Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease

Department of Pathology, University of British Columbia, Vancouver, BC, Canada.
BMC Neurology (Impact Factor: 2.04). 02/2006; 6(1):32. DOI: 10.1186/1471-2377-6-32
Source: PubMed


Many cases of frontotemporal dementia (FTD) are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T). Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir), dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U). Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII). NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease.
We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63), including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available) and with those of healthy controls (n = 94). High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats). For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract length was confirmed by capillary electrophoresis. In addition, immunohistochemistry using a monoclonal antibody that recognizes proteins containing expanded polyglutamines (1C2) was performed on sections of post mortem brain tissue from subjects with NII.
No significant polyglutamine-encoding repeat expansions were identified in the DNA from any of our FTLD-U patients. NII in the FTLD-U cases showed no 1C2 immunoreactivity.
We find no evidence to suggest that autosomal dominant FTLD-U with NII is a polyglutamine expansion disease.

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    • "Some neurological TRDs show a preferential maternal transmission, such as fragile X syndrome, [132] Friedreich ataxia, [133] spino-cerebellar ataxia type 8 [63] and myotonic dystrophy [134]. Trinucleotide expansions may also be involved in some cases of frontotemporal dementia, although results are not conclusive [135,136]. There is currently no evidence for trinucleotide repeat expansions in AD. "
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    • "Many families in this group carry mutations in the gene encoding microtubule-associated protein tau (MAPT) and neuropathological examination reveals neuronal and glial tau-positive inclusions affected areas. Recently, it was shown that several large kindreds linked to chromosome 17 but lacking tau mutations and tau-immunoreactive inclusions represented a subtype of FTLD characterized by neuronal ubiquitin-positive, tau-negative inclusions (FTLD-U) [Mackenzie et al., 2006; Mukherjee et al., 2006; Rosso et al., 2001; Behrens et al., 2007]. Null mutations in the progranulin gene (GRN; MIM# 138945) were reported to cause disease in these families [Baker et al., 2006; Cruts et al., 2006]. "
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