Characterization of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72.

BACKGROUND The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the underlying genetic cause of many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychologic, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism, and ALS spectrum. OBJECTIVE To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72. DESIGN Clinical series. SETTING Tertiary care academic medical center. PATIENTS The members of a family affected by the mutation with features of FTD and/or ALS. MAIN OUTCOME MEASURES Clinical, neuropsychologic, and neuroimaging assessments. RESULTS All 3 examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and 1 had ALS. Magnetic resonance imaging showed symmetric bilateral frontal, temporal, insular, and cingulate atrophy. CONCLUSIONS This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the cliniconeuroimaging-neuropathologic correlations.

[1]  David T. Jones,et al.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 , 2012, Brain : a journal of neurology.

[2]  C. Jack,et al.  Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics , 2012, Brain : a journal of neurology.

[3]  T. Ferman,et al.  Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72 , 2011, Acta Neuropathologica.

[4]  B. Boeve,et al.  Neuropsychological assessment of patients with dementing illness , 2011, Nature Reviews Neurology.

[5]  Bruce L. Miller,et al.  Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS , 2011, Neuron.

[6]  David Heckerman,et al.  A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD , 2011, Neuron.

[7]  Nick C Fox,et al.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. , 2011, Brain : a journal of neurology.

[8]  D. Hernandez,et al.  Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p , 2011, Journal of Neurology.

[9]  B. Miller,et al.  Classification of primary progressive aphasia and its variants , 2011, Neurology.

[10]  B. Boeve,et al.  Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family , 2010, Journal of Neurology, Neurosurgery & Psychiatry.

[11]  C. van Broeckhoven,et al.  Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. , 2010, Archives of neurology.

[12]  S. Heath,et al.  Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease , 2009, Neurology.

[13]  P. Schofield,et al.  Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9 , 2008, BMC neurology.

[14]  Clifford R. Jack,et al.  Alzheimer's disease diagnosis in individual subjects using structural MR images: Validation studies , 2008, NeuroImage.

[15]  V. Meininger,et al.  Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. , 2007, Archives of neurology.

[16]  C. Duijn,et al.  Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 , 2006, Nature.

[17]  S. Melquist,et al.  Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 , 2006, Nature.

[18]  F. Baas,et al.  Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. , 2006, Brain : a journal of neurology.

[19]  H. Horvitz,et al.  A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia , 2006, Neurology.

[20]  Karl J. Friston,et al.  Unified segmentation , 2005, NeuroImage.

[21]  M. Swash,et al.  El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis , 2000, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[22]  R. Faber,et al.  Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. , 1999, Neurology.

[23]  M. Freedman,et al.  Frontotemporal lobar degeneration , 1998, Neurology.

[24]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[25]  K P Offord,et al.  A short test of mental status: description and preliminary results. , 1987, Mayo Clinic proceedings.