Does arsenic in soil contribute to arsenic urinary concentrations in a French population living in a naturally arsenic contaminated area?

International audienceA cross sectional study using environmental and biological samples was implemented to assess the association between arsenic (As) concentrations in the environment and urinary As levels of residents living in an area where the soil is naturally As rich. As was measured in drinking water, atmospheric particulate matter, and soil and a geographic information system was used to assign environmental concentrations closest to the participants' dwellings and the sum of inorganic As and metabolites in urine samples. The only potential source of As environmental contamination was from soil with a range of 13–131 mg As/kg of dry matter. As(V) was the only species present among As extracted from the analyzed soil samples. The chemical extraction showed a poor mobility of As soil. There was no difference between child and teenager, and adult urinary As concentrations, though men had higher urinary As concentrations than women (pb0.001). Given the important differences in lifestyle between 7–18 year olds, men, and women, these groups were analyzed separately. Whilst we were unable to find a stable model for the 7–18 year old group, for the adult men group we found that seafood consumption in the 3 days prior to the investigation (p=0.02), and beer (p=0.03) and wine consumption in the 4 days before the study, were associated with As urinary levels (μg/L). In adult women, creatinine was the only variable significantly associated with As urinary concentration (μg/L). The concentrations we measured in soils were variable and although high, only moderately so and no link between As concentrations in the soil and urinary As concentrations could be found for either men or women. Some individual factors explained half of the variability of adult men urinary As levels. The unexplained part of the variability should be searched notably in As mobility in soil and uncharacterized human behavior

Complementarity of electrophoretic, mass spectrometric, and gene sequencing techniques for the diagnosis and characterization of congenital disorders of glycosylation

International audienceCongenital disorders of glycosylation (CDG) are rare autosomal genetic diseases affecting the glycosylation of proteins and lipids. Since CDG-related clinical symptoms are classically extremely variable and nonspecific, a combination of electrophoretic, mass spectrometric, and gene sequencing techniques is often mandatory for obtaining a definitive CDG diagnosis, as well as identifying causative gene mutations and deciphering the underlying biochemical mechanisms. Here, we illustrate the potential of integrating data from capillary electrophoresis of transferrin, two-dimensional electrophoresis of N- and O-glycoproteins, mass spectrometry analyses of total serum N-linked glycans and mucin core1 O-glycosylated apolipoprotein C-III for the determination of various culprit CDG gene mutations. "Step-by-step" diagnosis pathways of four particular and new CDG cases, including MGAT2-CDG, ATP6V0A2-CDG, SLC35A2-CDG, and SLC35A3-CDG, are described as illustrative examples

POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation.

International audienceBACKGROUND: Alpha-dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. Although six genetic causes have been identified (FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE) many alpha-dystroglycanopathy patients remain without a genetic diagnosis after standard exon sequencing. To date POMT2 mutations have been identified in CMD cases with a wide range of clinical severities from Walker-Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement. METHODS: We analyzed POMT2 in six CMD patients, who had severe diffuse muscle weakness, generalized joint contractures, microcephaly, severe mental retardation and elevated CK levels. Eye involvement was absent or limited to myopia or strabismus. We sequenced the coding regions of POMT2 using genomic DNA and cDNA generated from blood lymphocytes or B lymphoblastoid cell lines. Quantitative PCR analysis of genomic DNA was used to identify and determine the breakpoints of large deletions. RESULTS: We report five novel mutations in POMT2, four of which were outside of coding exons, two large genomic deletions and two intronic single base substitutions that induced aberrant mRNA splicing. CONCLUSIONS: Large scale DNA rearrangements (such as large deletions) and cryptic splice mutations, that can be missed on standard sequencing of genomic DNA, may be relatively common in POMT2. Additional techniques, such as sequencing of cDNA are needed to identify all mutations. These results also confirm that POMT2 mutations are an important cause of the less severe alpha-dystroglycanopathy phenotypes

CCDC115-CDG: A new rare and misleading inherited cause of liver disease

International audienceCongenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement. Biological results were similar to previously described patients, including hypercholesterolemia, elevated alkaline phosphatases and defects in copper metabolism. CDG screening and glycosylation study finally led to the molecular diagnosis of CCDC115-CDG. Besides pointing to the importance of CDG screening in patients with unexplained and severe liver disease, these reports expand the clinical and molecular phenotypes of CCDC115-CDG. The hepatic involvement is particularly addressed. Furthermore, hypothesis concerning the pathogenesis of the liver disease and of major biological abnormalities are proposed

From splitting GLUT1 deficiency syndromes to overlapping phenotypes.

International audienceIntroduction Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare genetic disorder due to mutations or deletions in SLC2A1, resulting in impaired glucose uptake through the blood brain barrier. The classic phenotype includes pharmacoresistant epilepsy, intellectual deficiency, microcephaly and complex movement disorders, with hypoglycorrhachia, but milder phenotypes have been described (carbohydrate-responsive phenotype, dystonia and ataxia without epilepsy, paroxysmal exertion-induced dystonia). The aim of our study was to provide a comprehensive overview of GLUT1DS in a French cohort. Methods 265 patients were referred to the French national laboratory for molecular screening between July 2006 and January 2012. Mutations in SLC2A1 were detected in 58 patients, with detailed clinical data available in 24, including clinical features with a focus on their epileptic pattern and electroencephalographic findings, biochemical findings and neuroimaging findings. Results 53 point mutations and 5 deletions in SLC2A1 were identified. Most patients (87.5%) exhibited classic phenotype with intellectual deficiency (41.7%), epilepsy (75%) or movement disorder (29%) as initial symptoms at a medium age of 7.5 months, but diagnostic was delayed in most cases (median age at diagnostic 8 years 5 months). Sensitivity to fasting or exertion in combination with those 3 main symptoms were the main differences between mutated and negative patients (p < 0.001). Patients with myoclonic seizures (52%) evolved with more severe intellectual deficiency and movement disorders compared with those with Early Onset Absence Epilepsy (38%). Three patients evolved from a classic phenotype during early childhood to a movement disorder predominant phenotype at a late childhood/adulthood. Conclusions Our data confirm that the classic phenotype is the most frequent in GLUT1DS. Myoclonic seizures are a distinctive feature of severe forms. However a great variability among patients and overlapping through life from milder classic phenotype to paroxysmal-prominent- movement-disorder phenotype are possible, thus making it difficult to identify definite genotype–phenotype correlations