Elsevier

Neurobiology of Aging

Volume 33, Issue 10, October 2012, Pages 2527.e11-2527.e16
Neurobiology of Aging

Genetic reports abstract
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Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis

https://doi.org/10.1016/j.neurobiolaging.2012.05.011Get rights and content

Abstract

Recently, a hexanucleotide repeat expansion in C9orf72 was identified as the most common cause of both sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Western populations. We analyzed 563 Japanese patients with ALS (552 sporadic and 11 familial) using fluorescent fragment-length analysis of C9orf72 and repeat-primed polymerase chain reaction analysis. Haplotype analysis was performed for 42 single nucleotide polymorphisms in patients with C9orf72 repeat expansion. C9orf72 repeat expansion was found in 2 patients with sporadic ALS (2/552 = 0.4%) and no patients with familial ALS (0/11 = 0%). In the probands' families, 1 primary progressive aphasia patient and 1 asymptomatic 76-year-old individual exhibited C9orf72 repeat expansion. All of the patients with the C9orf72 repeat expansion carried the 20-single nucleotide polymorphism consensus risk haplotype. The frequency of the C9orf72 repeat expansion among Japanese patients is much lower than in Western populations. The existence of a 76-year-old asymptomatic carrier supported the notion of incomplete penetrance. The C9orf72 mutation should be analyzed in sporadic ALS patients after determining their family histories not only of frontotemporal dementia but also of primary progressive aphasia.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons in the spinal cord, brain stem, and cerebral cortex, typically leading to death within a few years. Five to ten percent of ALS cases are familial, and the remaining cases are believed to be sporadic (Valdmanis et al., 2009). A number of genes causing ALS with a dominant mode of inheritance have been discovered, such as SOD1, TARDBP, FUS, VAPB, ANG, VCP, OPTN (Ticozzi et al., 2011), and UBQLN2 (Deng et al., 2011). Moreover, there is increasing clinical and pathological evidence for the hypothesis that ALS and frontotemporal dementia (FTD) constitute an overlapping continuum of diseases (Lomen-Hoerth et al., 2002, Neumann et al., 2006). Recently, the expansion of a noncoding GGGGCC hexanucleotide repeat in the C9orf72 gene has been reported to be a major cause of both ALS and FTD (DeJesus-Hernandez et al., 2011, Gijselinck et al., 2012, Renton et al., 2011) and the most common genetic abnormality in familial and sporadic forms of both ALS and FTD, particularly in Western populations (Chiò et al., 2012, DeJesus-Hernandez et al., 2011, Gijselinck et al., 2012, Renton et al., 2011; Sabatelli et al., 2012; Stewart et al., 2012). In the present study, we describe the incidence and demographic and clinical features associated with the C9orf72 mutation in a large cohort of Japanese ALS patients. We also perform haplotype analysis to investigate whether Japanese patients have the same risk haplotype as European patients (Gijselinck et al., 2012, Laaksovirta et al., 2010, Mok et al., 2012).

Section snippets

Subjects

We obtained a total of 760 DNA samples from the Japanese Consortium for Amyotrophic Lateral Sclerosis Research (JaCALS; Appendix A). A total of 563 (11 familial and 552 sporadic) patients were diagnosed with ALS according to the El Escorial revised criteria (Brooks et al., 2000) and classified as bulbar-onset, spinal-onset, FTD-ALS, or other (see Supplementary Table 1 for details). We had determined the family histories of ALS but not FTD or primary progressive aphasia (PPA) in all of the

Detection of C9orf72 repeat expansion

The C9orf72 repeat expansion was found in 2 of 522 Japanese patients (2/552 = 0.4%) with SALS and none of the 11 patients (0/11 = 0%) with familial ALS (FALS) using repeat-primed PCR (Table 1). Patient A-I with a C9orf72 mutation was classified as SALS in this study, but after detecting the mutation, we found that patient A-II (a brother of patient A-I) developed aphasia and dementia and had a C9orf72 mutation (Fig. 1). The average repeat number based on fluorescent fragment-length analysis was

Discussion

We began this study considering patients without family histories of ALS to be SALS because our cohort included only family histories of ALS but not FTD or PPA. Although it may be difficult to describe the real frequency in SALS because 1 of the SALS patients had a family member who developed PPA, the frequencies of the C9orf72 mutation in Japanese patients were 0.4% (2/552) in SALS and 0% (0/11) in FALS according to this classification. In contrast, the frequencies of the C9orf72 mutation fall

Disclosure statement

All of the authors disclose no conflicts of interest. The study was approved by the ethical committees of the participating centers. All participants gave written informed consent.

Acknowledgements

The authors thank all of the participants in this study. The authors also thank Dr. Mariely DeJesus-Hernandez, Dr. Ilse Gijselinck, Dr. Marc Cruts, and Dr. Christine Van Broeckhoven for technical advice. This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (21229011, 21390272, 21591098, 22790817, 22790829, and 23659452), the Ministry of Welfare, Health and Labor of Japan (20261501, 22140501, 22140901, and CCT-B-1701), the Japan Science and

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