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Abstract: The removal of 13 polycyclic aromatic hydrocarbons, 7 polychlorobiphenyls and nonylphenol was measured during the continuous anaerobic digestion of five different sludge samples. The reactors were fed with one of the following: primary/secondary sludge (PS/SS), thermally treated PS, cellulose-added SS, or SS augmented with dissolved and colloidal matter (DCM). These various feeding conditions induced variable levels of micropollutant bioavailability (assumed to limit their biodegradation) and overall metabolism (supposed to be linked to micropollutant metabolism throughout co-metabolism). On the one hand, overall metabolism was higher with secondary sludge than with primary and the same was observed for micropollutant removal. However, when overall metabolism was enhanced thanks to cellulose addition, a negative influence on micropollutant removal was observed. This suggests that either the co-metabolic synergy would be linked to a specific metabolism or co-metabolism was not the limiting factor in this case. On the other hand, micropollutant bioavailability was presumably diminished by thermal treatment and increased by DCM addition. In both cases, micropollutant removal was reduced. These results suggest that neither overall metabolism nor bioavailability would absolutely limit micropollutant removal. Each phenomenon might alternatively predominate depending on the feed characteristics. [Copyright &y& Elsevier]

Abstract: STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, has been reported in Ohtahara syndrome, a rare epileptic encephalopathy with suppression burst pattern on EEG, in patients with infantile spasms and in a few patients with nonsyndromic mental retardation without epilepsy. We report a patient who presented late onset infantile spasms. Epilepsy was controlled but the patient developed severe mental delay. A first diagnosis of mitochondrial disease was based on clinical presentation and on a partial deficit of respiratory chain complex IV, but molecular screening for mitochondrial genes was negative. The sequencing of STXBP1 gene found a de novo nonsense mutation (c.585C>G/p.Tyr195X). This observation widens the clinical spectrum linked to STXBP1 mutations with the description of a patient with late onset infantile spasms. It raises the question of the value of epilepsy genes screening in patients with uncertain, partial or unconfirmed mitochondrial dysfunction. [Copyright &y& Elsevier]

We report clinical and biochemical finding from three unrelated patients presenting ONCE (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined oxidative phosphorylation deficiency) syndrome. Whole-exome sequencing (WES) of the three patients and the healthy sister of one of them was used to identify the carry gene. Clinical and biochemical findings were used to filter variants, and molecular, in silico and genetic studies were performed to characterize the candidate variants. Mitochondrial DNA (mtDNA) defects involving mutations, deletions or depletion were discarded, whereas WES uncovered a double homozygous mutation in the MTO1 gene (NM_001123226:c.1510C>T, p.R504C, and c.1669G>A, p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. Therefore, our data confirm p.R504C as pathogenic mutation responsible of ONCE syndrome, and p.V557M as a rare polymorphic variant. [ABSTRACT FROM AUTHOR]

Neuromuscular disorders (NMD) with neonatal or perinatal onset are usually severe. The establishment of a definite diagnosis relies on the combination of clinical examination, enzymatic tests, muscle morphology analyses, and genetic investigations, and is essential to provide a vital prognosis, propose adequate genetic counseling, consider treatment options, and include the patients into clinical trials for innovative therapies. However, the recent and rapid advancements of panel, exome, and genome sequencing questions the utility of invasive muscle biopsies and the contribution of histological and ultrastructural studies of muscle sections to the diagnosis process. Here, we explored the relevance of muscle biopsies collected at the Institute of Myology in Paris over a period of more than 50 years (1970-2021) in light of the evolution of Sanger and next-generation sequencing (NGS) technologies. Altogether, 82% of the biopsies showed typical structural myofiber anomalies highly suggestive of specific NMD classes (congenital myopathies, metabolic myopathies, lower motor neuron (LMN) and neuromuscular junction (NMJ) disorders, muscular dystrophies, inflammatory myopathies), while the remaining 18% showed no or only non-specific histological abnormalities. The diagnosis success rate differed among the NMD classes and changed over time following the identification of major disease genes like SMN1 or DMD , shifting the focus to direct gene sequencing and reducing the necessity of muscle biopsies. Ultrastructural investigations were of particular importance for the diagnosis of congenital myopathies and less relevant for the other NMD categories. Typical myofiber lesions found in congenital myopathies as intranuclear rods in ACTA1-related nemaline myopathy are barely discernible under the light microscope and solely detectable by electron microscopy (EM). This shows that the higher resolution of EM is not only a feature complementing light microscopy, but also a powerful diagnostic method. From our experience, morphological muscle biopsy examinations were frequently accurate and either pointed to a group of myopathies or to single genes. In conclusion, this retrospective study describes a unique collection of neonatal muscle biopsies and illustrates that the thorough analysis of muscle sections was of major diagnostic relevance in the past and still plays an important role nowadays - either by directing purposeful gene sequencing or by complementing clinical findings and biochemical analysis methods. [ABSTRACT FROM AUTHOR]

Background: Individuals with pathogenic variants in SATB2 display intellectual disability, speech and behavioral disorders, dental abnormalities and often features of Pierre Robin sequence. SATB2 encodes a transcription factor thought to play a role in bone remodeling. The primary aim of our study was to systematically review the skeletal manifestations of SATB2-associated syndrome. For this purpose, we performed a non-interventional, multicenter cohort study, from 2017 to 2018. We included 19 patients, 9 females and 10 males ranging in age from 2 to 19 years-old. The following data were collected prospectively for each patient: clinical data, bone markers and calcium and phosphate metabolism parameters, skeletal X-rays and bone mineral density.Results: Digitiform impressions were present in 8/14 patients (57%). Vertebral compression fractures affected 6/17 patients (35%). Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae (15/17) were the most frequent radiological features at the spine. Long bones were generally demineralized (18/19). The distal phalanges were short, thick and abnormally shaped. C-telopeptide (CTX) and Alkaline phosphatase levels were in the upper normal values and osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%).Conclusion: We conclude that SATB2 pathogenic variants are responsible for skeletal demineralization and osteoporosis. We found increased levels of bone formation markers, supporting the key role of SATB2 in osteoblast differentiation. These results support the need for bone evaluation in children and adult patients with SATB2-associated syndrome (SAS). [ABSTRACT FROM AUTHOR]

Résumé La génétique des troubles du spectre autistique (TSA) a longtemps été limitée à une approche relevant purement de la recherche et peu de cliniciens en percevaient l’intérêt concret pour leurs patients. L’arrivée des nouvelles techniques moléculaires a révolutionné la génétique des TSA et cette approche fait aujourd’hui partie de la pratique clinique courante. En effet, il est désormais possible de poser un diagnostic étiologique et de proposer dans de nombreux cas un conseil génétique singulier pour une famille. Le travail de lien mené depuis les années 1990 entre le service de génétique de l’hôpital Necker à Paris et l’association l’Élan Retrouvé a permis de déployer un vaste programme de diagnostic étiologique des TSA comprenant trois niveaux d’approche : standard (recherche des anomalies de l’X et caryotype de haute résolution ou CGH Array), avancé (puces de reséquençage ou panel de gènes) et de recherche (exome). La combinaison de ces trois approches permet de poser un diagnostic étiologique dans 35 à 40 % des TSA, la plupart des remaniements retrouvés étant de novo, c’est-à-dire non hérités des parents. Il n’est donc pas exclu de penser qu’un jour, chaque enfant bénéficiera d’un diagnostic et recevra un traitement médicamenteux personnalisé. Le fait de poser un diagnostic permet de comprendre les symptômes présentés par l’enfant mais s’avère aussi souvent un immense soulagement pour les familles. The genetics of autism spectrum disorders (ASD) has long been limited to a research approach and few clinicians perceived the concrete interest for their patients. The arrival of new molecular techniques has revolutionized genetics of ASD and this approach is now part of routine clinical practice. Indeed, it is now possible to determine an etiologic diagnosis and in many cases to offer a unique genetic counseling for families. The work conducted since the 1990s between the genetics department of Necker Hospital in Paris and the association “l’Élan Retrouvé” helped deploy a broad ASD etiologic diagnosis program. This program includes three levels of approach: standard (searching abnormalities of the X chromosome and high resolution karyotype – CGH Array), advanced (gene panel testing) and research (exome sequencing). The combination of these three approaches helps to diagnose a rare genetic disease in 35 to 40 % of ASD. The majority of the found mutations or rearrangements occurs de novo and is not inherited from the parents. It is not excluded that one day, every child will receive a diagnosis and a personalized treatment. Having a diagnosis leads to understand the symptoms presented by the child. It is also a huge relief for families. [ABSTRACT FROM AUTHOR]