Publications by authors named "Perry T C van Doormaal"

15 Publications

  • Page 1 of 1

The role of de novo mutations in the development of amyotrophic lateral sclerosis.

Hum Mutat 2017 11 3;38(11):1534-1541. Epub 2017 Aug 3.

Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.

The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 × 10 ). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599399PMC
November 2017

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1037-42. Epub 2016 Jul 25.

Neurogenetics Group, Division of Brain Sciences, Imperial College London, London, UK.

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560030PMC
September 2016

Large-scale screening in sporadic amyotrophic lateral sclerosis identifies genetic modifiers in C9orf72 repeat carriers.

Neurobiol Aging 2016 Mar 29;39:220.e9-15. Epub 2015 Dec 29.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

Sporadic amyotrophic lateral sclerosis (ALS) is considered to be a complex disease with multiple genetic risk factors contributing to the pathogenesis. Identification of genetic risk factors that co-occur frequently could provide relevant insight into underlying mechanisms of motor neuron degeneration. To dissect the genetic architecture of sporadic ALS, we undertook a large sequencing study in 755 apparently sporadic ALS cases and 959 controls, analyzing 10 ALS genes: SOD1, C9orf72, TARDBP, FUS, ANG, CHMP2B, ATXN2, NIPA1, SMN1, and UNC13A. We observed sporadic cases with multiple genetic risk variants in 4.1% compared with 1.3% in controls. The overall difference was not in excess of what is to be expected by chance (binomial test, p = 0.59). We did, however, observe a higher frequency than expected of C9orf72 repeat carriers with co-occurring susceptibility variants (ATXN2, NIPA1, and SMN1; p = 0.001), which is mainly because of the co-occurrence of NIPA1 repeats in 15% of C9orf72 repeat carriers (p = 0.006).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2015.12.012DOI Listing
March 2016

Effect of Presymptomatic Body Mass Index and Consumption of Fat and Alcohol on Amyotrophic Lateral Sclerosis.

JAMA Neurol 2015 Oct;72(10):1155-62

Department of Neurology, Rudolf Magnus Brain Centre, University Medical Centre Utrecht, Utrecht, the Netherlands.

Importance: Because dietary intake may influence pathophysiologic mechanisms in sporadic amyotrophic lateral sclerosis (ALS), the association between premorbid dietary intake and the risk of sporadic ALS will provide insight into which mechanisms are possibly involved in ALS pathophogenesis.

Objective: To systematically determine the association between premorbid dietary intake and the risk of sporadic ALS.

Design, Setting, And Participants: A population-based case-control study was conducted in a general community setting in the Netherlands from January 1, 2006, to September 30, 2011. Analysis was conducted April 1, 2013, to November 15, 2014. All patients with a new diagnosis of possible, probable (laboratory supported), or definite ALS according to the revised El Escorial criteria were included and multiple sources were used to ensure complete case ascertainment. Of 986 eligible patients, 674 gave informed consent and returned a complete questionnaire; 2093 controls randomly selected from the general practitioners' registers and frequency matched to the patients for sex and age were included.

Main Outcomes And Measures: We studied the premorbid intake of nutrients in association with the risk of ALS by using a 199-item food frequency questionnaire adjusted for confounding factors and corrected for multiple comparisons while minimizing recall bias.

Results: Presymptomatic total daily energy intake in patients, reported as mean (SD), was significantly higher compared with controls (2258 [730] vs 2119 [619] kcal/day; P < .01), and presymptomatic body mass index (calculated as weight in kilograms divided by height in meters squared) was significantly lower in patients (25.7 [4.0] vs 26.0 [3.7]; P = .02). With values reported as odds ratio (95% CI), higher premorbid intake of total fat (1.14; 1.07-1.23; P < .001), saturated fat (1.43; 1.25-1.64; P < .001), trans-fatty acids (1.03; 1.01-1.05; P < .001), and cholesterol (1.08; 1.05-1.12; P < .001) was associated with an increased risk of ALS; higher intake of alcohol (0.91; 0.84-0.99; P = .03) was associated with a decreased risk of ALS. These associations were independent of total energy intake, age, sex, body mass index, educational level, smoking, and lifetime physical activity. No significant associations between dietary intake and survival were found.

Conclusions And Relevance: The combination of independent positive associations of a low premorbid body mass index and a high fat intake together with prior evidence from ALS mouse models transgenic for SOD1 and earlier reports on premorbid body mass index support a role for increased resting energy expenditure before clinical onset of ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2015.1584DOI Listing
October 2015

Prior medical conditions and the risk of amyotrophic lateral sclerosis.

J Neurol 2014 Oct 25;261(10):1949-56. Epub 2014 Jul 25.

Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.

Sporadic amyotrophic lateral sclerosis (ALS) is believed to be a complex disease in which multiple exogenous and genetic factors interact to cause motor neuron degeneration. Elucidating the association between medical conditions prior to the first symptoms of ALS could lend support to the theory that specific subpopulations are at risk of developing ALS and provide new insight into shared pathogenic mechanisms. We performed a population-based case-control study in the Netherlands, including 722 sporadic ALS patients and 2,268 age and gender matched controls. Data on medical conditions and use of medication were obtained through a structured questionnaire. Multivariate analyses showed that hypercholesterolemia (OR 0.76, 95% CI 0.63-0.92, P = 0.006), the use of statins (OR 0.45, 95% CI 0.35-0.59, P = 1.86 × 10(-9)) or immunosuppressive drugs (OR 0.26, 95% CI 0.08-0.86, P = 0.03) were associated with a decreased risk of ALS. Head trauma was associated with an increased ALS susceptibility (OR 1.95, 95% CI 1.11-3.43, P = 0.02). No association was found with autoimmune diseases, cancer, psychiatric disorders or cardiovascular diseases, or survival. The lower frequency of hypercholesterolemia and less use of statins in ALS patients indicate a favorable lipid profile prior to symptom onset in at least a subpopulation of ALS. Prior head trauma is a risk factor for ALS and the significantly lower use of immunosuppressive drugs in ALS patients could suggest a protective effect. The identification of specific subpopulations at risk for ALS may provide clues towards possible pathogenic mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-014-7445-1DOI Listing
October 2014

Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study.

Neurobiol Aging 2014 Oct 19;35(10):2420.e13-4. Epub 2014 Apr 19.

The Institute of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.

Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 (KIFAP3) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect of genetic variation in rs1541160. The previously reported beneficial genotype did not show a significant improvement in survival in this patient group.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2014.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496711PMC
October 2014

Lifetime physical activity and the risk of amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2013 Sep 16;84(9):976-81. Epub 2013 Feb 16.

Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: It has been hypothesised that physical activity is a risk factor for developing amyotrophic lateral sclerosis (ALS), fuelled by observations that professional soccer players and Gulf War veterans are at increased risk. In a population based study, we determined the relation between physical activity and risk of sporadic ALS, using an objective approach for assessing physical activity.

Methods: 636 sporadic ALS patients and 2166 controls, both population based, completed a semistructured questionnaire on lifetime history of occupations, sports and hobbies. To objectively compare the energy cost of a lifetime history of occupational and leisure time physical activities and to reduce recall bias, metabolic equivalent scores were assigned to each activity based on the Compendium of Physical Activities.

Results: ALS patients had significantly higher levels of leisure time physical activity compared with controls (OR 1.08, 95% CI 1.02 to 1.14, p=0.008). No significant difference was found between patients and controls in the level of vigorous physical activities, including marathons and triathlons, or in occupational activity. Cumulative measures of physical activity in quartiles did not show a dose-response relationship.

Conclusions: An increased risk of ALS with higher levels of leisure time physical activity was found in the present study. The lack of association with occupational physical activity and the absence of a dose-response relationship strengthen the hypothesis that not increased physical activity per se but rather a genetic profile or lifestyle promoting physical fitness increases ALS susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2012-304724DOI Listing
September 2013

H63D polymorphism in HFE is not associated with amyotrophic lateral sclerosis.

Neurobiol Aging 2013 May 11;34(5):1517.e5-7. Epub 2012 Oct 11.

Department of Neurology, Rudolph Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands.

The H63D polymorphism in HFE has frequently been associated with susceptibility to amyotrophic lateral sclerosis (ALS). Regarding the role of HFE in iron homeostasis, iron accumulation is considered an important process in ALS. Furthermore, novel therapeutic strategies are being developed targeting this process. Evidence for this genetic association is, however, limited to several small studies. For this reason we studied the H63D polymorphism in a large European cohort including 3962 ALS patients and 5072 control subjects from 7 countries. After meta-analysis of previous studies and current findings we conclude that the H63D polymorphism in HFE is not associated with susceptibility to ALS, age at disease onset, or survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2012.07.020DOI Listing
May 2013

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

Neurology 2012 Aug 25;79(9):878-82. Epub 2012 Jul 25.

Department of Neurology, Rudolph Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht.

Objective: To assess the frequency and phenotype of hexanucleotide repeat expansions in C9ORF72 in a large cohort of patients of Dutch descent with familial (fALS) and sporadic (sALS) amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), and primary lateral sclerosis (PLS).

Methods: Included were 78 patients with fALS, 1,422 with sALS, 246 with PMA, and 110 with PLS, and 768 control subjects. Repeat expansions were determined by a repeat primed PCR. Familial aggregation of dementia and Parkinson disease (PD) was examined among patients with ALS who carried the repeat expansion.

Results: The expanded repeat was found in 33 (37%) of all patients with fALS, in 87 (6.1%) patients with sALS, in 4 (1.6%) patients with PMA, and in 1 (0.9%) patient with PLS. None of the controls carried the mutation. Patients with ALS with the repeat expansion had an earlier age at onset (median 59.3 vs 61.9 years, hazard ratio 1.55, p = 5 × 10(-5)) and shorter survival (median 2.5 vs 2.7 years, hazard ratio 1.46, p = 8 × 10(-4)). Dementia, but not PD, occurred nearly twice as often in relatives of patients with the expansion compared to all patients with ALS or controls (p = 9 × 10(-4)).

Conclusions: The hexanucleotide repeat expansion in C9ORF72 is a major cause of fALS and apparently sporadic ALS in the Netherlands. Patients who carry the repeat expansion have an earlier onset, shorter survival, and familial aggregation of dementia. These results challenge the classic definition of fALS and may justify genetic testing in patients with sALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0b013e3182661d14DOI Listing
August 2012

UBQLN2 in familial amyotrophic lateral sclerosis in The Netherlands.

Neurobiol Aging 2012 Sep 5;33(9):2233.e7-2233.e8. Epub 2012 Jun 5.

Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands.

Recently it was discovered that mutations in the UBQLN2 gene were a cause of an X-linked dominant type of familial amyotrophic lateral sclerosis (ALS). We investigated the frequency of mutations in this gene in a cohort of 92 families with ALS in the Netherlands. Eight families were excluded because of male-to-male transmission. In the remaining 84 familial ALS cases no mutations were discovered in UBQLN2. Hence, UBQLN2 was not found to be a cause of familial ALS in the Netherlands.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2012.02.032DOI Listing
September 2012

CGG-repeat expansion in FMR1 is not associated with amyotrophic lateral sclerosis.

Neurobiol Aging 2012 Aug 15;33(8):1852.e1-3. Epub 2012 Apr 15.

Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.

Recently, repeat expansions in several genes have been shown to cause or be associated with amyotrophic lateral sclerosis (ALS). It has been demonstrated that an intronic hexanucleotide repeat expansion in C9ORF72 is a major cause of both familial (approximately 40%) and sporadic (approximately 5%) ALS, as well as frontotemporal dementia (FTD). In addition, a CAG-repeat expansion in exon 1 of ATXN2, otherwise known to cause spinocerebellar ataxia type 2, has been identified as a major risk factor for sporadic ALS. Intermediate repeat expansions in the fragile X mental retardation 1 (FMR1) gene (55-200 repeats) are known to cause fragile X-associated premature ovarian insufficiency [(FX)POI; female carriers] or fragile X-associated tremor/ataxia syndrome (FXTAS; male carriers) by CGG-mediated RNA toxicity. The present investigation involves screening FMR1 repeat length in 742 sporadic ALS patients and 792 matched controls. Our conclusion is that FMR1 repeat expansions are not associated with ALS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2012.03.007DOI Listing
August 2012

Population based epidemiology of amyotrophic lateral sclerosis using capture-recapture methodology.

J Neurol Neurosurg Psychiatry 2011 Oct 27;82(10):1165-70. Epub 2011 May 27.

Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background: Variation in the incidence rate in epidemiological studies on amyotrophic lateral sclerosis (ALS) may be due to a small population size and under ascertainment of patients. The previously reported incidence decline in the elderly and a decrease in the male:female ratio in postmenopausal age groups have yet to be confirmed.

Methods: ALS epidemiology in a large population based register in The Netherlands was studied between 1 January 2006 and 31 December 2009, and applied capture-recapture methodology in separate age and gender groups to adjust for the number of unobserved patients.

Results: 1217 incident patients were observed, and a capture-recapture incidence of 2.77 per 100 000 person-years (95% CI 2.63 to 2.91). Prevalence on 31 December 2008 was 10.32 per 100 000 individuals (95% CI 9.78 to 10.86). The incident cohort had a higher median age at onset (63.0 vs 58.1 years) and more bulbar onset patients (30.0% vs 19.1%) compared with the prevalent cohort. Incidence and prevalence peaked in the 70-74 year age group followed by a rapid decline in older age. The male:female ratio in the premenopausal age group (1.91, 95% CI 1.32 to 2.79) was not significantly higher than that in the postmenopausal age group (1.50, 95% CI 1.34 to 1.67).

Conclusion: The marked difference in patient characteristics between incident and prevalent cohorts underscores the importance of including incident patients when studying susceptibility or disease modifying factors in ALS. The incidence decline in the elderly may suggest that ALS is not merely the result of ageing. Absence of a significant postmenopausal drop in the male:female ratio suggests that the protective role of female sex hormones in ALS is limited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp.2011.244939DOI Listing
October 2011

High-flow extracranial-to-intracranial excimer laser-assisted nonocclusive anastomosis bypass for symptomatic carotid artery occlusion.

Neurosurgery 2011 Jun;68(6):1687-94; discussion 1694

Department of Neurosurgery, University Medical Center Utrecht, Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands.

Background: A high-flow bypass is theoretically more effective than a conventional low-flow bypass in preventing strokes in patients with symptomatic carotid artery occlusion and a compromised hemodynamic state of the brain.

Objective: To study the results of excimer laser-assisted nonocclusive anastomosis (ELANA) high-flow extracranial-to-intracranial (EC-IC) bypass surgery in these patients.

Methods: Between August 1998 and May 2008, 24 patients underwent ELANA EC-IC bypass surgery because of transient ischemic attacks or minor ischemic stroke associated with carotid artery occlusion. We retrospectively collected information. Follow-up data were updated by structured telephone interviews between May and September 2008.

Results: In all patients, the ELANA EC-IC bypass was patent at the end of surgery with a mean flow of 106 ± 41 mL/min. Within 30 days after the operation, 22 patients (92%) had no major complication, whereas 2 patients (8%) had a fatal intracerebral hemorrhage. During follow-up of a mean 4.4 ± 2.4 years, the bypass remained patent in 18 of the 22 surviving patients (82%) with a mean flow of 141 ± 59 mL/min. All patients with a patent bypass remained free of transient ischemic attacks and ischemic stroke. In 4 patients, the bypass occluded, accompanied by ipsilateral transient ischemic attacks in 2 patients, ipsilateral ischemic stroke in 1 patient, and contralateral ischemic stroke in another patient.

Conclusion: ELANA EC-IC bypass surgery in patients with carotid artery occlusion is technically feasible and results in cessation of ongoing transient ischemic attacks and minor ischemic strokes, but carries a risk of postoperative hemorrhage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1227/NEU.0b013e318214e2e7DOI Listing
June 2011

Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis.

Nat Genet 2009 Oct 6;41(10):1083-7. Epub 2009 Sep 6.

Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

We conducted a genome-wide association study among 2,323 individuals with sporadic amyotrophic lateral sclerosis (ALS) and 9,013 control subjects and evaluated all SNPs with P < 1.0 x 10(-4) in a second, independent cohort of 2,532 affected individuals and 5,940 controls. Analysis of the genome-wide data revealed genome-wide significance for one SNP, rs12608932, with P = 1.30 x 10(-9). This SNP showed robust replication in the second cohort (P = 1.86 x 10(-6)), and a combined analysis over the two stages yielded P = 2.53 x 10(-14). The rs12608932 SNP is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. Follow-up of additional SNPs showed genome-wide significance for two further SNPs (rs2814707, with P = 7.45 x 10(-9), and rs3849942, with P = 1.01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.442DOI Listing
October 2009