PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-12 (12)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
2.  Multiple System Atrophy and Repeat Expansions in C9orf72 
JAMA neurology  2014;71(9):1191-1192.
doi:10.1001/jamaneurol.2014.1811
PMCID: PMC4211280  PMID: 25200544
3.  Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family with Hexanucleotide Repeat Expansions in C9orf72 
JAMA neurology  2014;71(6):771-774.
Importance
To report a family with coexistence of multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) with hexanucleotide repeat expansions in C9orf72.
Observations
A 65 year-old woman had a 2-year history of ataxia with autonomic dysfunction but without motor neuron signs. She was diagnosed with MSA based on her clinical history and the hot cross bun sign on brain MRI. Her 62-year-old brother had progressive weakness, fasciculations, hyperreflexia, and active denervation on EMG without cerebellar ataxia. He was diagnosed with ALS. Both patients had a >44/2 hexanucleotide expansion in C9orf72.
Conclusion and Relevance
Patients with hexanucleotide repeat expansions in C9orf72 can present with MSA as well as ALS or FTD. We report this family with co-existing MSA and ALS, highlighting the phenotypic variability in neurological presentations with hexanucleotide repeat expansions in C9orf72.
doi:10.1001/jamaneurol.2013.5762
PMCID: PMC4051831  PMID: 24733620
multiple system atrophy; amyotrophic lateral sclerosis; neurodegeneration; ataxia; motor neuron disorders
4.  Amyotrophic Lateral Sclerosis and Spinocerebellar Ataxia Type 2 in a Family with Full CAG Repeat Expansions of ATXN2 
JAMA neurology  2013;70(10):1302-1304.
Importance
To report a family with coexistence of spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS).
Observations
The intermediate or full CAG repeat expansions of ATXN2 are associated with ALS. However, no coexistence of SCA2 and ALS in a family has been reported in the literature. We are reporting a 47 year-old woman with an 11-year history of ataxia and her paternal uncle with ALS who was evaluated at Columbia University Medical Center since July 2006. Both ataxia and ALS patient have full pathological CAG repeat expansions of ATXN2.
Conclusions and Relevance
This report highlights the diverse clinical phenotypes of ATXN2 CAG expansions and its coexistence in a single family. Also, the value of this report is to help clinicians consider the genetic diagnosis of SCA2 when encountering an ataxia patient with a family history of ALS.
doi:10.1001/jamaneurol.2013.443
PMCID: PMC4039635  PMID: 23959108
spinocerebellar ataxia type 2; amyotrophic lateral sclerosis; ATXN2; CAG repeats; TDP-43
5.  Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification 
Neurogenetics  2013;14(1):11-22.
Familial idiopathic basal ganglia calcification (IBGC) or Fahr’s disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient’s disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.
doi:10.1007/s10048-012-0349-2
PMCID: PMC4023541  PMID: 23334463
Basal ganglia calcification; Fahr’s; Genetics; Sequencing; Mutations
6.  C9ORF72 repeat expansions not detected in a group of patients with schizophrenia 
Neurobiology of aging  2012;34(4):1309.e9-1309.10.
A hexanucleotide repeat expansion in C9ORF72 was recently found to cause some cases of FTLD, FTD-ALS, and ALS. FTLD patients with the C9ORF72 repeat expansion are more likely than those without to present with psychosis. In this study, we screened DNA samples from 192 unrelated subjects with schizophrenia for the C9ORF72 repeat expansion. None of the subjects with schizophrenia had the pathogenic expansion. C9ORF72 repeat expansions either do not cause schizophrenia, or do so rarely (less than 1% of cases).
doi:10.1016/j.neurobiolaging.2012.08.011
PMCID: PMC3584690  PMID: 23036583
FTLD; Schizophrenia; C9ORF72 repeat expansion; psychosis
7.  New Approaches to Genetic Counseling and Testing for Alzheimer’s Disease and Frontotemporal Degeneration 
The discovery of new autosomal dominant and susceptibility genes for Alzheimer’s disease and frontotemporal dementia is revealing important new information about the neurodegenerative process and the risk for acquiring these diseases. It is becoming increasingly clear that both the mechanisms that drive these diseases and their phenotypes overlap. New technologies will assist access to genetic testing but may increase difficulty with genetic test interpretation. Thus, the process of genetic counseling and testing for these diseases is becoming more complex. This paper will review current knowledge on the genetics of AD and FTD and suggest clinical guidelines for helping families to navigate through these complexities. The implications of future discoveries will be offered.
doi:10.1007/s11910-012-0296-1
PMCID: PMC3437002  PMID: 22773362
Alzheimer’s disease; Frontotemporal degeneration; Genetics; Genetic counseling; Genetic testing; Neurogenetics; Family history
8.  Screening for C9ORF72 repeat expansion in FTLD 
Neurobiology of aging  2012;33(8):1850.e1-1850.11.
In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 FTLD patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-FTD and 2 FTD-ALS) out of 53 patients and one neurologically normal control. Interestingly, two of the C9ORF72 expansion carriers also carried two novel missense mutations in GRN (Y294C) and in PSEN-2 (I146V). Further, one of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TDP-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD or FTD-ALS and occasional comorbid conditions such as Alzheimer’s disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.
doi:10.1016/j.neurobiolaging.2012.02.017
PMCID: PMC3743244  PMID: 22459598
FTLD; bv-FTD; FTD-ALS; C9ORF72; GRN; PSEN-2; Alzheimer’s disease
9.  Genetic counseling for FTD/ALS caused by the C9ORF72 hexanucleotide expansion 
Frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) are related but distinct neurodegenerative diseases. The identification of a hexanucleotide repeat expansion in a noncoding region of the chromosome 9 open reading frame 72 (C9ORF72) gene as a common cause of FTD/ALS, familial FTD, and familial ALS marks the culmination of many years of investigation. This confirms the linkage of disease to chromosome 9 in large, multigenerational families with FTD and ALS, and it promotes deeper understanding of the diseases' shared molecular FTLD-TDP pathology. The discovery of the C9ORF72 repeat expansion has significant implications not only for familial FTD and ALS, but also for sporadic disease. Clinical and pathological correlates of the repeat expansion are being reported but remain to be refined, and a genetic test to detect the expansion has only recently become clinically available. Consequently, individuals and their families who are considering genetic testing for the C9ORF72 expansion should receive genetic counseling to discuss the risks, benefits, and limitations of testing. The following review aims to describe genetic counseling considerations for individuals at risk for a C9ORF72 repeat expansion.
doi:10.1186/alzrt130
PMCID: PMC3506941  PMID: 22808918
10.  Genetic counseling and testing for Alzheimer disease: Joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors 
Genetics in Medicine  2011;13(6):597-605.
Alzheimer disease is the most common cause of dementia. It occurs worldwide and affects all ethnic groups. The incidence of Alzheimer disease is increasing due, in part, to increased life expectancy and the aging baby boomer generation. The average lifetime risk of developing Alzheimer disease is 10–12%. This risk at least doubles with the presence of a first-degree relative with the disorder. Despite its limited utility, patients express concern over their risk and, in some instances, request testing. Furthermore, research has demonstrated that testing individuals for apoli-poprotein E can be valuable and safe in certain contexts. However, because of the complicated genetic nature of the disorder, few clinicians are prepared to address the genetic risks of Alzheimer disease with their patients. Given the increased awareness in family history thanks to family history campaigns, the increasing incidence of Alzheimer disease, and the availability of direct to consumer testing, patient requests for information is increasing. This practice guideline provides clinicians with a framework for assessing their patients’ genetic risk for Alzheimer disease, identifying which individuals may benefit from genetic testing, and providing the key elements of genetic counseling for AD.
doi:10.1097/GIM.0b013e31821d69b8
PMCID: PMC3326653  PMID: 21577118
Alzheimer disease; dementia; guideline; genetic testing; genetic counseling
11.  Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family 
Background
Frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) is a heritable form of FTD, but the gene(s) responsible for the majority of autosomal dominant FTD-ALS cases have yet to be found. Previous studies have identified a region on chromosome 9p that is associated with FTD and ALS.
Methods
The authors report the clinical, volumetric MRI, neuropathological and genetic features of a new chromosome 9p-linked FTD-ALS family, VSM-20.
Results
Ten members of family VSM-20 displayed heterogeneous clinical phenotypes of isolated behavioural-variant FTD (bvFTD), ALS or a combination of the two. Parkinsonism was common, with one individual presenting with a corticobasal syndrome. Analysis of structural MRI scans from five affected family members revealed grey- and white-matter loss that was most prominent in the frontal lobes, with mild parietal and occipital lobe atrophy, but less temporal lobe atrophy than in 10 severity-matched sporadic bvFTD cases. Autopsy in three family members showed a consistent and unique subtype of FTLD-TDP pathology. Genome-wide linkage analysis conclusively linked family VSM-20 to a 28.3 cM region between D9S1808 and D9S251 on chromosome 9p, reducing the published minimal linked region to a 3.7 Mb interval. Genomic sequencing and expression analysis failed to identify mutations in the 10 known and predicted genes within this candidate region, suggesting that next-generation sequencing may be needed to determine the mutational mechanism associated with chromosome 9p-linked FTD-ALS.
Conclusions
Family VSM-20 significantly reduces the region linked to FTD-ALS on chromosome 9p. A distinct pattern of brain atrophy and neuropathological findings may help to identify other families with FTD-ALS caused by this genetic abnormality.
doi:10.1136/jnnp.2009.204081
PMCID: PMC3017222  PMID: 20562461
12.  Genetic Aspects of Alzheimer Disease 
The neurologist  2009;15(2):80-86.
Background
Alzheimer disease (AD) is a genetically complex disorder. Mutations in 3 genes, presenilin 1, amyloid precursor protein, and presenilin 2, lead to early-onset familial AD in rare families with onset of disease occurring prior to age 65. Specific polymorphisms in apolipoprotein E are associated with the more common, late-onset AD occurring after age 65. In this review, we discuss current advances in AD genetics, the implications of the known AD genes, presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E, and other possible genes on the clinical diagnosis, treatment, and genetic counseling of patients and families with early- and late-onset AD.
Review Summary
In addition to the mutations in 4 known genes associated with AD, mutations in other genes may be implicated in the pathogenesis of the disease. Most recently, 2 different research groups have reported genetic association between 2 genes, sortilin-related receptor and GAB2, and AD. These associations have not changed the diagnostic and medical management of AD.
Conclusions
New research in the genetics of AD have implicated novel genes as having a role in the disease, but these findings have not been replicated nor have specific disease causing mutations been identified. To date, clinical genetic testing is limited to familial early-onset disease for symptomatic individuals and asymptomatic relatives and, although not recommended, amyloid precursor protein apolipoprotein E testing as an adjunct to diagnosis of symptomatic individuals.
doi:10.1097/NRL.0b013e318187e76b
PMCID: PMC3052768  PMID: 19276785
alzheimer disease; genetics; genetic testing; genetic counseling

Results 1-12 (12)