Abstract

To determine the genetic basis of familial frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS) we performed a clinical and genetic analysis of an affected family. A 51-year-old man with behavioral variant FTLD with ALS had a family history of the disease suggestive of autosomal dominant inheritance with incomplete penetrance. Genetic studies in this patient demonstrated the presence of an amplified hexanucleotide repeat (>30) polymorphism in the chromosome 9 open reading frame 72 (C9ORF72) gene which was previously identified as a cause of FTLD. Five others unaffected from the family were negative (all had less than 11 repeats). Because of the clinical and pathological overlap between FTLD and AD we performed a larger genome-wide association study and did not find association of single nucleotide polymorphisms (SNPs) in the C9ORF72 gene with Alzheimer’s disease (AD) risk. Bioinformatic analysis of C9ORF72 using the Gene Expression Omnibus database showed expression differences in patients with muscular dystrophy, neural tube defects, and schizophrenia. We also report analysis of gene expression in brain regions using the Allen Human Brain Atlas. Defects in this recently reported gene are now believed to be the most common cause of inherited ALS and an important cause of inherited FTLD. Our work suggests that the gene may also be important in other neurological and psychiatric conditions.

Highlights

  • AND BACKGROUND Frontotemporal lobar degeneration (FTLD), originally described by Alois Alzheimer’s contemporary Arnold Pick, has been recognized as the second leading cause of dementia in people under the age of 65 (Ratnavalli et al, 2002)

  • A 51-year-old man with behavioral variant frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS) had a family history of the disease suggestive of autosomal dominant inheritance with incomplete penetrance. Genetic studies in this patient demonstrated the presence of an amplified hexanucleotide repeat (>30) polymorphism in the chromosome 9 open reading frame 72 (C9ORF72) gene which was previously identified as a cause of FTLD

  • Significant results were observed with four single nucleotide polymorphisms (SNPs) (p < 0.05), but none of these findings remained significant after correction for multiple testing

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Summary

Introduction

AND BACKGROUND Frontotemporal lobar degeneration (FTLD), originally described by Alois Alzheimer’s contemporary Arnold Pick, has been recognized as the second leading cause of dementia in people under the age of 65 (Ratnavalli et al, 2002). A 51-year-old man with behavioral variant FTLD with ALS had a family history of the disease suggestive of autosomal dominant inheritance with incomplete penetrance. Genetic studies in this patient demonstrated the presence of an amplified hexanucleotide repeat (>30) polymorphism in the chromosome 9 open reading frame 72 (C9ORF72) gene which was previously identified as a cause of FTLD.

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