Genetic Epidemiology of Amyotrophic Lateral Sclerosis

Het doel van dit proefschrift was met epidemiologische onderzoeks methoden een gezamelijke genetische predispositie voor amyotro.sche lateraal sclerose (ALS), dementie en parkinsonisme, en de invloed van omgevingsfactoren te bestuderen. Hiervoor werd een patient-controle studie verricht van 1989 to 1991 op het Neurological Institute van het Columbia University Medical Center in New York. De onderzoekspopulatie bestond uit 151 patienten bij wie recent de diagnose ALS was gesteld en 140 controle patienten, met andere neurologische aandoeningen, die dezelfde leeftijd (+ 5 jaar) en geslacht hadden als de ALS patienten, en die in dezelfde klasse medisch verzekerd waren. Tot ver in de twintigste eeuw was men zich nauwelijks bewust van de erfelijke vormen van amyotro.sche lateral sclerose (ALS). Hierin kwam geleidelijk verandering na de publicatie van Kurland en Mulder in 1955, waarin zij een overzicht gaven van achtien families met ALS, die in de afgelopen 100 jaar in de literatuur werden beschreven. In hoofdstuk 2 wordt de huidige kennis over de relatie tussen ALS, dementie en parkinsonisme samengevat. Zoals in het overzichtsartikel (hoofdstuk 3) wordt beschreven heeft de groeiende belangstelling voor en onderzoek naar familiaire ALS er inmiddels toe geleid dat nu bekend is dat bij ongeveer 5 tot 10 procent van de ALS patienten een erfelijke vorm van de ziekte met een mendeliaans overervingspatroon voorkomt. Pas in het afgelopen decennium kon met de toepassing van moderne moleculaire onderzoekstechnieken het gen of de locatie van verschillende - maar lang nog niet alle- mendeliaans overervende vormen van ALS worden geidenti.ceerd. Inmiddels kennen we zes autosomaal dominant overervende en drie autosomaal recessief overervende erfelijke vormen van ALS. Bovendien worden in rap tempo steeds meer genen ontdekt, die het voorkomen van combinaties van ALS, frontaalkwab dementie en/of parkinsonisme in families verklaren. Ook worden, ondanks dat bij het merendeel (90%) van de ALS patienten de ziekte niet in de familie voorkomt, nu ook bij sporadische patienten veschillende genmutaties of ­polymorphismen waargenomen. Vermoedelijk bestaat er ook bij sporadische patienten een wisselwerking tussen predispositie genen en schadelijke omgevingsfactoren, die ieder opzich onvoldoende penetrant zijn om ALS te veroorzaken.This thesis aims to use epidemiologic methods to investigate genetic and environmental factors playing a role in ALS. We conducted a case control study between 1989-1991 at the Neurological Institute Columbia University Medical Center in New York. The study population consisted of 151 newly diagnosed ALS patients and 140 neurologic controls, matched for age (+ 5 years), gender (83 pairs of men and 57 pairs of women) and insurance status. In chapter 2 the current insights in the relation of ALS, dementia and parkinsonism is summarized. As described in the review (chapter 3) until the 1960s, ALS was considered to be a non-hereditary neurologic disease. In a land-mark report in 1955, Kurland and Mulder described 18 families with hereditary ALS from a 100-year review of the world literature. Only in the past decade, genetic analysis of familial forms of ALS led to the identi.cation of several mendelian inherited forms of ALS. These familial forms comprise 5-10% of all cases. Thus far six autosomal dominant and three autosomal recessive forms were found to be associated with familial ALS. In addition, a growing number of genetic defects are being associated with syndromes featuring familial recurrence of ALS, frontotemporal dementia and parkinsonism. In the 90% of cases were ALS is sporadic, changes in various genes have been linked to an increased risk for ALS, so called susceptibility genes. Susceptibility genes are thought to interact with other low penetrant genes and/or with environmental risk factors. In chapter 4 of this thesis we used epidemiologic methods to .nd evidence for a shared genetic susceptibility for ALS, dementia and parkinsonism. To do so, we investigated familial aggregation of these three disorders in families of ALS patients. In the case­control study we compared the family histories of ALS patients and controls. A semi­structured questionnaire was used to ascertain valid information on neurologic conditions for each sibling, parent and grandparent, individually. The data showed familial recurrence of ALS in .ve percent of the patients and not in controls. We found that the risk (cumulative incidence) of dementia was twofold increased for relatives of ALS patients

First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm

Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers–Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon–intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA

The role of renin-angiotensin-aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P=0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM

Avian influenza a virus in wild birds in highly urbanized areas

Avian influenza virus (AIV) surveillance studies in wild birds are usually conducted in rural areas and nature reserves. Less is known of avian influenza virus prevalence in wild birds located in densely populated urban areas, while these birds are more likely to be in close contact with humans. Influenza virus prevalence was investigated in 6059 wild birds sampled in cities in the Netherlands between 2006 and 2009, and compared with parallel AIV surveillance data from low urbanized areas in the Netherlands. Viral prevalence varied with the level of urbanization, with highest prevalence in low urbanized areas. Within cities virus was detected in 0.5% of birds, while seroprevalence exceeded 50%. Ring recoveries of urban wild birds sampled for virus detection demonstrated that most birds were sighted within the same city, while few were sighted in other cities or migrated up to 2659 km away from the sample location in the Netherlands. Here we show that urban birds were infected with AIVs and that urban birds were not separated completely from populations of long-distance migrants. The latter suggests that wild birds in cities may play a role in the introduction of AIVs into cities. Thus, urban bird populations should not be excluded as a human-animal interface for influenza viruses

Systematic Review of Genotype-Phenotype Correlations in Noncompaction Cardiomyopathy

Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to heart failure with major adverse cardiac events (MACE). Methods and Results To investigate genotype-phenotype correlations, the genotypes and clinical features of genetic NCCM patients were collected from the literature. We compared age at diagnosis, cardiac features and risk for MACE according to mode of inheritance and molecular effects for defects in the most common sarcomere genes and NCCM subtypes. Geno- and phenotypes of 561 NCCM patients from 172 studies showed increased risk in children for congenital heart defects (P<0.001) and MACE (P<0.001). In adult NCCM patients the main causes were single missense mutations in sarcomere genes. Children more frequently had an X-linked or mitochondrial inherited defect (P=0.001) or chromosomal anomalies (P<0.001). MYH7 was involved in 48% of the sarcomere gene mutations. MYH7 and ACTC1 mutations had lower risk for MACE than MYBPC3 and TTN (P=0.001). The NCCM/dilated cardiomyopathy cardiac phenotype was the most frequent subtype (56%; P=0.022) and was associated with an increased risk for MACE and high risk for left ventricular systolic dysfunction (<0.001). In multivariate binary logistic regression analysis MYBPC3, TTN, arrhythmia -, non-sarcomere non-arrhythmia cardiomyopathy-and X-linked genes were genetic predictors for MACE. Conclusions Sarcomere gene mutations were the most common cause in adult patients with lower risk of MACE. Children had multi-systemic disorders with severe outcome, suggesting that the diagnostic and clinical approaches should be adjusted to age at presentation. The observed genotype-phenotype correlations endorsed that DNA diagnostics for NCCM is important for clinical management and counseling of patients

Familial abdominal aortic aneurysm is associated with more complications after endovascular aneurysm repair

Objective A familial predisposition to abdominal aortic aneurysms (AAAs) is present in approximately one-fifth of patients. Nevertheless, the clinical implications of a positive family history are not known. We investigated the risk of aneurysm-related compli

Lower atherosclerotic burden in familial abdominal aortic aneurysm

Objective Despite the apparent familial tendency toward abdominal aortic aneurysm (AAA) formation, the genetic causes and underlying molecular mechanisms are still undefined. In this study, we investigated the association between familial AAA (fAAA) and atherosclerosis. Methods Data were collected from a prospective database including AAA patients between 2004 and 2012 in the Erasmus University Medical Center, Rotterdam, The Netherlands. Family history was obtained by written questionnaire (93.1% response rate). Patients were classified as fAAA when at least one affected first-degree relative with an aortic aneurysm was reported. Patients without an affected first-degree relative were classified as sporadic AAA (spAAA). A standardized ultrasound measurement of the common carotid intima-media thickness (CIMT), a marker for generalized atherosclerosis, was routinely performed and patients' clinical characteristics (demographics, aneurysm characteristics, cardiovascular comorbidities and risk factors, and medication use) were recorded. Multivariable linear regression analyses were used to assess the mean adjusted difference in CIMT and multivariable logistic regression analysis was used to calculate associations of increased CIMT and clinical characteristics between fAAA and spAAA. Results A total of 461 AAA patients (85% men, mean age, 70 years) were included in the study; 103 patients (22.3%) were classified as fAAA and 358 patients (77.7%) as spAAA. The mean (standard deviation) CIMT in patients with fAAA was 0.89 (0.24) mm and 1.00 (0.29) mm in patients with spAAA (P =.001). Adjustment for clinical characteristics showed a mean difference in CIMT of 0.09 mm (95% confidence interval, 0.02-0.15; P =.011) between both groups. Increased CIMT, smoking, hypertension, and diabetes mellitus were all less associated with fAAA compared with spAAA. Conclusions The current study shows a lower atherosclerotic burden, as reflected by a lower CIMT, in patients with fAAA compared with patients with spAAA, independent of common atherosclerotic risk factors. These results support the hypothesis that although atherosclerosis is a common underlying feature in patients with aneurysms, atherosclerosis is not the primary driving factor in the development of fAAA

A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier?

We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy (HMN) in a three-generation Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies (NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower (four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral disease was noted in three patients. Three also showed pyramidal features. A genome-wide search combining SNP arrays (250K) with parametric linkage analysis identified a novel locus on chromosome 16p (mLOD = 3.28) spanning 6 Mb (rs6500882-rs7192086). Direct sequencing excluded mutations in the SIMPLE/LITAF gene (mapping to the 16p locus) and identified a pathogenic mutation (p.N88S) in BCLS2 (11q12-q14). All 12 affected relatives had the BSCL2 mutation and the chromosome 16p haplotype and showed features of motor neuron degeneration. One patient had a very mild phenotype with bilateral pes cavus, normal concentric needle electromyography but signs of motor neuron involvement at electrophysiological muscle scan (EMS). Similar EMS abnormalities in addition to abnormal NCS and myography were observed in a clinically unaffected person (carrying only the 16p haplotype). These results expand the clinical spectrum of HMN and suggest a digenic inheritance of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype