Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p
Open accessAbstract
Families with autosomal dominant frontotemporal dementia and amyotrophic lateral sclerosis (FTD/ALS) have previously been linked to a locus on chromosome 9p21. We describe the clinical phenotype and pathology of a large family with autosomal dominant FTD/ALS with nine affected members originating from Gwent in South Wales, UK. We also further refine the locus on chromosome 9p21 using a haplotype sharing approach and assess heterogeneity in 9p21 linked families. Within this family, affected individuals present with either FTD or ALS or both diseases simultaneously. In addition there was marked phenotypic variation including ataxia, Parkinsonism, psychosis and visuo-spatial cognitive deficits. The pathological features of the three cases described were consistent with type 2 FTD pathology, as previously reported in similar families. However, we also report distinctive cerebellar and glial pathology and a significant proportion of TDP-43 negative inclusions. No mutations in known genes for FTD or ALS were found. We identified a large 4.8-megabase haplotype on chromosome 9p21, which was shared by all affected family members. This haplotype overlaps and limits the previously reported FTD/ALS linkage region on chromosome 9p21. Sequencing of this region did not identify any evidence of a pathogenic exonic mutation. This suggests that the pathogenic change affects non-coding DNA and that the disease is caused by variation in gene or protein expression.
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Correlation studies between molecular genetics and neuropathology indicate that for several autosomal dominant dementias, the presenting clinical phenotype may vary widely, from various dementia subtypes to parkinsonism to motor neuron disease-like, even among individuals with the same causative mutation.
“Correlation studies between molecular genetics and neuropathology also indicate that for several autosomal dominant dementias, the presenting clinical phenotype may vary widely, from various dementia subtypes to parkinsonism to motor neuron disease-like, even among individuals with the same causative mutation (44-47).”
From Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010 (2012) · cites this paper as [46]
The Results (Clinical features) and Comment describe markedly different presentations—including FTD, ALS and Parkinsonism—within one family with autosomal dominant FTD/ALS. But the Genetics section identifies a shared chromosome 9p21 haplotype, not a causative mutation, and the paper does not establish this pattern across several autosomal dominant dementias. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPhenotype is not rigidly linked to etiology and may be moldable to a large extent by an individual's genetic and epigenetic background and/or total environmental exposure.
“These findings suggest that phenotype is not rigidly linked to etiology and may be moldable to a large extent by an individual's genetic and epigenetic background and/or total environmental exposure.”
From Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010 (2012) · cites this paper as [46]
The Comment section (page unavailable) reports marked clinical heterogeneity among family members likely to share a single disease-causing mutation, supporting the point that this disease’s phenotype is not fixed by its apparent etiology. The paper does not attribute that variation to genetic or epigenetic background or environmental exposure, nor establish how extensively those factors mold phenotype. (LLM, conf=0.86)
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References 26 · Cited by 84
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- Authors
- Pearson, J. P., Williams, N. M., Majounie, E., Waite, A., Stott, J., Newsway, V., Murray, A., Hernandez, D., Guerreiro, R., Singleton, A. B., Neal, J., & Morris, H. R.
- Affiliations
- Cardiff University (GB)
- University Hospital of Wales (GB)
- National Institutes of Health (US)
- Royal Gwent Hospital (GB)
- Corresponding author
- Morris, Huw R.
- ORCID
- Venue
- Journal of Neurology
- Published
- 2010-11-12
- Volume
- 258
- Issue
- 4
- Pages
- 647-655
- ISSN
- 0012-1037 (ISSN-L)
- 0340-5354
- 1432-1459
- PMC
- PMC4696389
- OpenAlex
- W1998593155
- Cited by
- 84
- References
- 26
- Citations by year
- 2025: 1 · 2023: 3 · 2022: 1 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 5 · 2015: 6 · 2014: 3 · 2013: 8 · 2012: 36
- FWCI
- 10.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Motor Neurone Disease Association (Morris/Oct09/6057)
- National Institutes of Health
- National Institute on Aging (Z01AG000951, Z01AG000949)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- frontotemporal dementia, amyotrophic lateral sclerosis, autosomal dominant inheritance, chromosome 9p21, haplotype sharing, genetic linkage, cerebellar pathology, glial pathology, non-coding variants, phenotypic heterogeneity, parkinsonism, psychosis, ataxia
- MeSH terms
- Adult, Amyotrophic Lateral Sclerosis, Brain, Chromosomes, Human, Pair 9, DNA-Binding Proteins, Family Health, Female, Gene Frequency, Genetic Testing, Genotype, Glial Fibrillary Acidic Protein, Haplotypes, Humans, Male, Middle Aged, Spinal Cord, Polymorphism, Single Nucleotide, Frontotemporal Dementia
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