Summary Objective Mutations in the syntaxin binding protein 1 gene ( STXBP 1 ) have been associated mostly with early onset epileptic encephalopathies ( EOEE s) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography ( EEG ) features associated with STXBP 1 ‐related epilepsies to orient molecular screening. Methods We screened STXBP 1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging ( MRI ) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP 1 found using array comparative genomic hybridization ( CGH ). Results We found a mutation of STXBP 1 in 22 patients and included 2 additional patients with a deletion including STXBP 1 . In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression‐burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. Significance Our data confirm that STXBP 1 mutations are associated with neonatal‐infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG , and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP 1 molecular screening.
A previously healthy French-born 13-month-old ethnically African girl, weighing 10 kg, travelled to Comoros (South-East Africa) on 10 July. Her family history was notable for an autistic brother and two other brothers in good health. Her parents are of African origin and are not related. She was prescribed pyrimethamine, 50 mg once daily (adult dosage), as an antimalaria chemoprophylaxis by her physician prior to this first visit to Comoros. Her parents supervised administration of this medication and stated that she missed no dose. On 23 July, she presented to a clinic in Comoros with hyperthermia and generalized clonic seizures, continuous for the first 5–6 h and then intermittent for 24 h. She was admitted to the intensive care unit in Comoros where she was treated for presumed cerebral malaria with intravenous quinine despite a negative malaria test. During the next 15 days, she had many recurrent crises, with continued confusion and digestive problems. Her fever abated on 31 August. She was brought back to France and hospitalized in the Department of Paediatric Neurology (Hôpital Debrousse-Lyon-France). Search for Plasmodium and other microorganisms in the blood and in cerebral fluid were negative. She was discharged on 5 September with severe persistent neurological deficits. Cerebral magnetic resonance imaging performed on 6 September showed cortical and subcortical atrophy, and electroencephalograms showed the persistence of disturbed basic cortical activity. This adverse event was reported to the Lyon Pharmacovigilance Centre. A computerized prescribing error was suspected because the prescription was not handwritten. The prescribing physician, interviewed by telephone, confirmed that she has used Medigest, a drug management software. The principal indication for pyrimethamine in children is congenital toxoplasmosis, administered at a dose of 1 mg kg−1 day−1. Adverse effects occur with doses >20 mg kg−1 or with a recurrent dose >5 mg kg−1 day−1[1]. Seizures, coma and blindness have been reported [1–5]. Because of the high risk of severe neurological consequences and also Plasmodium resistance, pyrimethamine is no longer appropriate for the chemoprophylaxis of malaria [6]. In this case, the prescribing physician searched the drug management software (Medigest) for the indication of malaria prophylaxis by entering ‘Mal’. When we searched the same computerized system for ‘Mal’, pyrimethamine and atovaquone-proguanil displayed next to each other. We first selected pyrimethamine with a default adult dosage. There was no alert indicating that pyrimethamine is no longer prescribed alone as a chemoprophlaxis for malaria. When the patient’s characteristics and the disease (presumed P. falciparum) were entered we were alerted that ‘the 50 mg tablet is only to be prescribed for adults’. The use of information technology (IT) in routine clinical care has been promoted in Europe and the USA to improve patient safety and practice efficiency [7]. IT has been shown to reduce medical errors and improve the quality of healthcare in certain circumstances [8]. However, error reduction and improved patient safety cannot be achieved if prescribing errors are not addressed [9]. Many computerized order entry programs lack efficient alert systems to avoid overdoses, allergies, drug–drug interactions and contraindications or drugs unlaballed or unauthorized in children. IT solutions should provide physicians with reminders and alerts for evidence-based preventive care and disease management based on patient-specific drug, disease, and therapeutic information [9]. We wish to thank Dr N. R. Shah for reviewing this letter.
The c.429_452dup24 of the ARX gene is a rare genetic anomaly, leading to X-Linked Intellectual Disability without brain malformation. While in certain cases c.429_452dup24 has been associated with specific clinical patterns such as Partington syndrome, the consequence of this mutation has been also often classified as "non-specific Intellectual Disability". The present work aims at a more precise description of the clinical features linked to the c.429_452dup24 mutation. We clinically reviewed all affected patients identified in France over a five-year period, i.e. 27 patients from 12 different families. Detailed cognitive, behavioural, and motor evaluation, as well as standardized videotaped assessments of oro-lingual and gestural praxis, were performed. In a sub-group of 13 ARX patients, kinematic and MRI studies were further accomplished to better characterize the motor impairment prevalent in the ARX patients group. To ensure that data were specific to the ARX gene mutation and did not result from low-cognitive functioning per se, a group of 27 age- and IQ-matched Down syndrome patients served as control. Neuropsychological and motor assessment indicated that the c.429_452dup24 mutation constitutes a recognizable clinical syndrome: ARX patients exhibiting Intellectual Disability, without primary motor impairment, but with a very specific upper limb distal motor apraxia associated with a pathognomonic hand-grip. Patients affected with the so-called Partington syndrome, which involves major hand dystonia and orolingual apraxia, exhibit the most severe symptoms of the disorder. The particular "reach and grip" impairment which was observed in all ARX patients, but not in Down syndrome patients, was further characterized by the kinematic data: (i) loss of preference for the index finger when gripping an object, (ii) major impairment of fourth finger deftness, and (iii) a lack of pronation movements. This lack of distal movement coordination exhibited by ARX patients is associated with the loss of independent digital dexterity and is similar to the distortion of individual finger movements and posture observed in Limb Kinetic Apraxia. These findings suggest that the ARX c.429_452dup24 mutation may be a developmental model for Limb Kinetic Apraxia.
Early screening of children with Autism Spectrum Disorder (ASD) needs to be improved to propose early interventions. Parental questionnaires are useful to help primary care professionals and nurseries to detect children’s autism signs. Our primary objective is to estimate the positive predictive value of an early detection kit composed of 2 parental questionnaires M-CHAT-R/F™ (Modified-CHecklist for Autism in Toddlers-Revised/Follow-up) and CSBS DP™-ITC (Communication and Symbolic Behavior Scales Developmental Profile-Infant Toddler Checklist) followed by a psychologist’s confirmation. Methods and Analysis: Boys and girls aged 16 to 30 months, seen at their general or paediatric practice or attending nurseries or early childcare centers, never diagnosed ASD, are eligible. We plan to have a cohort of 1700 children filling the screening kit and expect to detect about 81 children confirmed positive . We also expect to detect other neurodevelopmental disorders than ASD. Discussion: The use of 2 questionnaires and the intervention of trained psychologists should optimize the access to early detection of ASD near home and links between childhood professionals. Our study is coherent with the French organization and existing tools.
Introduction The TransEAsome project, funded by the Agence Nationale de la Recherche, aims to evaluate the long-term outcomes of patients with oesophageal atresia (OA) between 13 and 14 years old and establish multiomics profiles using data from the world’s biggest OA registry. Methods and analysis TransEAsome is a national multicentre population-based cohort study recruiting participants from all qualified French centres for OA surgery at birth. The primary objective is to assess the prevalence of gastro-oesophageal reflux disease in adolescence among patients with OA, with several secondary objectives including the identification of risk factors and multiomic profiles from oesophageal biopsies and blood samples collected between 13 and 14 years old, compared with a control group. This comprehensive characterisation of phenotype and omic profiles aims to enhance the understanding of disease evolution in patients with OA and inform tailored care management strategies. Ethics and dissemination The study, coconstructed with input from patients, parents and research-expert adolescents, has obtained approval from the ethics research committee: Comité de protection des personnes Est II. Findings will be disseminated to various target audiences, including the scientific community, research participants, the patient community, the general public, regulatory authorities and policymakers. Data will be made available in a Findable, Accessible, Interoperable, Reusable format on the France Cohortes platform on study completion. Trial registration number NCT05995171 :Clinical trial
Background Intellectual Disability (ID) is characterized by deficits in intellectual functions such as reasoning, problem-solving, planning, abstract thinking, judgment, and learning. As new avenues are emerging for treatment of genetically determined ID (such as Down's syndrome or Fragile X syndrome), it is necessary to identify objective reliable and sensitive outcome measures for use in clinical trials. Objective We developed a novel visual analogical reasoning paradigm, inspired by the Progressive Raven's Matrices, but appropriate for Intellectually Disabled patients. This new paradigm assesses reasoning and inhibition abilities in ID patients. Methods We performed behavioural analyses for this task (with a reaction time and error rate analysis, Study 1) in 96 healthy controls (adults and typically developed children older than 4) and 41 genetically determined ID patients (Fragile X syndrome, Down syndrome and ARX mutated patients). In order to establish and quantify the cognitive strategies used to solve the task, we also performed an eye-tracking analysis (Study 2). Results Down syndrome, ARX and Fragile X patients were significantly slower and made significantly more errors than chronological age-matched healthy controls. The effect of inhibition on error rate was greater than the matrix complexity effect in ID patients, opposite to findings in adult healthy controls. Interestingly, ID patients were more impaired by inhibition than mental age-matched healthy controls, but not by the matrix complexity. Eye-tracking analysis made it possible to identify the strategy used by the participants to solve the task. Adult healthy controls used a matrix-based strategy, whereas ID patients used a response-based strategy. Furthermore, etiologic-specific reasoning differences were evidenced between ID patients groups. Conclusion We suggest that this paradigm, appropriate for ID patients and developmental populations as well as adult healthy controls, provides an objective and quantitative assessment of visual analogical reasoning and cognitive inhibition, enabling testing for the effect of pharmacological or behavioural intervention in these specific populations.
Introduction Early screening of children at-risk to develop Autism Spectrum Disorder (ASD) needs to be improved to propose early interventions. This detection should allow diagnosis of ASD before the age of 3. An early screening performed at the general practitioner of the family should facilitate accessibility to diagnosis and a better collaboration between professionals. Objectives Our primary objective is to estimate the positive predictive value of an early detection kit composed of 2 questionnaires (First screening: M-CHAT-R/F™ + CSBS DP™-ITC) and a confirmation of the detection with a phone call by a neuropsychologist. Patients with confirmed positive M-CHAT-R/F™ and/or CSBS DP™-ITC scores are referred to a level 2 team for pre-diagnosis and diagnosis assessment. Methods The KitCAT study is a cohort study of 1,700 children aged 16 to 24 months seen in routine care in general or pediatric practices, or in nurseries and child care centers. Results Seven hundred and five children have already been enrolled in the study. Twenty nine patients, ie 4.1%, (with a confirmed positive M-CHAT-R/F™ and/or CSBS DP™-ITC scores) were referred to a level 2 team where a pre-diagnosis assessment was conducted by using the following test: ADI-R, ADOS 2, BLR, WPPSI-IV and Vineland II. The diagnosis of ASD (using the same test than the pre-diagnosis) was confirmed for the first two patients aged of 3. Conclusions The preliminary results confirm that the use of 2 questionnaires may optimize the reliability of the screening. A thousand children are still needed for the final analysis and further results are expected. Disclosure No significant relationships.
