Publications by authors named "Meriem Tazir"

50 Publications

Clinical management and disease-modifying treatment for amyotrophic lateral sclerosis in African hospital centers: the TROPALS study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Aug 28:1-5. Epub 2021 Aug 28.

INSERM, Univ. Limoges, CHU Limoges, IRD, U1094 Tropical Neuroepidemiology, Institute of Epidemiology and Tropical Neurology, GEIST, Limoges, France.

To assess the availability of health workers and medications for clinical management of amyotrophic lateral sclerosis (ALS) in African hospital centers. Availability and affordability analyses of disease-modifying treatments were performed. : A multicenter observational study involving African hospitals was conducted. A standard questionnaire was developed based on the European Federation of the Neurological Societies (EFNS) guidelines. We collected data on multidisciplinary care and availability of medicines. The availability and affordability were evaluated according to the WHO guidelines. : Nine hospital centers from eight African countries participated. We observed a low degree of implementation of multidisciplinary care in ALS management. Riluzole was only available in centers from South Africa, Senegal, Tunisia, and Togo. This treatment was unaffordable and the adjusted price was highly variable among countries. The cost of riluzole was partly or fully covered by patients, which implies a substantial economic burden. : Our findings strengthen the need to promote multidisciplinary care in the clinical management of ALS in Africa. Disease-modifying medication should be both available and affordable. Local and international collaboration is needed to improve ALS health care access in Africa.
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http://dx.doi.org/10.1080/21678421.2021.1961806DOI Listing
August 2021

NTRK1 gene-related congenital insensitivity to pain with anhidrosis: a nationwide multicenter retrospective study.

Neurogenetics 2021 10 17;22(4):333-341. Epub 2021 Aug 17.

Institut de Myologie, Paris, France.

Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disease resulting from mutations in the NTRK1 gene encoding the neurotrophic tyrosine kinase-1 receptor. In this multicenter observational retrospective study, we investigated CIPA patients identified from French laboratories sequencing the NTRK1 gene, and seven patients were identified. Patients originated from France (2), Suriname (2), Mali (1), Kazakhstan (1), and Algeria (1). Mean age of patients was 9.8 years (4-20), four patients were female (57%), infant developmental milestones were delayed in four cases (57%), and four patients had a family history of consanguinity (57%). Mean age at diagnosis was 4.8 months (3-6), and all patients presented with pain insensitivity, anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, and autonomous nervous system impairment. Patients also showed an assortment of associated findings, including hyperactivity (86%), emotional lability (86%), joint deformities (71%), bone fractures (57%), abnormal sense of touch, vibration and position (50%), skin, hair and nails abnormalities (28%), and hypothermia episodes (28%). Two patients died at age 9 and 12 years from infection. In three cases, nerve conduction studies showed absent lower limbs sensory nerve action potentials. In one case, sensory nerve biopsy showed complete absence of unmyelinated fibers. Nine NTRK1 pathogenic variants were found, including three newly described mutations. This nationwide study confirms that NTRK1 gene-related CIPA is an extremely rare disorder and expands the genotypic spectrum of NTRK1 mutations.
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http://dx.doi.org/10.1007/s10048-021-00668-zDOI Listing
October 2021

Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations.

Neurogenetics 2021 03 23;22(1):71-79. Epub 2021 Jan 23.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, DMU Neuroscience 6, Paris, France.

Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.
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http://dx.doi.org/10.1007/s10048-020-00633-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997841PMC
March 2021

Characterization of Recessive Parkinson Disease in a Large Multicenter Study.

Ann Neurol 2020 10 28;88(4):843-850. Epub 2020 Jul 28.

Behavioral Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.
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http://dx.doi.org/10.1002/ana.25787DOI Listing
October 2020

Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance.

Mov Disord 2020 10 14;35(10):1755-1764. Epub 2020 Jul 14.

Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown.

Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD.

Methods: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups.

Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (OR , 0.38; 95% CI, 0.21-0.67 and OR , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (OR , 0.19; 95% CI, 0.07-0.50 and OR , 0.51; 95% CI, 0.28-0.91).

Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572560PMC
October 2020

Characterization of recessive Parkinson's disease in a large multicenter study.

Ann Neurol 2020 May 30. Epub 2020 May 30.

Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson's disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1587 cases. Mutations were found in 14.1% of patients: 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ana.25787DOI Listing
May 2020

A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs).

Ann Neurol 2019 07 27;86(1):55-67. Epub 2019 May 27.

Department of Neurology, Università Magna Graecia di Catanzaro, Catanzaro, Italy.

Objective: Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B.

Methods: We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score.

Results: There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations.

Interpretation: This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019.
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http://dx.doi.org/10.1002/ana.25500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581441PMC
July 2019

Clinical features and prognosis of amyotrophic lateral sclerosis in Africa: the TROPALS study.

J Neurol Neurosurg Psychiatry 2019 01 21;90(1):20-29. Epub 2018 Sep 21.

INSERM, U1094, Tropical Neuroepidemiology, Limoges, France

Objective: We describe and compare the sociodemographic and clinical features, treatments, and prognoses and survival times of patients with amyotrophic lateral sclerosis (ALS) in Africa.

Methodology: We conducted a multicentre, hospital-based cohort study in Africa. Patients with ALS diagnosed in the neurology departments of participating hospitals from 2005 to 2017 were included. Subgroup analysis was performed by subcontinent. Survival analyses were conducted using the Cox proportional hazards model.

Results: Nine centres from eight African countries participated. A total of 185 patients with ALS were included: 114 from Northern Africa, 41 from Western Africa and 30 from Southern Africa. A male predominance (male to female ratio 2.9) was evident. The median age at onset was 53.0 years (IQR 44.5-64.0 years). The onset was bulbar in 22.7%. Only 47 patients (26.3%) received riluzole, mainly in Northern and Western Africa. The median survival from the time of diagnosis was 14.0 months (95% CI 10.7 to 17.2 months). The median survival was longer in Northern Africa (19.0 months, 95% CI 10.8 to 27.2 months) than in Western (4.0 months, 95% CI 0.8 to 7.1 months) and Southern (11.0 months, 95% CI 5.6 to 16.4 months) Africa (Breslow test, p<0.0001). Both subcontinental location and riluzole treatment independently affected survival.

Conclusion: More African patients with ALS were male and younger and exhibited a lower proportion of bulbar onset compared with patients with ALS from Western nations. Survival was consistent with that in Western registers but far shorter than what would be expected for young patients with ALS. The research improves our understanding of the disease in Africa.
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http://dx.doi.org/10.1136/jnnp-2018-318469DOI Listing
January 2019

Some new proposals for the classification of inherited myopathies.

J Neurol Sci 2018 08 19;391:118-119. Epub 2018 Jun 19.

Department of Neurology (National reference center 'neuropathies périphériques rares'), University Hospital Dupuytren, 2 avenue Martin Luther King, 87042 Limoges, France. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2018.06.014DOI Listing
August 2018

The classification of Charcot-Marie-Tooth diseases, a never-ending story: CMT4?

Brain 2018 09;141(9):e70

Department of Neurology, Nerve-Muscle Unit, CHU Bordeaux (Pellegrin University Hospital), University of Bordeaux, Place Amélie Raba-Léon, Bordeaux, France.

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http://dx.doi.org/10.1093/brain/awy207DOI Listing
September 2018

Updating the classification of inherited neuropathies: Results of an international survey.

Neurology 2018 03 2;90(10):e870-e876. Epub 2018 Feb 2.

From the Department of Neurology (L.M., J.-M.V.), Centre de Référence Neuropathies Rares, CHU Limoges; Department of Neurology, Nerve-Muscle Unit (S.M., G.L.M.), and Department of Neurogenetics (C.G.), CHU Bordeaux (Pellegrin Hospital), France; and Department of Neurology (M.T.), CHU Mustapha Bacha, Algiers, Algeria.

Objective: The continual discovery of disease-causing gene mutations has led to difficulties in the complex classification of Charcot-Marie-Tooth diseases (CMT) that needs to be revised.

Methods: We recently published a proposal to update the classification of inherited neuropathies. The reactions from colleagues prompted us to diffuse the proposal and ask people if they would be ready for such a change. We therefore performed an internet survey (from October 1, 2016, to December 1, 2016) that included more than 300 CMT worldwide specialists (practitioners and scientists) from various countries. A questionnaire (with proposals to update and simplify the way in which CMT is classified) was sent by e-mail to all participants in the last International Charcot-Marie-Tooth and Related Neuropathy Consortium meeting held in Venice, September 8-10, 2016 (as identified through an e-mail list).

Results: Of the 107 CMT specialists who answered the survey, 65% considered that changes are needed and that our proposals constituted an improvement over the historical classification of CMT.

Conclusions: Based on recent proposals in the medical literature, these results highlight that most specialists think that changes are needed to the classification of CMT.
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http://dx.doi.org/10.1212/WNL.0000000000005074DOI Listing
March 2018

Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.

JAMA Neurol 2018 04;75(4):495-502

Pediatric Neurology, Emma Children's Hospital, University of Amsterdam, Amsterdam, the Netherlands.

Importance: Ataxia with oculomotor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia due to mutations in the aprataxin gene (APTX) that is characterized by early-onset cerebellar ataxia, oculomotor apraxia, axonal motor neuropathy, and eventual decrease of albumin serum levels.

Objectives: To improve the clinical, biomarker, and molecular delineation of AOA1 and provide genotype-phenotype correlations.

Design, Setting, And Participants: This retrospective analysis included the clinical, biological (especially regarding biomarkers of the disease), electrophysiologic, imaging, and molecular data of all patients consecutively diagnosed with AOA1 in a single genetics laboratory from January 1, 2002, through December 31, 2014. Data were analyzed from January 1, 2015, through January 31, 2016.

Main Outcomes And Measures: The clinical, biological, and molecular spectrum of AOA1 and genotype-phenotype correlations.

Results: The diagnosis of AOA1 was confirmed in 80 patients (46 men [58%] and 34 women [42%]; mean [SD] age at onset, 7.7 [7.4] years) from 51 families, including 57 new (with 8 new mutations) and 23 previously described patients. Elevated levels of α-fetoprotein (AFP) were found in 33 patients (41%); hypoalbuminemia, in 50 (63%). Median AFP level was higher in patients with AOA1 (6.0 ng/mL; range, 1.1-17.0 ng/mL) than in patients without ataxia (3.4 ng/mL; range, 0.8-17.2 ng/mL; P < .01). Decreased albumin levels (ρ = -0.532) and elevated AFP levels (ρ = 0.637) were correlated with disease duration. The p.Trp279* mutation, initially reported as restricted to the Portuguese founder haplotype, was discovered in 53 patients with AOA1 (66%) with broad white racial origins. Oculomotor apraxia was found in 49 patients (61%); polyneuropathy, in 74 (93%); and cerebellar atrophy, in 78 (98%). Oculomotor apraxia correlated with the severity of ataxia and mutation type, being more frequent with deletion or truncating mutations (83%) than with presence of at least 1 missense variant (17%; P < .01). Mean (SD) age at onset was higher for patients with at least 1 missense mutation (17.7 [11.4] vs 5.2 [2.6] years; P < .001).

Conclusions And Relevance: The AFP level, slightly elevated in a substantial fraction of patients, may constitute a new biomarker for AOA1. Oculomotor apraxia may be an optional finding in AOA1 and correlates with more severe disease. The p.Trp279* mutation is the most frequent APTX mutation in the white population. APTX missense mutations may be associated with a milder phenotype.
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http://dx.doi.org/10.1001/jamaneurol.2017.4373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933354PMC
April 2018

Nerve Biopsy Is Still Useful in Some Inherited Neuropathies.

J Neuropathol Exp Neurol 2018 Feb;77(2):88-99

Department and Laboratory of Neurology, 'Centre de Référence Neuropathies Périphériques Rares', University Hospital, Limoges, France.

In hereditary neuropathies, next-generation sequencing techniques are producing a vast number of candidate gene mutations that need to be verified or excluded by careful genotype-phenotype correlation analysis. In most cases, clinical acumen is still important but needs to be combined with data from nerve conduction studies and, in some cases, from nerve biopsy examinations. Indeed, characteristic clinical, electrophysiological, and sometimes pathological features may be suggestive of a particular subtype of Charcot-Marie-Tooth (CMT) disease. Microscopical (mainly ultrastructural) human nerve biopsy patterns may be related to CMT diseases and gene defects. Even today, it is important to recognize these characteristic lesions in the context of a chronic idiopathic neuropathy as they may help search for or reveal a sporadic form of CMT. In practice, these different types of lesions are often linked to the known function of the mutated genes. Only a few patients diagnosed or suspected as having a CMT disease need a nerve biopsy that can help find or confirm the causative gene mutation. The indication for this procedure should be based on a case-by-case discussion.
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http://dx.doi.org/10.1093/jnen/nlx111DOI Listing
February 2018

History and current difficulties in classifying inherited myopathies and muscular dystrophies.

J Neurol Sci 2018 Jan 2;384:50-54. Epub 2017 Nov 2.

Department of Neurology, University Hospital Dupuytren, 2 avenue Martin Luther King, 87042 Limoges, France; National reference center 'neuropathies périphériques rares', University Hospital Dupuytren, 2 avenue Martin Luther King, 87042 Limoges, France. Electronic address:

The wide spectrum of hereditary muscular disorders leads to unavoidable difficulties in their classification, even for specialists. For this reason, new proposals are required that would ultimately replace our current rather complex classifications by a simpler structure. Our proposal will be limited to dystrophic and non-dystrophic myopathies (excluding metabolic disorders, mitochondriopathies, and channelopathies) for which similar proposals would also be relevant. Various genes (encoding structural proteins associated with the sarcolemma, nuclear membrane proteins, and proteins involved in myofiber metabolism have now been sequenced and mutations ascribed to specific forms of inherited muscular disorders. Based on our observations and our recent proposals in other neurogenetic conditions and informal discussions with specialists of neuromuscular disorders, the prerequisite for a simple and sound classification for inherited muscular disorders should encompass the clinical and pathological phenotypes (described in a simple and clear manner), the mode of inheritance, and the mutated gene. We think that the denomination of the different subtypes could be simplified considerably, although any new proposal of classification of muscular disorders will need to be discussed in the neurological and genetic communities.
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http://dx.doi.org/10.1016/j.jns.2017.10.051DOI Listing
January 2018

DNM3 and genetic modifiers of age of onset in LRRK2 Gly2019Ser parkinsonism: a genome-wide linkage and association study.

Lancet Neurol 2016 Nov 28;15(12):1248-1256. Epub 2016 Sep 28.

Centre for Applied Neurogenetics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Background: Leucine-rich repeat kinase 2 (LRRK2) mutation 6055G→A (Gly2019Ser) accounts for roughly 1% of patients with Parkinson's disease in white populations, 13-30% in Ashkenazi Jewish populations, and 30-40% in North African Arab-Berber populations, although age of onset is variable. Some carriers have early-onset parkinsonism, whereas others remain asymptomatic despite advanced age. We aimed to use a genome-wide approach to identify genetic variability that directly affects LRRK2 Gly2019Ser penetrance.

Methods: Between 2006 and 2012, we recruited Arab-Berber patients with Parkinson's disease and their family members (aged 18 years or older) at the Mongi Ben Hamida National Institute of Neurology (Tunis, Tunisia). Patients with Parkinson's disease were diagnosed by movement disorder specialists in accordance with the UK Parkinson's Disease Society Brain Bank criteria, without exclusion of familial parkinsonism. LRRK2 carrier status was confirmed by Sanger sequencing or TaqMan SNP assays-on-demand. We did genome-wide linkage analysis using data from multi-incident Arab-Berber families with Parkinson's disease and LRRK2 Gly2019Ser (with both affected and unaffected family members). We assessed Parkinson's disease age of onset both as a categorical variable (dichotomised by median onset) and as a quantitative trait. We used data from another cohort of unrelated Tunisian LRRK2 Gly2019Ser carriers for subsequent locus-specific genotyping and association analyses. Whole-genome sequencing in a subset of 14 unrelated Arab-Berber individuals who were LRRK2 Gly2019Ser carriers (seven with early-onset disease and seven elderly unaffected individuals) subsequently informed imputation and haplotype analyses. We replicated the findings in separate series of LRRK2 Gly2019Ser carriers originating from Algeria, France, Norway, and North America. We also investigated associations between genotype, gene, and protein expression in human striatal tissues and murine LRRK2 Gly2019Ser cortical neurons.

Findings: Using data from 41 multi-incident Arab-Berber families with Parkinson's disease and LRRK2 Gly2019Ser (150 patients and 103 unaffected family members), we identified significant linkage on chromosome 1q23.3 to 1q24.3 (non-parametric logarithm of odds score 2·9, model-based logarithm of odds score 4·99, θ=0 at D1S2768). In a cohort of unrelated Arab-Berber LRRK2 Gly2019Ser carriers, subsequent association mapping within the linkage region suggested genetic variability within DNM3 as an age-of-onset modifier of disease (n=232; rs2421947; haplotype p=1·07 × 10). We found that DNM3 rs2421947 was a haplotype tag for which the median onset of LRRK2 parkinsonism in GG carriers was 12·5 years younger than that of CC carriers (Arab-Berber cohort, hazard ratio [HR] 1·89, 95% CI 1·20-2·98). Replication analyses in separate series from Algeria, France, Norway, and North America (n=263) supported this finding (meta-analysis HR 1·61, 95% CI 1·15-2·27, p=0·02). In human striatum, DNM3 expression varied as a function of rs2421947 genotype, and dynamin-3 localisation was perturbed in murine LRRK2 Gly2019Ser cortical neurons.

Interpretation: Genetic variability in DNM3 modifies age of onset for LRRK2 Gly2019Ser parkinsonism and informs disease-relevant translational neuroscience. Our results could be useful in genetic counselling for carriers of this mutation and in clinical trial design.

Funding: The Canada Excellence Research Chairs (CERC), Leading Edge Endowment Fund (LEEF), Don Rix BC Leadership Chair in Genetic Medicine, National Institute on Aging, National Institute of Neurological Disorders and Stroke, the Michael J Fox Foundation, Mayo Foundation, the Roger de Spoelberch Foundation, and GlaxoSmithKline.
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http://dx.doi.org/10.1016/S1474-4422(16)30203-4DOI Listing
November 2016

Reasons Charcot-Marie-Tooth disease due to mutations in the MME gene should not be named AR-CMT2T.

Ann Neurol 2016 09 4;80(3):477. Epub 2016 Aug 4.

Department of Neurology, (National reference center "Rare Peripheral Neuropathies"), Dupuytren University Hospital, Limoges, France.

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http://dx.doi.org/10.1002/ana.24741DOI Listing
September 2016

Validation of a clinical practice-based algorithm for the diagnosis of autosomal recessive cerebellar ataxias based on NGS identified cases.

J Neurol 2016 Jul 3;263(7):1314-22. Epub 2016 May 3.

Laboratoire de Génétique de Maladies Rares, Institut Universitaire de Recherche Clinique, Université de Montpellier, EA 7402, CHU Montpellier, 34093, Montpellier, France.

Establishing a molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to phenotype and genotype heterogeneity. We report the validation of a previously published clinical practice-based algorithm to diagnose ARCA. Two assessors performed a blind analysis to determine the most probable mutated gene based on comprehensive clinical and paraclinical data, without knowing the molecular diagnosis of 23 patients diagnosed by targeted capture of 57 ataxia genes and high-throughput sequencing coming from a 145 patients series. The correct gene was predicted in 61 and 78 % of the cases by the two assessors, respectively. There was a high inter-rater agreement [K = 0.85 (0.55-0.98) p < 0.001] confirming the algorithm's reproducibility. Phenotyping patients with proper clinical examination, imaging, biochemical investigations and nerve conduction studies remain crucial for the guidance of molecular analysis and to interpret next generation sequencing results. The proposed algorithm should be helpful for diagnosing ARCA in clinical practice.
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http://dx.doi.org/10.1007/s00415-016-8112-5DOI Listing
July 2016

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.

Am J Hum Genet 2016 Mar;98(3):500-513

Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.
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http://dx.doi.org/10.1016/j.ajhg.2016.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800038PMC
March 2016

Arginine:glycine amidinotransferase (AGAT) deficiency: Clinical features and long term outcomes in 16 patients diagnosed worldwide.

Mol Genet Metab 2015 Dec 17;116(4):252-9. Epub 2015 Oct 17.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Background: Arginine:glycine aminotransferase (AGAT) (GATM) deficiency is an autosomal recessive inborn error of creative synthesis.

Objective: We performed an international survey among physicians known to treat patients with AGAT deficiency, to assess clinical characteristics and long-term outcomes of this ultra-rare condition.

Results: 16 patients from 8 families of 8 different ethnic backgrounds were included. 1 patient was asymptomatic when diagnosed at age 3 weeks. 15 patients diagnosed between 16 months and 25 years of life had intellectual disability/developmental delay (IDD). 8 patients also had myopathy/proximal muscle weakness. Common biochemical denominators were low/undetectable guanidinoacetate (GAA) concentrations in urine and plasma, and low/undetectable cerebral creatine levels. 3 families had protein truncation/null mutations. The rest had missense and splice mutations. Treatment with creatine monohydrate (100-800 mg/kg/day) resulted in almost complete restoration of brain creatine levels and significant improvement of myopathy. The 2 patients treated since age 4 and 16 months had normal cognitive and behavioral development at age 10 and 11 years. Late treated patients had limited improvement of cognitive functions.

Conclusion: AGAT deficiency is a treatable intellectual disability. Early diagnosis may prevent IDD and myopathy. Patients with unexplained IDD with and without myopathy should be assessed for AGAT deficiency by determination of urine/plasma GAA and cerebral creatine levels (via brain MRS), and by GATM gene sequencing.
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http://dx.doi.org/10.1016/j.ymgme.2015.10.003DOI Listing
December 2015

All-trans-retinoic acid modulates nitric oxide and interleukin-17A production by peripheral blood mononuclear cells from patients with Alzheimer's disease.

Neuroimmunomodulation 2015 8;22(6):385-93. Epub 2015 Aug 8.

Cytokines and NO Synthases, Immunity and Pathogeny Team, Laboratory of Cellular and Molecular Biology (LBCM), Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria.

Background: Alzheimer's disease (AD), the most common form of dementia in the elderly, is a neurodegenerative disorder associated with a complex pathophysiology. It is accepted that inflammation contributes to the pathogenesis of AD. All-trans-retinoic acid (ATRA) is a bioactive derivative of vitamin A that has shown immunomodulatory effects in many immune disorders.

Objectives: In our study, we aimed to investigate in vitro immunomodulatory effects of ATRA on inducible nitric oxide synthase (iNOS) expression and interleukin-17A production during AD.

Methods: Peripheral blood mononuclear cells (PBMCs) isolated from 30 Algerian AD patients and 14 age-matched nondemented controls were treated (or not) with ATRA. Production of NO and IL-17A in culture media was measured by the modified Griess method and enzyme-linked immunosorbent assay, respectively. Expression of iNOS in PBMCs was examined by fluorescence immunostaining.

Results: Our results showed higher spontaneous in vitro production of NO related to overexpression of iNOS in AD patients compared to controls. Remarkably, ATRA treatment showed an important downregulatory effect on NO production and iNOS expression in patients. This effect was associated with a reduction in IL-17A production and increased IL-10 release.

Conclusions: Taken together, our results indicate that ATRA exerts anti-inflammatory effects in AD. Furthermore, ATRA represents a promising tool for monitoring inflammatory responses associated with disease progression.
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http://dx.doi.org/10.1159/000435885DOI Listing
August 2016

Charcot-Marie-Tooth diseases: an update and some new proposals for the classification.

J Med Genet 2015 Oct 5;52(10):681-90. Epub 2015 Aug 5.

Department of Neurology (National Reference Center "Neuropathies Périphériques Rares"), University Hospital Dupuytren, Limoges, France.

Background: Charcot-Marie-Tooth (CMT) disease, the most frequent form of inherited neuropathy, is a genetically heterogeneous group of disorders of the peripheral nervous system, but with a quite homogeneous clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss and usually decreased tendon reflexes). Our aim was to review the various CMT subtypes identified at the present time.

Methods: We have analysed the medical literature and performed a historical retrospective of the main steps from the individualisation of the disease (at the end of the nineteenth century) to the recent knowledge about CMT.

Results: To date, >60 genes (expressed in Schwann cells and neurons) have been implicated in CMT and related syndromes. The recent advances in molecular genetic techniques (such as next-generation sequencing) are promising in CMT, but it is still useful to recognise some specific clinical or pathological signs that enable us to validate genetic results. In this review, we discuss the diagnostic approaches and the underlying molecular pathogenesis.

Conclusions: We suggest a modification of the current classification and explain why such a change is needed.
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http://dx.doi.org/10.1136/jmedgenet-2015-103272DOI Listing
October 2015

Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia.

BMC Med Genet 2015 Jun 12;16:36. Epub 2015 Jun 12.

Laboratoire de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, USTHB, Alger, Algeria.

Background: Autosomal recessive cerebellar ataxias (ARCA) are a complex group of neurodegenerative disorders with great genetic and phenotypic heterogeneity, over 30 genes/loci have been associated with more than 20 different clinical forms of ARCA. Genetic heterogeneity combined with highly variable clinical expression of the cerebellar symptoms and overlapping features complicate furthermore the etiological diagnosis of ARCA. The determination of the most frequent mutations and corresponding ataxias, as well as particular features specific to a population, are mandatory to facilitate and speed up the diagnosis process, especially when an appropriate treatment is available.

Methods: We explored 166 patients (115 families) refered to the neurology units of Algiers central hospitals (Algeria) with a cerebellar ataxia phenotype segregating as an autosomal recessive pattern of inheritance. Genomic DNA was extracted from peripheral blood samples and mutational screening was performed by PCR and direct sequencing or by targeted genomic capture and massive parallel sequencing of 57 genes associated with inherited cerebellar ataxia phenotypes.

Results: In this work we report the clinical and molecular results obtained on a large cohort of Algerian patients (110 patients/76 families) with genetically determined autosomal recessive ataxia, representing 9 different types of ARCA and 23 different mutations, including 6 novel ones. The five most common ARCA in this cohort were Friedreich ataxia, ataxia with isolated vitamin E deficiency, ataxia with oculomotor apraxia type 2, autosomal recessive spastic ataxia of Charlevoix-Saguenay and ataxia with oculomotor apraxia type 1.

Conclusion: We report here a large cohort of patients with genetically determined autosomal recessive ataxia and the first study of the genetic context of ARCA in Algeria. This study showed that in Algerian patients, the two most common types of ataxia (Friedreich ataxia and ataxia with isolated vitamin E deficiency) coexist with forms that may be less common or underdiagnosed. To refine the genotype/phenotype correlation in rare and heteregeneous diseases as autosomal recessive ataxias, more extensive epidemiological investigations and reports are necessary as well as more accurate and detailed clinical characterizations. The use of standardized clinical and molecular protocols would thus enable a better knowledge of the different forms of ARCA.
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http://dx.doi.org/10.1186/s12881-015-0180-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630839PMC
June 2015

Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update.

J Neurol Sci 2014 Dec 16;347(1-2):14-22. Epub 2014 Oct 16.

Centre de Référence Neuropathies Périphériques Rares, Service et Laboratoire de Neurologie, University Hospital, Limoges, France.

Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment.
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http://dx.doi.org/10.1016/j.jns.2014.10.013DOI Listing
December 2014

IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients.

J Interferon Cytokine Res 2014 Nov 15;34(11):839-47. Epub 2014 May 15.

1 Team: Cytokines and NO-Synthases, Laboratory of Cellular and Molecular Biology, Faculty of Biological Science , USTHB, Algiers, Algeria .

Alzheimer's disease (AD) is a neurodegenerative disease leading to a progressive and irreversible loss of mental functions. It is characterized by 3 stages according to the evolution and the severity of the symptoms. This disease is associated with an immune disorder, which appears with significant rise in the inflammatory cytokines and increased production of free radicals such as nitric oxide (NO). Our study aims to investigate interferon (IFN)-γ and tumor necrosis factor-α (TNF-α) involvement in NO production, in vivo and ex vivo, in peripheral blood mononuclear cells from Algerian patients (n=25), according to the different stages of the disease (mild Alzheimer's, moderate Alzheimer's, and severe Alzheimer's) in comparison to mild cognitive impairment (MCI) patients. Interestingly, we observed that in vivo IFN-γ and TNF-α levels assessed in patients with AD in mild and severe stages, respectively, are higher than those observed in patients with moderate stage and MCI. Our in vivo and ex vivo results show that NO production is related to the increased levels of IFN-γ and TNF-α, in mild and severe stages of AD. Remarkably, significant IFN-γ level is only detected in mild stage of AD. Our study suggests that NO production is IFN-γ dependent both in MCI and mild Alzheimer's patients. Further, high levels of NO are associated with an elevation of TNF-α levels in severe stage of AD. Collectively, our data indicate that the proinflammatory cytokine production seems, in part, to be involved in neurological deleterious effects observed during the development of AD through NO pathway.
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http://dx.doi.org/10.1089/jir.2013.0085DOI Listing
November 2014

Peripheral myelin protein 22 gene duplication with atypical presentations: a new example of the wide spectrum of Charcot-Marie-Tooth 1A disease.

Neuromuscul Disord 2014 Jun 13;24(6):524-8. Epub 2014 Apr 13.

Centre de référence «neuropathies périphériques rares», service et laboratoire de Neurologie, CHU Limoges, France.

Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are both autosomal-dominant disorders linked to peripheral myelin anomalies. CMT1A is associated with a Peripheral Myelin Protein 22 (PMP22) duplication, whereas HNPP is due to a PMP22 deletion on chromosome 17. In spite of this crucial difference, we report three observations of patients with the 1.4 megabase CMT1A duplication and atypical presentation (electrophysiological, clinical or pathological): a 10 year-old girl with tomaculous lesions on nerve biopsy; a 26 year-old woman with recurrent paresthesiae and block conduction on the electrophysiological study; a 46 year-old woman with transient recurrent nerve palsies mimicking HNPP. These observations highlight the wide spectrum of CMT1A and the overlap between CMT1A and HNPP (both linked to the PMP22 gene), and finally illustrate the complexity of the genotype-phenotype correlations in Charcot-Marie-Tooth diseases.
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http://dx.doi.org/10.1016/j.nmd.2014.03.014DOI Listing
June 2014

Hyperhomocysteinemia is a risk factor for Alzheimer's disease in an Algerian population.

Arch Med Res 2014 Apr 20;45(3):247-50. Epub 2014 Mar 20.

Département de Biologie Cellulaire et Moléculaire, Faculté des Sciences Biologiques, Université des Sciences et de la Technologie Houari Boumediene Alger, Algérie.

Background And Aims: There is growing evidence that increased blood concentration of total homocysteine (tHcy) may be a risk factor for Alzheimer's disease (AD). The present study was conducted to evaluate the association of serum tHcy and other biochemical risk factors with AD.

Methods: This is a case-control study including 41 individuals diagnosed with AD and 46 nondemented controls. Serum levels of all studied biochemical parameters were performed.

Results: Univariate logistic regression showed a significant increase of tHcy (p = 0.008), urea (p = 0.036) and a significant decrease of vitamin B12 (p = 0.012) in AD group vs. controls. Using multivariate logistic regression, tHcy (p = 0.007, OR = 1.376) appeared as an independent risk factor predictor of AD. There was a significant positive correlation between tHcy and creatinine (p <0.0001). A negative correlation was found between tHcy and vitamin B12 (p <0.0001).

Conclusions: Our findings support that hyperhomocysteinemia is a risk factor for AD in an Algerian population and is also associated with vitamin B12 deficiency.
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http://dx.doi.org/10.1016/j.arcmed.2014.03.001DOI Listing
April 2014

Autosomal recessive Charcot-Marie-Tooth disease: from genes to phenotypes.

J Peripher Nerv Syst 2013 Jun;18(2):113-29

Service de Neurologie, University Hospital Mustapha Bacha, Alger, Algeria.

The prevalence of Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy (HMSN) varies in different populations. While in some countries of Western Europe, the United States and Japan the dominant form of HMSN is the most frequent, in other countries such as those of the Mediterranean Basin, the autosomal recessive form (AR-CMT) is more common. Autosomal recessive CMT cases are generally characterized by earlier onset, usually before the age of 2 or 3 years, and rapid clinical progression that results in severe polyneuropathy and more marked distal limb deformities such as pes equino-varus, claw-like hands, and often major spinal deformities. Recent clinical, morphological and molecular investigations of CMT families with autosomal recessive inheritance allowed the identification of many genes such as GDAP1, MTMR2, SBF2, NDRG1, EGR2, SH3TC2, PRX, FGD4, and FIG4, implicated in demyelinating forms (ARCMT1 or CMT4), and LMNA, MED25, HINT1, GDAP1, LRSAM1, NEFL, HSPB1 and MFN2 in axonal forms (ARCMT2). However, many patients remain without genetic diagnosis to date, prompting investigations into ARCMT families in order to help discover new genes and common pathways. This review summarizes recent advances regarding the genotypes and corresponding phenotypes of AR-CMT.
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http://dx.doi.org/10.1111/jns5.12026DOI Listing
June 2013

Multicenter transversal two-phase study to determine a national prevalence of epilepsy in Algeria.

Neuroepidemiology 2012 9;39(2):131-4. Epub 2012 Aug 9.

Service de Neurologie et Laboratoire de Recherche en Neurosciences, Université d'Alger, CHU Mustapha Bacha, Algiers, Algeria.

Background/aims: The prevalence of epilepsy in Algeria is unknown. The aims of this multicenter transversal study were to determine the national prevalence and clinical characteristics of epilepsy in the Algerian population.

Methods: This two-phase study was conducted in 5 circumscriptions and included 8,046 subjects aged over 2 months who attended the randomly selected public and private primary care clinics. In the phase 1 study, a questionnaire was submitted to the sample of patients. In the phase 2 study, all potentially epileptic people were examined by neurologists and a second questionnaire was submitted, eventually assessed by appropriate investigations.

Results: Sixty-seven patients were identified as having active epilepsy, giving a crude prevalence ratio of 8.32 per 1,000 (95% CI, 6.34-10.3) and an age-adjusted prevalence ratio of 8.9 per 1,000. The highest age-specific ratio was found in patients aged 10-19 years (16.92 per 1,000). Generalized seizures (68.7%) were more common than partial seizures (29.8%). Perinatal injuries were the major leading putative causes (11.9%).

Conclusion: The prevalence of epilepsy of 8.32 determined in this study is relatively high. These results provide new epidemiological data and suggest that epilepsy remains an important public health issue to consider in Algeria.
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http://dx.doi.org/10.1159/000339637DOI Listing
February 2013

Novel mutations in the PRX and the MTMR2 genes are responsible for unusual Charcot-Marie-Tooth disease phenotypes.

Neuromuscul Disord 2011 Aug 7;21(8):543-50. Epub 2011 Jul 7.

Service de Neurologie, CHU Mustapha Bacha, Algiers, Algeria.

Autosomal recessive Charcot-Marie-Tooth diseases, relatively common in Algeria due to high prevalence of consanguineous marriages, are clinically and genetically heterogeneous. We report on two consanguineous families with demyelinating autosomal recessive Charcot-Marie-Tooth disease (CMT4) associated with novel homozygous mutations in the MTMR2 gene, c.331dupA (p.Arg111LysfsX24) and PRX gene, c.1090C>T (p.Arg364X) respectively, and peculiar clinical phenotypes. The three patients with MTMR2 mutations (CMT4B1 family) had a typical phenotype of severe early onset motor and sensory neuropathy with typical focally folded myelin on nerve biopsy. Associated clinical features included vocal cord paresis, prominent chest deformities and claw hands. Contrasting with the classical presentation of CMT4F (early-onset Dejerine-Sottas phenotype), the four patients with PRX mutations (CMT4F family) had essentially a late age of onset and a protracted and relatively benign evolution, although they presented marked spine deformities. These observations broaden the spectrum of clinical phenotypes associated with these two CMT4 forms.
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http://dx.doi.org/10.1016/j.nmd.2011.04.013DOI Listing
August 2011
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