Hereditary spastic paraplegia is not associated with C9ORF72 repeat expansions in a Danish cohort

Nielsen, Troels Tolstrup; Svenstrup, Kirsten; Dunø, Morten; Nielsen, Jimmi

doi:10.1038/sc.2013.116

Cited by 5 publications

(2 citation statements)

References 18 publications

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“…To establish if C9ORF72 might be a modifier of the HSP phenotype, a Danish cohort of 182 HSP cases was screened for the repeat expansion [45]. However, no mutations were identified.…”

Section: C9orf72 In Als and Other Motor Phenotypesmentioning

confidence: 99%

“…Hereditary spastic paraplegia (HSP) describes a group of over 50 genetically heterogeneous diseases which are characterised by a progressive dying back of the distal axons of upper motor neurons, leading to lower limb spasticity, pyramidal distribution weakness in the lower limbs and brisk reflexes. To establish if C9ORF72 might be a modifier of the HSP phenotype, a Danish cohort of 182 HSP cases was screened for the repeat expansion [ 45 ]. However, no mutations were identified.…”

Section: C9orf72 In Als and Other Motor Phenotypesmentioning

confidence: 99%

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The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype

2014

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The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS–FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72-ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington-like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer’s disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation.

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“…To establish if C9ORF72 might be a modifier of the HSP phenotype, a Danish cohort of 182 HSP cases was screened for the repeat expansion [45]. However, no mutations were identified.…”

Section: C9orf72 In Als and Other Motor Phenotypesmentioning

confidence: 99%

Section: C9orf72 In Als and Other Motor Phenotypesmentioning

confidence: 99%

The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype

2014

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The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis

et al. 2015

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The discovery that a hexanucleotide repeat expansion in C9orf72 is the most numerous genetic variant of both amyotrophic lateral sclerosis and frontotemporal dementia has opened a rapidly growing field, which may provide long hoped for advances in the understanding and treatment of these devastating diseases. In this review we describe the various phenotypes, clinical and pathological, associated with expansion of C9orf72, which go beyond amyotrophic lateral sclerosis and frontotemporal dementia to include neurodegeneration more broadly. Next we take a step back and summarize the current understanding of the C9orf72 expansion and its protein products at a molecular level. Three mechanisms are prominent: toxicity mediated directly by RNA transcribed from the repeat; toxicity mediated by dipeptide repeat proteins translated from the repeat sequence; and haploinsufficiency resulting from reduced transcription of the C9orf72 exonic sequence. A series of exciting advances have recently described how dipeptide repeat proteins might interfere with the normal role of the nucleolus in maturation of RNA binding proteins and in production of ribosomes. Importantly, these mechanisms are unlikely to be mutually exclusive. We draw attention to the fact that clinical and pathological similarities to other genetic variants without a repeat expansion must not be overlooked in ascribing a pathogenic mechanism to C9orf72-disease. Finally, with a view to impact on patient care, we discuss current practice with respect to genetic screening in patients with and without a family history of disease, and the most promising developments towards therapy that have been reported to date.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-015-0342-1) contains supplementary material, which is available to authorized users.

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Expanding the spectrum of C9ORF72-related neurodegenerative disorders in the Greek population

Kartanou¹,

Kontogeorgiou²,

Rentzos³

et al. 2022

Journal of the Neurological Sciences

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Hereditary spastic paraplegia is not associated with C9ORF72 repeat expansions in a Danish cohort

Cited by 5 publications

References 18 publications

The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype

The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype

The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis

Expanding the spectrum of C9ORF72-related neurodegenerative disorders in the Greek population

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