Khan BK, Yokoyama JS, Takada LT, et al. Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion

Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
Journal of neurology, neurosurgery, and psychiatry (Impact Factor: 6.81). 04/2012; 83(4):358-64. DOI: 10.1136/jnnp-2011-301883
Source: PubMed


Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD 'phenocopies' or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described.
384 patients with an FTD clinical spectrum and Alzheimer's disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls.
Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable.
C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.

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    • "GRN mutations are associated with more markedly asymmetric frontotemporal atrophy that also involves the parietal lobes (Figure 5a) and cases that eventually may evolve clinical features of CBS, whereas cases with MAPT mutations tend to have less atrophy and a stronger predilection for temporal areas with more focal involvement [38]. Finally, both familial and sporadic cases with C9ORF72 repeat expansions have more variable presentations including slowly progressive variants [114] and prominent neuropsychiatric illness [115], as well as association with motoneuron disease; atrophy tends to be more symmetrical involving the dorsolateral, medial, and orbitofrontal lobes [116]. The primary psychoses, such as bipolar disorder and schizophrenia, can also present with prominent behavioral features and are also considered in the differential diagnosis. "
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    ABSTRACT: This paper summarizes the body of literature about early-onset dementia (EOD) that led to recommendations from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. A broader differential diagnosis is required for EOD compared with late-onset dementia. Delays in diagnosis are common, and the social impact of EOD requires special care teams. The etiologies underlying EOD syndromes should take into account family history and comorbid diseases, such as cerebrovascular risk factors, that may influence the clinical presentation and age at onset. For example, although many EODs are more likely to have Mendelian genetic and/or metabolic causes, the presence of comorbidities may drive the individual at risk for late-onset dementia to manifest the symptoms at an earlier age, which contributes further to the observed heterogeneity and may confound diagnostic investigation. A personalized medicine approach to diagnosis should therefore be considered depending on the age at onset, clinical presentation, and comorbidities. Genetic counseling and testing as well as specialized biochemical screening are often required, especially in those under the age of 40 and in those with a family history of autosomal dominant or recessive disease. Novel treatments in the drug development pipeline for EOD, such as genetic forms of Alzheimer's disease, should target the specific pathogenic cascade implicated by the mutation or biochemical defect.
    Alzheimer's Research and Therapy 07/2013; 5(Suppl 1):S7. DOI:10.1186/alzrt197 · 3.98 Impact Factor
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    • "When therapeutic interventions are identified, patient-specific cell lines can be used to test the toxicology and potential benefit for that individual patient. Given the heterogeneity of C9ORF72 phenotypes, with both slowly and rapidly progressive forms of disease [50], use of patient-specific induced pluripotent stem cells may be particularly useful for C9ORF72-related disease. "
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    ABSTRACT: Frontotemporal dementia (FTD) is a common dementia syndrome in patients under the age of 65 years with many features overlapping with amyotrophic lateral sclerosis (ALS). The link between FTD and ALS has been strengthened by the discovery that a hexanucleotide repeat expansion in a non-coding region of the C9ORF72 gene causes both familial and sporadic types of these two diseases. As we begin to understand the pathophysiological mechanisms by which this mutation leads to FTD and ALS (c9FTD/ALS), new targets for disease-modifying therapies will likely be unveiled. Putative C9ORF72 expansion pathogenic mechanisms include loss of C9ORF72 protein function, sequestration of nucleic acid binding proteins due to expanded hexanucleotide repeats, or a combination of the two. New animal models and other research tools informed by work in other repeat expansion neurodegenerative diseases such as the spinocerebellar ataxias will help to elucidate the mechanisms of C9ORF72-mediated disease. Similarly, re-examining previous studies of drugs developed to treat ALS in light of this new mutation may identify novel FTD treatments. Ultimately, research consortiums incorporating animal models and well-characterized clinical populations will be necessary to fully understand the natural history of the c9FTD/ALS clinical phenotypes and identify biomarkers and therapeutic agents that can cure the most common form of genetically determined FTD and ALS.
    Alzheimer's Research and Therapy 11/2012; 4(6):46. DOI:10.1186/alzrt149 · 3.98 Impact Factor
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    • "This diffuse atrophy pattern is much less common in other genetic and sporadic forms of FTD and may be a hallmark of C9ORF72 expansion. Interestingly, some C9+ patients have been described as clinically affected yet demonstrate no visually detectable brain atrophy [8,9,14]; a recent report described two such patients with slowly progressive bvFTD (bvFTD-SP) characterized by a long disease course and non-progressive brain atrophy, and both of them were C9+ [14]. "
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    ABSTRACT: Hexanucleotide expansion intronic to chromosome 9 open reading frame 72 (C9ORF72) has recently been identified as the most common genetic cause of both familial and sporadic amyotrophic lateral sclerosis and of frontotemporal dementia with or without concomitant motor neuron disease. Given the common frequency of this genetic aberration, clinicians seek to identify neuroimaging hallmarks characteristic of C9ORF72-associated disease, both to provide a better understanding of the underlying degenerative patterns associated with this mutation and to enable better identification of patients for genetic screening and diagnosis. A survey of the literature describing C9ORF72 neuroimaging thus far suggests that patients with this mutation may demonstrate symmetric frontal and temporal lobe, insular, and posterior cortical atrophy, although temporal involvement may be less than that seen in other mutations. Some studies have also suggested cerebellar and thalamic involvement in C9ORF72-associated disease. Diffuse cortical atrophy that includes anterior as well as posterior structures and subcortical involvement thus may represent unique features of C9ORF72.
    Alzheimer's Research and Therapy 11/2012; 4(6):45. DOI:10.1186/alzrt148 · 3.98 Impact Factor
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