Hexanucleotide repeat expansions in
            <i>C9ORF72</i>
            in the spectrum of motor neuron diseases

Rheenen, Wouter van; Blitterswijk, Marka van; Huisman, Mark; Vlam, Lotte; Doormaal, Perry T C van; Seelen, Meinie; Medic, Jelena; Dooijes, Dennis; Visser, Marjolein; Kooi, Anneke J. van der; Raaphorst, Joost; Schelhaas, Helenius J.; Pol, W. Ludo van der; Veldink, Jan H.; Berg, Leonard H. van den

doi:10.1212/wnl.0b013e3182661d14

Cited by 104 publications

(75 citation statements)

References 18 publications

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“…1 Patients with a hexanucleotide (GGGGCC) expansion mutation in the C9orf72 gene have shorter survival than the average ALS patient. [25][26][27][28] Even within families in which members carry the same mutation, variability in progression rates is large. [29][30][31] This finding suggests that there is no straightforward relationship between the genetic cause and phenotype but, rather, that factors-either genetic or e nvironmental-modify the phenotypic expression, and in particular age at onset and disease progression.…”

Section: Age At Onsetmentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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| Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3-5 years after onset-a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.

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Section: Age At Onsetmentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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“…4,8,28,29 Earlier age at onset in C9Pos patients has been used as a rationale to describe C9orf72-related ALS as a more aggressive form of the disease. Our inability to confirm this finding might be explained by our study design, which compared the C9Pos group to a concurrent and unselected group of patients with ALS, rather than a designated comparison cohort.…”

Section: Demographic and Clinical Information Acquisitionmentioning

confidence: 99%

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Umoh

Fournier

et al. 2016

Neurology

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Objective: We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features.Methods: Between 2001 and, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives.Results: The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank x 2 [1] 5 45.323, p , 0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD. Conclusions:Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.

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“…[9][10][11][12][13][14][15][16] This mutation is currently recognized as a major genetic cause of ALS and FTLD, responsible for up to 40% of familial ALS, 5% to 10% of sporadic ALS, about 20% of familial FTLD, and 5% of sporadic FTLD. 15,[17][18][19][20] At the neuropathological level, most forms of ALS are characterized by the presence of inclusions in degenerating motor neurons staining positively for ubiquitin and TAR DNAbinding protein 43. Whereas the presence of LMN degeneration can be confirmed by electrodiagnostic testing, there is no widely accepted biomarker for UMN involvement.…”

mentioning

confidence: 99%

Value of¹⁸Fluorodeoxyglucose–Positron-Emission Tomography in Amyotrophic Lateral Sclerosis

et al. 2014

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IMPORTANCE Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting the motor system, with extramotor involvement to a variable extent. Biomarkers for early differential diagnosis and prognosis are needed. An autosomal dominant hexanucleotide (GGGGCC) expansion in the noncoding region of the chromosome 9 open reading frame 72 (C9orf72) gene is the most frequent genetic cause of ALS, but its metabolic pattern has not been studied systematically.OBJECTIVES To evaluate the use of 18 fluorodeoxyglucose-positron-emission tomography as a marker of ALS pathology and investigate whether a specific metabolic signature is present in patients with C9orf72 mutations. DESIGN, SETTING, AND PARTICIPANTSIn total, 81 patients with a suspected diagnosis of ALS at University Hospital Leuven were prospectively investigated. All underwent detailed neurological examination and electrodiagnostic and genetic testing for the major known genetic causes of ALS (C9orf72, SOD1, TARDBP, and FUS). A diagnosis of ALS was made in 70 of 81 patients. Of these, 11 were C9orf72 positive and 59 were C9orf72 negative. In 7 patients, the diagnosis of primary lateral sclerosis was made; 4 patients had progressive muscular atrophy. A screened healthy control population was used for comparison. MAIN OUTCOMES AND MEASURESPositron-emission tomographic data were spatially normalized and analyzed using a predefined volume of interest and a voxel-based analysis (SPM8). Discriminant analysis was done both volume of interest based and voxel based using a support vector machine approach.RESULTS Compared with control participants, 18 fluorodeoxyglucose-positron-emission tomography showed perirolandic and variable prefrontal hypometabolism in most patients. Patients with primary lateral sclerosis showed a similar pattern. Patients with C9orf72-positive ALS had discrete relative hypometabolism in the thalamus and posterior cingulate compared with those with C9orf72-negative ALS. A posteriori-corrected discriminant analysis was able to correctly classify 95% of ALS cases and 71% of primary lateral sclerosis cases. Prefrontal hypometabolism was associated with reduced clinical functioning (ALS Functional Rating Scale). Extensive hypometabolism in the prefrontal or anterior temporal areas was present in 10% of patients and associated with significantly shorter survival as an independent factor (n = 63, P < .001). Patients who were C9orf72 positive did not differ in survival compared with those who were C9orf72 negative. 18 Fluorodeoxyglucose-positron-emission tomography is a useful early diagnostic and prognostic marker for ALS. Amyotrophic lateral sclerosis that is positive for C9orf72 is characterized by only mild cerebral metabolic differences that show no prognostic difference. CONCLUSIONS AND RELEVANCE

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Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases

Cited by 104 publications

References 18 publications

The phenotypic variability of amyotrophic lateral sclerosis

The phenotypic variability of amyotrophic lateral sclerosis

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Value of¹⁸Fluorodeoxyglucose–Positron-Emission Tomography in Amyotrophic Lateral Sclerosis

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Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor neuron diseases

Cited by 104 publications

References 18 publications

The phenotypic variability of amyotrophic lateral sclerosis

The phenotypic variability of amyotrophic lateral sclerosis

Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population

Value of18Fluorodeoxyglucose–Positron-Emission Tomography in Amyotrophic Lateral Sclerosis

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Value of¹⁸Fluorodeoxyglucose–Positron-Emission Tomography in Amyotrophic Lateral Sclerosis