Searching for a link between the L-BMAA neurotoxin and amyotrophic lateral sclerosis: a study protocol of the French BMAALS programme

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is the most common motor neurone disease. It occurs in two forms: (1) familial cases, for which several genes have been identified and (2) sporadic cases, for which various hypotheses have been formulated. Notably, the β-N-methylamino-L-alanine (L-BMAA) toxin has been postulated to be involved in the occurrence of sporadic ALS. The objective of the French BMAALS programme is to study the putative link between L-BMAA and ALS.

Methods and analysis: The programme covers the period from 1 January 2003 to 31 December 2011. Using multiple sources of ascertainment, all the incident ALS cases diagnosed during this period in the area under study (10 counties spread over three French regions) were collected. First, the standardised incidence ratio will be calculated for each municipality under concern. Then, by applying spatial clustering techniques, overincidence and underincidence zones of ALS will be sought. A case-control study, in the subpopulation living in the identified areas, will gather information about patients' occupations, leisure activities and lifestyle habits in order to assess potential risk factors to which they are or have been exposed. Specimens of drinking water, food and biological material (brain tissue) will be examined to assess the presence of L-BMAA in the environment and tissues of ALS cases and controls.

Ethics and dissemination: The study has been reviewed and approved by the French ethical committee of the CPP SOOM IV (Comité de Protection des Personnes Sud-Ouest & Outre-Mer IV). The results will be published in peer-reviewed journals and presented at national and international conferences.

Keywords: EPIDEMIOLOGY; PUBLIC HEALTH.

Figure 1

Areas under study in the BMAALS programme. BMAALS is a French project with collaboration between three regions: Limousin, Languedoc-Roussillon (2 departments out of 5) and Rhône-Alpes (5 departments out of 8).

Figure 2

Multiple sources of case ascertainment. For the application of a capture–recapture method, three sources were solicited: (1) the French national coordination of amyotrophic lateral sclerosis (ALS) referral centres, (2) public and private hospitals and (3) health insurance structures.

Figure 3

The three levels considered for geostatistical analyses. Aims and methodologies applied are represented for each of the three levels: from the smallest geographic unit for calculating ALS incidence; through the average geographic unit for studying the cyanobacteria extent; to finally the largest geographic unit for assessing exposure of patients with ALS (ALS, amyotrophic lateral sclerosis; P, phosphorus; N, nitrogen).

Figure 4

Residential migration rate of the French population. These maps reflect the intraregional mobility of the French people from 1975 to 2004. The residential migration rate is expressed per 1000 persons. (Data from INSEE, Institut National de la Statistique et des Etudes Economiques).

Figure 5

L-BMAA quantification in molluscs throughout the world. A comparison of three quantification methods and teams highlights discrepancies in L-BMAA titration. Does that reveal a difference in selectivity of the method or the existence of a gradient of the neurotoxin? L-BMAA levels are expressed as µg L-BMAA/g dry weight±SE (FD, fluorescence detection; L-BMAA, β-N-methylamino-L-alanine; LC, liquid chromatography; LC-MS/MS: LC coupled to tandem mass spectrometry; HPLC, high-pressure LC; rHPLC: reverse phase HPLC; SPE, solid phase extraction; UHPLC, ultra HPLC).