Clinical/Scientific Notes

Meinie Seelen, MD Roel C.H. Vermeulen, PhD Levien S. van Dillen, MD Anneke J. van der Kooi, MD, PhD Anke Huss, PhD Marianne de Visser, MD, PhD Leonard H. van den Berg, MD, PhD* Jan H. Veldink, MD, PhD*

Supplemental data at Neurology.org

RESIDENTIAL EXPOSURE TO EXTREMELY LOW FREQUENCY ELECTROMAGNETIC FIELDS AND THE RISK OF ALS

Several studies have reported on the possible association between the risk of developing amyotrophic lateral sclerosis (ALS) and employment in the electrical industry, which may be related to extremely low frequency electromagnetic field (ELF-EMF) exposure or the risk of experiencing an electric shock, although no direct association has been proven.1 Three previous studies reported on ALS risk related to living near power lines, an important source of ELF-EMF exposure for the general population.2–4 These studies reported a null finding but had some shortcomings as they were based on registry data and had no detailed clinical data available. We therefore performed a large population-based case-control study with detailed phenotypic data to assess the relation between residential exposure to ELF-EMF from power lines and the risk of ALS. Methods. We included a total of 1,139 patients with ALS and 2,864 frequency-matched controls, derived from a large population-based casecontrol study performed in the Netherlands from January 2006 to January 2013.5 Controls were selected from the roster of the general practitioner of the patient and were matched to the patient on sex and age. The Netherlands has an extensive network of overhead power lines, the locations of which are known exactly. 6 These power lines were classified into high voltage (50 kV, 110 kV, and 150 kV) and very high voltage (220 kV and 380 kV) lines. We collected data on lifetime residential history from the Municipal Personal Records Database. Residential data of patients with ALS and controls were geocoded (assigned coordinates to the addresses) taking the time of onset of disease into account. Since distance to power lines is closely associated with ELF-EMF exposure, we categorized places of residence into corridors of distance (0–, 50 meters, 50–,200 meters, 200–,600 meters, and $600 meters). We determined the shortest distance to any power line before onset of disease, and computed the cumulative years lived within

100 meters of a power line, divided into 4 categories (,5 years, 5–,10 years, 10–,15 years, and $15 years), to detect a possible dose–response relation. Statistical analyses were performed using logistic regression for the association with ALS, adjusted for sex and age (age at onset for patients and age at inclusion for controls). Subsequently, we used Cox regression for the association with survival (adjusted for sex, age at onset, and site of onset) and for the association with age at onset (adjusted for sex and site of onset), with the exposure variable dichotomized into living ,200 meters and $200 meters from a power line. Results. Baseline characteristics of patients and controls are shown in table e-1 on the Neurology® Web site at Neurology.org. We found no increased risk of ALS in persons living in close vicinity of a power line compared to persons who had always lived at a distance of at least 600 meters (table 1). Cumulative exposure in years showed no dose–response relationship (data not shown). Survival analysis in patients with ALS showed a nonsignificant hazard ratio (HR) of 1.27 (95% confidence interval [CI] 0.87–1.86, p 5 0. 22). There was no association between distance from a power line and age at onset (HR 1.22, 95% CI 0.89–1.67, p 5 0.22). Discussion. Subsequent to our null findings, we performed a meta-analysis combining our results with 2 previously published case-control studies.3,4 A fixed effect model showed an overall odds ratio of 0.90 (95% CI 0.73–1.10) for subjects living ,200 meters compared with $200 meters from any highvoltage power line (figure e-1). One of these studies only assessed the current address at time of death,3 so important historical residential data regarding ELFEMF exposure before onset of disease might be missing. A third cohort study substantiated our negative results, reporting a HR of 0.88 (95% CI 0.47–1.64).2 We did not find an association of ALS with residential exposure to ELF-EMF. This is consistent with the lack of such an association in a previously published meta-analysis of electrical occupations.1 Neurology 83

November 4, 2014

1767

Table 1

Frequencies and ORs of patients with ALS and controls in relation to the shortest distance ever lived from a power line Patients with ALS, n (%)

Controls, n (%)

OR

95% CI

p Value

0–,50

0 (0.0)

1 (0.0)







50–,200

2 (0.2)

7 (0.2)

0.73

0.15–3.50

0.69

200–,600

23 (2.0)

44 (1.5)

1.31

0.79–2.18

0.30

‡600

1,114 (97.8)

2,812 (98.2)

1.00

Reference



0–,50

6 (0.5)

14 (0.5)

1.05

0.40–2.75

0.92

50–,200

32 (2.8)

88 (3.1)

0.91

0.60–1.37

0.64

200–,600

90 (7.9)

249 (8.7)

0.89

0.69–1.14

0.36

‡600

1,011 (88.8)

2,513 (87.7)

1.00

Reference



Distance, m Very high voltage (220–380 kV)

High voltage (50–150 kV)

Abbreviations: ALS 5 amyotrophic lateral sclerosis; CI 5 confidence interval; OR 5 odds ratio. ORs were computed by logistic regression adjusting for sex and age.

Strengths of this study are the population-based study design, inclusion of large numbers of patients and age- and sex-matched controls, and prevention of recall bias by the use of the Municipal Personal Records Database for collection of residential data. A limitation of this study may be the low number of participants living in close vicinity to power lines (,200 meters). However, taking all studies together, one can conclude that exposure to ELF-EMF from power lines does not increase the risk of developing ALS.

consultants in rehabilitation medicine, and other health care providers for enrolling patients with ALS; and the patients with ALS and controls.

*These authors contributed equally to this work.

Disclosure: M. Seelen, R. Vermeulen, L. van Dillen, A. van der Kooi, A. Huss, and M. de Visser report no disclosures relevant to the manuscript. L. van den Berg received travel grants and consultancy fees from Baxter and serves on the advisory board for Biogen, Cytokinetics. J. Veldink received travel grants from Baxter. Go to Neurology.org for full disclosures.

From the Brain Center Rudolf Magnus (M.S., L.S.v.D., L.H.v.d.B., J.H.V.), University Medical Center Utrecht; Institute for Risk Assessment Sciences (R.C.H.V., A.H.), Division of Epidemiology, Utrecht University; and Amsterdam Medical Center (A.J.v.d.K., M.d.V.), University of Amsterdam, the Netherlands.

1768

Study funding: Supported by the Prinses Beatrix Fonds (PB 0703), VSB fonds, H. Kersten and M. Kersten (Kersten Foundation), The Netherlands ALS Foundation, and J.R. van Dijk and the Adessium Foundation. The research leading to these results has received funding from the European Community’s Health Seventh Framework Programme (FP7/2007-2013) under grant agreement 259867. R.C.H. Vermeulen and A. Huss were supported by The Netherlands Organization for Health Research (ZonMW) within the program Electromagnetic Fields and Health Research under grant numbers 85200001 and 85800001.

Received January 20, 2014. Accepted in final form May 23, 2014.

Author contributions: Meinie Seelen: drafting the manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, acquisition of data, statistical analysis. Roel C.H. Vermeulen: revising the manuscript for content, including medical writing for content, study concept or design, acquisition of data. Levien S. van Dillen: revising the manuscript for content, including medical writing for content, acquisition of data, statistical analysis. Anneke J. van der Kooi: revising the manuscript for content, including medical writing for content, study concept or design, acquisition of data. Anke Huss: revising the manuscript for content, including medical writing for content, acquisition of data. Marianne de Visser: revising the manuscript for content, including medical writing for content, study concept or design, acquisition of data. Leonard H. van den Berg: revising the manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, study supervision or coordination, obtaining funding. Jan H. Veldink: revising the manuscript for content, including medical writing for content, study concept or design, analysis or interpretation of data, statistical analysis, study supervision or coordination.

Correspondence to Dr. Veldink: [email protected]

Acknowledgment: The authors thank Petra Berk, PhD (University Medical Center Utrecht), Hermieneke Vergunst (University Medical Center Utrecht), and Dorien Standaar (Amsterdam Medical Center) for technical assistance; all neurologists,

4.

Neurology 83

November 4, 2014

© 2014 American Academy of Neurology 1.

2.

3.

Vergara X, Kheifets L, Greenland S, Oksuzyan S, Cho YS, Mezei G. Occupational exposure to extremely low-frequency magnetic fields and neurodegenerative disease: a meta-analysis. J Occup Environ Med 2013; 55:135–146. Huss A, Spoerri A, Egger M, Röösli M. Residence near power lines and mortality from neurodegenerative diseases: longitudinal study of the Swiss population. Am J Epidemiol 2009; 169:167–175. Marcilio I, Gouveia N, Pereira Filho ML, Kheifets L. Adult mortality from leukemia, brain cancer, amyotrophic lateral sclerosis and magnetic fields from power lines: a casecontrol study in Brazil. Rev Bras Epidemiol 2011;14: 580–588. Frei P, Poulsen AH, Mezei G, et al. Residential distance to high-voltage power lines and risk of neurodegenerative diseases: a Danish population-based case-control study. Am J Epidemiol 2013;177:970–978.

5.

Roberto Di Fabio, MD, PhD Francesca Moro, PhD Liliana Pestillo, MD Maria C. Meschini, PhD Francesco Pezzini, PhD Stefano Doccini, PhD Carlo Casali, MD Francesco Pierelli, MD Alessandro Simonati, MD Filippo M. Santorelli, MD

Supplemental data at Neurology.org

Huisman MH, de Jong SW, van Doormaal PT, et al. Population based epidemiology of amyotrophic lateral sclerosis using capture-recapture methodology. J Neurol Neurosurg Psychiatry 2011;82:1165–1170.

PSEUDO-DOMINANT INHERITANCE OF A NOVEL CTSF MUTATION ASSOCIATED WITH TYPE B KUFS DISEASE

Neuronal ceroid lipofuscinosis (NCL) has different forms, of which Kufs disease (KD) is the least frequent and the most difficult to diagnose.1 KD can, in turn, be divided into type A, characterized by progressive myoclonus epilepsy and cognitive decline, and type B, characterized by movement and behavioral abnormalities and dementia.2 Mutations in CLN6 and DNAJC5 are responsible for, respectively, the autosomal recessive (AR) (MIM 204300) and autosomal dominant (MIM 162350) forms of type A KD.3 Mutations in cathepsin F (CTSF) have recently been discovered in AR type B KD families of French-Canadian, Australian, and Italian origin.4 We present a family in which pseudodominant transmission of type B KD was explained by a novel homozygous mutation in CTSF. Case report. The clinical presentation of the family members (figure 1A) is briefly outlined below, while complete case histories are provided in appendix e-1 on the Neurology® Web site at www.neurology.org. The 42-year-old proposita (IV-3) presented tonic-clonic seizures from the age of 23 years, followed by the development of cerebellar dysarthria and cognitive decline, evolving into frank dementia by age 30 years. In the course of her disease, she showed transient perioral dyskinesias and segmental myoclonic jerks. Her deceased mother (III-4), a maternal aunt (III-5), and a cousin (V-1) (figure 1A) showed similar neurologic pictures, consisting of tonicclonic seizures (mean age at onset 31.8 6 21.2 years) followed by mental deterioration (40 6 19.9 years). Two additional deceased cases (III-6 and IV-1) were defined as affected on the basis of clinical notes only. In subjects III-5, IV-3, and V-1, we detected a new homozygous c.21311G.C mutation in CTSF (figure e-1B). The same mutation was found to be heterozygous in asymptomatic relatives, while it was excluded in 150 ethnically matched controls and in the Single Nucleotide PolymorphismDatabase, 1,000 Genomes Project, and Exome Sequencing Project (appendix e-1). Testing in cultured skin fibroblasts from III-5 and IV-3 showed c.21311G.C to result in stable mRNA lacking exon 1 (figure e-1D). Ultrastructurally, we detected osmiophilic cytoplasmic inclusions in skin biopsies of both these patients, and regarded those

6.

Tenne T. Netkaart Nederland 2011. Available at: http:// www.tennet.eu/nl/nl/over-tennet/nieuws-pers-publicaties/ publicaties/technische-publicaties.html. Accessed May 7, 2013.

features as suggestive of NCL, recognizing the considerable overlap with age-related deposits of lipofuscin (figure 1, B and C). Six members of this family had a neurologic syndrome compatible with KD. The 2 instances of parent-to-child transmission (figure 1A), initially suggesting Parry disease3,5 or PSEN1-related early-onset Alzheimer disease,6 constituted initial confounding factors in the ascertainment of the causative mutation. Careful clinical assessment of the patients, meticulous collection of family history (from local general practitioners and through direct interviews with senior family members), and recognition of the high degree of inbreeding in the isolated community of Fondi, a municipality in central Italy numbering approximately 40,000 inhabitants, were crucial in suggesting an AR pattern of inheritance, leading to identification of mutations in CTSF. The novel c.21311G.C in CTSF affects correct splicing, removing exon 1, and predicts a truncated N-terminus of cathepsin F. The 20% shorter protein could exert a possible loss-of-function mechanism. Overexpression of N-terminus truncated forms of human cathepsin F (D-CtsF) in HEK 293T cells has recently been associated with features suggestive of aggresome-like inclusions.7 In the work in question, the truncated forms of human cathepsin F appeared to be colocalized with aggresome-related proteins such as p62/sqstm1, a multifunctional polyubiquitinbinding protein commonly seen in diseases with protein aggregation. We observed ultrastructural features resembling aggresome-like structures in skin biopsies (figure 1B). Likewise, cellular aggresomes were detected by fluorescence microscopy in cultured fibroblasts (figure e-2), where we also detected enhanced expression of polyubiquitinated proteins and higher levels of Lamp2 and p62/ sqstm1 in a soluble fraction of cells from subject IV-3 by Western blotting (figure e-3). We also demonstrated higher expression of LC3II protein (figure e-3) (a finding reminiscent of the overexpression of the D-CtsF proteins modeled in HEK 293T cells),7 which is an indication of dysregulated autophagy. Further investigations will clarify whether aggresome-like structures are present in neuronal cells of CTSF patients and whether these patients’ clinical features are related to cytoplasmic toxicity. Discussion. The mutations previously reported in CTSF4 (4 missense, 1 frameshift) caused a clinical Neurology 83

November 4, 2014

1769

Residential exposure to extremely low frequency electromagnetic fields and the risk of ALS Meinie Seelen, Roel C.H. Vermeulen, Levien S. van Dillen, et al. Neurology 2014;83;1767-1769 Published Online before print October 1, 2014 DOI 10.1212/WNL.0000000000000952 This information is current as of October 1, 2014 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/83/19/1767.full.html

Supplementary Material

Supplementary material can be found at: http://www.neurology.org/content/suppl/2014/10/01/WNL.0000000000 000952.DC1.html

References

This article cites 5 articles, 3 of which you can access for free at: http://www.neurology.org/content/83/19/1767.full.html##ref-list-1

Subspecialty Collections

This article, along with others on similar topics, appears in the following collection(s): Amyotrophic lateral sclerosis http://www.neurology.org//cgi/collection/amyotrophic_lateral_sclerosis _ Case control studies http://www.neurology.org//cgi/collection/case_control_studies Risk factors in epidemiology http://www.neurology.org//cgi/collection/risk_factors_in_epidemiology

Permissions & Licensing

Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions

Reprints

Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Residential exposure to extremely low frequency electromagnetic fields and the risk of ALS.

Residential exposure to extremely low frequency electromagnetic fields and the risk of ALS. - PDF Download Free
211KB Sizes 0 Downloads 13 Views