 years; range, 55-66 years). The pattern of cerebral atrophy varied widely in the affected individuals. Neuropathologic features in 6 individuals included frontotemporal lobar degeneration with ubiquitin-positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U with NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), which caused a frameshift (p.Thr52HisfsX2) and, therefore, creation of a premature termination codon and a likely null allele. Conclusions: In this large kindred, most affected individuals had clinical presentations that resembled Alzheimer disease or amnestic mild cognitive impairment associated with a mutation in PGRN and underlying FTLD-U with NII neuropathologic abnormalities. This finding is in distinct contrast to previously reported kindreds, in which clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age at onset between generations requires further study. ©2010 American Medical Association. All rights reserved.
Kauffman M.A.,University of Buenos Aires |
Kauffman M.A.,Neurogenetics Laboratory |
Gonzalez-Moron D.,University of Buenos Aires |
Garcea O.,Hospital JM Ramos Mejia |
Villa A.M.,Hospital JM Ramos Mejia
Molecular Biology Reports | Year: 2012
Systemic autoinflammatory diseases are genetic disorders characterized by seemingly unprovoked inflammation, without major involvement of the adaptive immune system. Among them it is recognized the TNF receptor associated periodic syndrome (TRAPS) caused by mutations in the TNFRSF1A gene and characterized by symptoms such as recurrent high fevers, rash, abdominal pain, arthralgia and myalgia. Recent studies have recognized the potential role of TNFRSF1A mutations in Multiple Sclerosis (MS). Our aim was to investigate the role of TNFRSF1A R92Q gene mutation in a cohort of 90 Argentinean MS patients, where we determined the frequency of the TNFRSF1A R92Q mutation. We also compared autoinflammatory symptoms, MS clinical characteristics and treatment response and tolerability in R92Q carriers and non-carriers. Also, we used a case-control study design to obtain the genotypes of 78 healthy controls and assess the role of this mutation as a risk factor for MS. We found that five patients (5.5%) carried the R92Q mutation, four reported autoinflammatory symptoms previous to MS onset. We found no differences in MS clinical features, treatment response and tolerability between carriers and non-carriers. R92Q mutation was more frequent in MS patients as compared to controls. This increases the risk to develop MS in about 4.5 times. The TNFRSF1A R92Q mutation is a common finding in Argentinean MS patients. This genetic variant might be a risk factor for MS. © 2011 Springer Science+Business Media B.V.
De Mena L.,Hospital Central Asturias Maternidad |
Coto E.,Hospital Central Asturias Maternidad |
Coto E.,University of Oviedo |
Cardo L.F.,Hospital Central Asturias Maternidad |
And 10 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2010
MicroRNAs are small RNA sequences that negatively regulate gene expression by binding to the 3′ untranslated regions of mRNAs. MiR-133b has been implicated in Parkinson's disease (PD) by a mechanism that involves the regulation of the transcription factor PITX3. The variation in these genes could contribute to the risk of developing PD. We searched for DNA variants in miR-133 and PITX3 genes in PD patients and healthy controls from Spain. We found common DNA variants in the three miR-133 genes. Genotyping of a first set of patients (n=777) and controls (n=650) showed a higher frequency of homozygous for a miR-133b variant (-90 del A) in PD-patients (6/575; 1%) than in healthy controls (0/650) (P=0.03). However, this association was not confirmed in a second set of patients (1/250; 0.4%) and controls (2/210; 1%). No common PITX3 variants were associated with PD, although a rare missense change (G32S) was found in only one patient and none of the controls. In conclusion, we report the variation in genes of a pathway that has been involved in dopaminergic neuron differentiation and survival. Our work suggests that miR-133 and PITX3 gene variants did not contribute to the risk for PD. © 2010 Wiley-Liss, Inc.