Sex differences in the prevalence of genetic mutations in FTD and ALS

Curtis, Ashley; Masellis, Mario; Hsiung, Ging-Yuek Robin; Moineddin, Rahim; Zhang, Kathy; Au, Bonnie; Millett, Geneva; Mackenzie, Ian R.; Rogaeva, Ekaterina; Tierney, Mary C.

doi:10.1212/wnl.0000000000004494

Cited by 51 publications

(40 citation statements)

References 53 publications

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“…There were no statistically significant differences between the two groups with respect to median disease duration and male‐to‐female ratio; but there were more women in FTLD‐GRN (57%) than FTLD‐C9ORF72 (27%). This observation fits with a recent meta‐analyses showing that FTLD‐GRN is more common in women than men …”

Section: Resultssupporting

confidence: 93%

Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations

Sakae

Roemer

Bieniek

et al. 2019

Ann Clin Transl Neurol

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Objective To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD‐GRN) and chromosome 9 open reading frame 72 (FTLD‐C9ORF72). Methods We performed quantitative neuropathologic comparison of 17 FTLD‐C9ORF72 and 15 FTLD‐GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD‐GRN and 13 FTLD‐C9ORF72). Neuropathological analyses were limited to TDP‐43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD‐GRN and 11 FTLD‐C9ORF72). FTLD cases were also compared to age– and sex–matched normal controls. Immunohistochemistry was performed for pTDP‐43, IBA‐1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information. Results FTLD‐GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD‐C9ORF72 had greater hippocampal tau pathology and more TDP‐43 neuronal cytoplasmic inclusions. FTLD‐GRN had more neocortical microvacuolation, as well as more IBA‐1–positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD‐GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD‐GRN and FTLD‐C9ORF72 differed from controls. Interpretation Our findings underscore differences in microglial response in FTLD‐C9ORF72 and FTLD‐GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD‐GRN and FTLD‐C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

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Section: Resultssupporting

confidence: 93%

Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations

Sakae

Roemer

Bieniek

et al. 2019

Ann Clin Transl Neurol

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“…Interestingly, all of our TIA1 mutations carriers were female, despite there being no sex bias in the case series in which they were identified. This finding is all the more striking, given that ALS, in general, is reported to be more common in men with a ratio of males to females of 1.7:1 [ 21 ] and could indicate that some factor associated with biological sex affects the penetrance of TIA1 mutations, similar to what has been reported for some other genetic subtypes of ALS/FTD [ 6 ]. This association will need to be investigated further in additional case series and we note that one affected member of UBCU2 was male, although no source of DNA was available to confirm his genetic status.…”

Section: Discussionsupporting

confidence: 59%

Clinical and neuropathological features of ALS/FTD with TIA1 mutations

Hirsch‐Reinshagen

Pottier

Nicholson

et al. 2017

acta neuropathol commun

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Mutations in the stress granule protein T-cell restricted intracellular antigen 1 (TIA1) were recently shown to cause amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). Here, we provide detailed clinical and neuropathological descriptions of nine cases with TIA1 mutations, together with comparisons to sporadic ALS (sALS) and ALS due to repeat expansions in C9orf72 (C9orf72+). All nine patients with confirmed mutations in TIA1 were female. The clinical phenotype was heterogeneous with a range in the age at onset from late twenties to the eighth decade (mean = 60 years) and disease duration from one to 6 years (mean = 3 years). Initial presentation was either focal weakness or language impairment. All affected individuals received a final diagnosis of ALS with or without FTD. No psychosis or parkinsonism was described. Neuropathological examination on five patients found typical features of ALS and frontotemporal lobar degeneration (FTLD-TDP, type B) with anatomically widespread TDP-43 proteinopathy. In contrast to C9orf72+ cases, caudate atrophy and hippocampal sclerosis were not prominent. Detailed evaluation of the pyramidal motor system found a similar degree of neurodegeneration and TDP-43 pathology as in sALS and C9orf72+ cases; however, cases with TIA1 mutations had increased numbers of lower motor neurons containing round eosinophilic and Lewy body-like inclusions on HE stain and round compact cytoplasmic inclusions with TDP-43 immunohistochemistry. Immunohistochemistry and immunofluorescence failed to demonstrate any labeling of inclusions with antibodies against TIA1. In summary, our TIA1 mutation carriers developed ALS with or without FTD, with a wide range in age at onset, but without other neurological or psychiatric features. The neuropathology was characterized by widespread TDP-43 pathology, but a more restricted pattern of neurodegeneration than C9orf72+ cases. Increased numbers of round eosinophilic and Lewy-body like inclusions in lower motor neurons may be a distinctive feature of ALS caused by TIA1 mutations.

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“…On the contrary, there is a satisfying amount of data that the expansion may be one of the leading genetic causes of HD‐phenocopies in populations of European origin. By comparing the segregate data on prevalence from the reviewed studies to the figures reported in the latest published meta‐analysis of ALS and FTD related to C9orf72 , we noticed a big gap in the observed frequencies and the number of cases, questioning the relevance of C9orf72 to parkinsonian disorders (Fig. ).…”

Section: Resultsmentioning

confidence: 95%

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

Bourinaris

Houlden

2018

Movement Disord Clin Pract

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Background The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders. Its significance, though outside the FTD/ALS spectrum, is not well defined. Methods A comprehensive search of the literature was performed. All relevant papers, including reviews and case series/reports on movement disorder phenotypes reported with the C9orf72 repeat expansion, were reviewed. Data on frequency, natural history, phenotype, genetics, and possible underlying mechanisms were assessed. Results and Discussion In a number of studies, C9orf72 accounts for a small fraction of typical PD. Atypical parkinsonian syndromes, including CBS, PSP, and MSA have also been reported. Features that increase the probability of positive testing include early cognitive and/or behavioral symptoms, positive family history of ALS or FTD, and the presence of UMN and LMN signs. Furthermore, several studies conclude that C9orf72 is the most common cause of HD‐phenocopies. Interestingly, many cases with the parkinsonian phenotype that bear an intermediate range of repeats are also reported, questioning the direct causal role of C9orf72 and suggesting the possibility of being a susceptibility factor, while the presence of the expansion in normal controls questions its clinical significance. Finally, studies on pathology reveal a distinctive broad range of C9orf72‐related neurodegeneration that could explain the wide phenotypic variation.

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Sex differences in the prevalence of genetic mutations in FTD and ALS

Abstract: Higher female prevalence of hexanucleotide repeat expansions in ALS and mutations in FTD suggest that sex-related risk factors might moderate andmediated phenotypic expression.

Cited by 51 publications

References 53 publications

Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations

Microglia in frontotemporal lobar degeneration with progranulin or C9ORF72 mutations

Clinical and neuropathological features of ALS/FTD with TIA1 mutations

C9orf72 and its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature

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