Several genes have been implicated in Rett syndrome (RTT) in its typical and variant forms. We applied next‐generation sequencing (NGS) to evaluate for mutations in known or new candidate genes in ...patients with variant forms of Rett or Rett‐like phenotypes of unknown molecular aetiology. In the first step, we used NGS with a custom panel including MECP2, CDKL5, FOXG1, MEF2C and IQSEC2. In addition to a FOXG1 mutation in a patient with all core features of the congenital variant of RTT, we identified a missense (p.Ser240Thr) in CDKL5 in a patient who appeared to be seizure free. This missense was maternally inherited with opposite allele expression ratios in the proband and her mother. In the asymptomatic mother, the mutated copy of the CDKL5 gene was inactivated in 90% of blood cells. We also identified a premature stop codon (p.Arg926*) in IQSEC2 in a patient with a Rett‐like phenotype. Finally, exome sequencing enabled us to characterize a heterozygous de novo missense (p.Val408Ala) in KCNA2 encoding the potassium channel Kv 1.2 in a girl with infantile‐onset seizures variant of RTT. Our study expands the genetic heterogeneity of RTT and RTT‐like phenotypes. Moreover, we report the first familial case of CDKL5‐related disease.
Lyme borreliosis (LB) diagnosis currently relies mainly on serological tests and sometimes PCR or culture. However, other biological assays are being developed to try to improve Borrelia-infection ...diagnosis and/or monitoring.
To analyse available data on these unconventional LB diagnostic assays through a systematic literature review.
We searched PubMed and Cochrane Library databases according to the PRISMA-DTA method and the Cochrane Handbook for Systematic Reviews of Interventions. We analysed controlled and uncontrolled studies (published 1983–2018) on biological tests for adults to diagnose LB according to the European Study Group for Lyme Borreliosis or the Infectious Diseases Society of America definitions, or identify strongly suspected LB. Two independent readers evaluated study eligibility and extracted data from relevant study reports; a third reader analysed full texts of papers to resolve disagreements. The quality of each included study was assessed with the QUADAS-2 evaluation scale.
Forty studies were included: two meta-analyses, 25 prospective controlled studies, five prospective uncontrolled studies, six retrospective controlled studies and two case reports. These biological tests assessed can be classified as: (i) proven to be effective at diagnosing LB and already in use (CXCL-13 for neuroborreliosis), but not enough to be standardized; (ii) not yet used routinely, requiring further clinical evaluation (CCL-19, OspA and interferon-α); (iii) uncertain LB diagnostic efficacy because of controversial results and/or poor methodological quality of studies evaluating them (lymphocyte transformation test, interferon-γ, ELISPOT); (iv) unacceptably low sensitivity and/or specificity (CD57+ natural killer cells and rapid diagnostic tests); and (v) possible only for research purposes (microscopy and xenodiagnoses).
QUADAS-2 quality assessment demonstrated high risk of bias in 25/40 studies and uncertainty regarding applicability for 32/40, showing that in addition to PCR and serology, several other LB diagnostic assays have been developed but their sensitivities and specificities are heterogeneous and/or under-evaluated or unassessed. More studies are warranted to evaluate their performance parameters. The development of active infection biomarkers would greatly advance LB diagnosis and monitoring.
The CDKL5 gene has been implicated in the molecular etiology of early‐onset intractable seizures with infantile spasms (IS), severe hypotonia and atypical Rett syndrome (RTT) features. So far, 48 ...deleterious alleles have been reported in the literature. We screened the CDKL5 gene in a cohort of 177 patients with early‐onset seizures, including 30 men and 10 girls with Aicardi syndrome. The screening was negative for all men as well as for women with Aicardi syndrome, excluding the CDKL5 gene as a candidate for this neurodevelopmental disorder. We report 11 additional de novo mutations in CDKL5 in female patients. For the first time, the MLPA approach allowed the identification of a partial deletion encompassing the promoter and the first two exons of CDKL5. The 10‐point mutations consist of five missenses (with recurrent amino acid changes at p.Ala40 and p.Arg178), four splicing variants and a 1‐base pair duplication. We present a review of all mutated alleles published in the literature. In our study, the overall frequency of mutations in CDKL5 in women with early‐onset seizures is around 8.6%, a result comparable with previous reports. Noteworthy, the CDKL5 mutation rate is high (28%) in women with early‐onset seizures and IS.
The 13 subtypes of oral–facial–digital syndrome (OFDS) belong to the heterogeneous group of ciliopathies. Disease‐causing genes encode for centrosomal proteins, components of the transition zone or ...proteins implicated in ciliary signaling. A unique consanguineous family presenting with an unclassified OFDS with skeletal dysplasia and brachymesophalangia was explored. Homozygosity mapping and exome sequencing led to the identification of a homozygous mutation in IFT57, which encodes a protein implicated in ciliary transport. The mutation caused splicing anomalies with reduced expression of the wild‐type transcript and protein. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects' fibroblasts compared with controls. Sanger sequencing of IFT57 in 13 OFDS subjects and 12 subjects with Ellis–Van Creveld syndrome was negative. This report identifies the implication of IFT57 in human pathology and highlights the first description of a ciliary transport defect in OFDS, extending the genetic heterogeneity of this subgroup of ciliopathies.
Assessing disease activity in patients suffering from autoimmune diseases is complex. Symptoms are multiple, often subjective and there are no reliable biomarkers. Many activity scores have been ...implemented to compare treatment efficacy in clinical trials. Their use in clinical practice is largely unknown. We performed a practical survey to analyze the use of activity scores in clinical practice to consider treatment response and to assess the determinants of their use.
A sample of French internists answered a questionnaire about activity scores of systemic lupus erythematosus, Sjögren's syndrome, autoimmune myositis and necrotizing vasculitis of small vessels. The frequency of use of these tools, the causes of their non-use, and the general opinion of practitioners about the place of theses scores in current practice were described.
The form was completed by 92 internists. Seventy percent of them supported the use of activity scores in consultations, but actually used them in less than 25% of patient visits. The reasons for the low use of these scores are mainly the ignorance of their existence (42%) and their length or complexity (28%).
The discrepancy between the ratio of practitioners who believe that scores have a place in daily practice and their actual use shows that the current scores do not meet the needs. The implementation of easily usable activity scores in inflammatory diseases remains a challenge for the internists.
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