Mortality in French people with polyhandicap/profound intellectual and multiple disabilities.

BACKGROUND: In recent decades, progress has been made in the care of people with polyhandicap/profound intellectual and multiple disabilities (PIMD) through a better understanding of the pathophysiology and the development of new care management and rehabilitation strategies adapted to these extreme pathologies. Although there is a lack of knowledge about the health status and care management of the oldest people, a better understanding of the natural course of life of people with polyhandicap/PIMD would consequently allow the optimisation of preventive and curative care management strategies. Few robust data on mortality and life expectancy have been documented for this population in France. Our aims are to estimate the median survival time and assess the factors associated with mortality in people with polyhandicap/PIMD receiving care in France. METHODS: This study included people with polyhandicap/PIMD, followed by the French national cohort 'Eval-PLH' since 2015. These individuals were included in specialised rehabilitation centres and residential institutions. The people included in the first wave of the cohort (2015-2016) were eligible for the present study. Vital status on 1 January 2022 (censoring date) was collected in two ways: (1) spontaneous reporting by the participating centre to the coordinating team and (2) systematic checking on the French national death platform. According to the vital status, survival was calculated in years from the date of birth to the date of death or from the date of birth to the censoring date. The factors associated with mortality were evaluated using the Cox proportional regression hazards model. RESULTS: Data from 780 individuals aged between 3 and 67 years were analysed. At the censoring date, 176 (22.6%) had died, and the mean survival was 52.8 years (95% confidence interval: 51.1-54.5). Mortality was significantly associated with a progressive aetiology, recurrent pulmonary infections, drug-resistant epilepsy and a higher number of medical devices. CONCLUSIONS: This study shows for the first time the survival and impact of factors associated with mortality in people with polyhandicap/PIMD in France.

Clinical characteristics of COVID-19 infection in polyhandicapped persons in France.

AIM: Little is known about the clinical profile of COVID-19 infection in polyhandicapped persons. This study aimed to describe the characteristics of this infection among individuals with polyhandicap. METHOD: This was a retrospective observational study. Polyhandicap was defined by the combination of motor deficiency, profound mental retardation, and age at onset of cerebral lesion younger than 6 years. A positive COVID-19 status was considered for patients with a positive COVID-19 laboratory test result, or patients presenting with compatible symptoms and living in an institution or at home with other patients or relatives who had laboratory-confirmed COVID-19 infection. Data collection included sociodemographic data, clinical and paraclinical characteristics, as well as the management and treatment for COVID-19 infection. RESULTS: We collected 98 cases, with a sex ratio of 0.98 and a mean age of 38.5 years (3 months to 73 years). COVID-19 infection was paucisymptomatic in 46% of patients, 20.6% of patients presented with dyspnea, while the most frequent extra-respiratory symptoms were digestive (26.5%) and neurological changes (24.5%); 18 patients required hospital admission, four adults died. The mean duration of infection was longer for adults than for children, and the proportion of taste and smell disorders was higher in older patients. CONCLUSION: These findings suggest that PLH persons often develop paucisymptomatic forms of COVID-19 infection, although they may also experience severe outcomes, including death. Clinicians should be aware that COVID-19 symptoms in PLH persons are often extra-respiratory signs, mostly digestive and neurologic, which may help in the earlier identification of COVID-19 infection in this particular population of patients.

Development and initial validation of the polyhandicap severity scale.

OBJECTIVES: Providing a new tool, based on the point of view of experts in polyhandicap, which assesses the global severity of the health status of polyhandicapped persons is necessary. We present herein the initial validation of the polyhandicap severity scale (PSS). METHODS: The initial development of the tool was undertaken in two steps: item selection and validation process. The final set included 10 items related to abilities and 17 items related to comorbidities and impairments. The patient selection criteria were as follows: age>3 years, age at onset of cerebral lesion under 3 years old, with a combination of motor deficiency and profound intellectual impairment, associated with restricted mobility and everyday life dependence. External validity, reproducibility (20 patients), responsiveness (38 patients), and acceptability were explored. RESULTS: During the 18-month study period, a total of 875 patients were included. Two scores were calculated: an abilities score and a comorbidities/impairments score (higher score, higher severity). The 2 scores were higher for: older patients, patients with a progressive etiology, patients with more devices and more medications, patients with higher dependency and lower mobility. Indicators of reproducibility and responsiveness were satisfactory. The mean time duration of fulfilling was 22minutes (standard deviation 5). CONCLUSIONS: Quantifying the health severity of polyhandicapped persons is necessary for both healthcare workers and health decision makers. The polyhandicap severity scale provides the first reliable and valid measure of the health severity status for children and adults.

Health issues in polyhandicapped patients according to age: Results of a large French cross-sectional study.

INTRODUCTION: A better understanding of the natural course of the health status of patients with polyhandicap may optimize preventive and curative care management. From a large sample of patients aged from 3 to 25 years, we reported the description of their health status. METHODS: This was an 18-month cross-sectional study including patients aged from 3 to 25 years with a combination of severe motor deficiency and profound intellectual impairment. The patients were recruited from 4 specialized rehabilitation centers, 9 residential facilities, and a pediatric/neurological department. The following data were collected: polyhandicap etiology, health status (impairments, comorbidities, and neurodevelopmental status), medical devices, and rehabilitation procedures. RESULTS: A total of 545 patients were included (n=80 [3-5 years], n=166 [6-11 y], n=155 [12-17 y], and n=144 [18-25 y]). The etiology of polyhandicap was unknown for 11.5% of the cases. Behavioral disorders and (orthopedic and digestive) comorbidities were more frequent in the oldest age classes. The neurodevelopmental status of the patients was close to those of a 5- to 7-month-old child without progression across age. Gastrostomy was the most frequent device needed by the patients. DISCUSSION/CONCLUSION: Early detection and management of impairments and comorbidities may improve the disease course of the patients.

Health characteristics and health care trajectory of polyhandicaped person before and after 1990.

INTRODUCTION: Polyhandicap is defined as the combination of severe mental impairment and severe motor deficit resulting in reduced mobility and an extreme reduction in autonomy. Over the last 20years, care management for these patients has become more structured, however, their care pathway is not always optimal. OBJECTIVE: To describe/compare the health characteristics, treatment and history of the care pathways of subjects who received care before and after 1990. METHOD: Multicentre cross-sectional study, population studied: patients with polyhandicap: (i) causal brain damage<3years, (ii) severe mental impairment, (iii) motor disability, (iv) reduced mobility, (v) extreme restriction of autonomy. DATA COLLECTED: clinical and medical, care procedures, treatments, history of care pathways. RESULTS: Patients are divided into 2 groups: 545 patients who received care after 1990 and 330 before 1990. Older patients present more recurrent urinary infections, slow transit, behavioural disorders and pain, and are prescribed a greater number of drugs. For those who received care before 1990, the age of admission to an establishment is lower, with one-third receiving a consultation dedicated to the transition from paediatric to adult teams. DISCUSSION/CONCLUSION: The care sector for patients with polyhandicap makes it possible to meet their needs throughout their lives, however, there is still progress to be made in terms of formalisation and of coordinating the care pathway in order to facilitate the transition from paediatric to adult services/establishments.

Monoamine neurotransmitters and movement disorders in children and adults.

Neurotransmitter disorders comprise a rapidly expanding phenotypically and genetically heterogeneous group. Most of these disorders start in infancy through to childhood, although some forms may arise in adolescence and adulthood, and have various presentations. They may be overlooked if the phenotype leads to misdiagnoses involving various combinations of developmental disorders, hypotonia and movement disorders (dystonia, hyperkinesia, parkinsonism) or other clinical manifestations, such as sleep alterations and mood disorders. Neurotransmitter metabolite levels in cerebrospinal fluid (CSF) may help us to analyze and better understand the metabolic cascade and changes in dopamine and serotonin synthesis, and also guide genetic testing. Indeed, it is important to recognize these disorders in their early stages as they can be greatly improved by drug treatments, and if clinical responses are insufficient, then other agents that may enhance neurotransmission, such as serotonergic drugs and tetrahydrobiopterin (BH4) supplementation, could be considered. Also, a precise genetic diagnosis should be established by gene panels for dystonia, SNP microarrays and whole-exome sequencing. The present brief survey aims to review the present state of the art for the most commonly described and rare disorders of dopamine and serotonin, as well as cofactor deficiencies and dysfunctions, with an overview of clinical features, diagnostic strategies and treatments. Moreover, although these are mainly disorders of infants and children, many may nevertheless reach adulthood; thus, their evolution and treatments should be well known not only by pediatricians, but by neurologists as well, as the latter may be in charge at the stage of diagnosis (rarely) and during the follow-up of these rare patients.

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients.

Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.

The Discrepancy between Performance-Based Measures and Questionnaires when Assessing Clinical Outcomes and Quality of Life in Pediatric Patients with Neurological Disorders.

In clinical outcome assessment, the relation between performance-based measures and questionnaire ratings of the same domain is weak, but correlations between questionnaires proposed for the evaluation of different domains are strong. The present study aims to illustrate these phenomena in a group of patients with neurofibromatosis type 1 (NF1) and to propose an explanatory hypothesis. A single neuropsychologist interviewed the parents about the child's situation and current difficulties and then assessed this parental view as overall positive or overall negative. The same assessor then administered the Wechsler Intelligence Scales and neuropsychological tests to 78 children and adolescents with NF1 (5-18 years). Parents then completed the Child Behavioral Checklist (CBCL), the Conners' Parent Rating Scale, the Behavior Rating Inventory of Executive Function (BRIEF), as well as questionnaires assessing quality of life, impact of the medical disorder, and their own difficulties. All questionnaires were inter-correlated (r = 0.29 - 0.84) and associated with the overall positive or negative parental view of the child's progress (effect size = 0.41-1.46). Conversely, questionnaires were weakly or not significantly related to intelligence, cognitive measures, or clinical severity. In conclusion, the parental view of the child's progress was related to the answers to questionnaires assessing quality of life or strengths and difficulties of patients with a neurological disorder. This factor should be assessed independently and taken into account when assessing clinical outcome.

Neuropsychological evaluation and parental assessment of behavioral and motor difficulties in children with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant multisystem disorder, with large inter and intrafamilial clinical variability and uncertain prognosis. In children with NF1 cognitive disorders, learning difficulties and behavioral problems are common. The present study aims to establish the neuropsychological and behavioral profiles of 78 patients with NF1, aged between 5 and 18 years, and to examine the relationship between these profiles and the transmission of NF1 (sporadic vs. familial), clinical manifestations, and environmental factors. We used several questionnaires completed by parents and neuropsychological tests. The results confirmed specific neuropsychological disabilities in children with NF1, especially involving visuospatial and fine motor skills, learning difficulties and behavioral problems. Cognitive difficulties were significantly more frequent in patients with familial than in those with sporadic NF1. All parental questionnaires were correlated with each other, but parental reports were not associated with FSIQ, SES, school status, and clinical manifestations of the disease. Neuropsychological tests were poorly related to parental reports of cognitive and behavioral difficulties.

[Guillain-Barré syndrome in infancy: The importance of electroneuromyography]. / Syndrome de Guillain-Barré chez le nourrisson: importance de l'électro-neuromyographie.

Guillain-Barré Syndrome (GBS) is rare in infancy, and the diagnosis of atypical forms is difficult in this age range. The main differential diagnoses include congenital neuropathy. Biological and electrophysiological investigations remain important to confirm diagnosis and start treatment quickly. We report the case of an 8-month-old boy who presented with acquired hypotonia due to progressive descending limb paralysis, predominant in the upper limbs, associated with unexplained severe neutropenia. GBS was diagnosed thanks to the association of albuminocytologic dissociation on cerebrospinal fluid and demyelinating sensomotor polyradiculoneuropathy on electroneuromyography. Only one cycle of treatment with intravenous immunoglobulins was sufficient to achieve complete recovery after 1 year. Physicians should know that atypical forms of GBS exist in infants, in order to recognize the syndrome, rule out differential diagnoses, and start treatment as soon as possible. Medical follow-up remains important before and after remission, especially in infants, to identify relapses, which might be the symptom of a genetic neuropathy or a chronic inflammatory disease.

Advances in the metabolic profiling of acidic compounds in children's urines achieved by comprehensive two-dimensional gas chromatography.

The main objective of this work was to evaluate a comprehensive two-dimensional gas chromatographic (GCxGC) coupled to quadrupole mass spectrometry (qMS) method in the field of biomarker candidates' discovery. To this purpose we developed a GCxGC-qMS method suitable for the separation of organic acids and other classes of compounds with silylable polar hydrogen such as sugars, amino-acids, and vitamins. As compared to those obtained by a widely used 1D-GC method, the urinary chromatographic profiles performed by the proposed 2D-GC method exhibit higher resolution and sensitivity, leading to the detection of up to 92 additional compounds in some urine samples including some well-known biomarkers. In order to validate the proposed method we focused on three metabolites of interest with various functional groups and polarities including CH3-malonic acid (MMA: biomarker of methylmalonic acidemia), 3-hydroxy-3-methyl-glutaric acid (3-OHMGA: biomarker of 3-hydroxy-3-methylglutaric acidemia), and phenylpiruvic acid (PhPA: marker of phenylketonuria). While these three metabolites can be considered as representative of organic acids classically determined by 1D-GC, they cannot be representative of new detected metabolites. Thus, we also focused on quinolic acid (QUIN), taken as an example of biomarker not detected at basal levels with the classical 1D GC-qMS method. In order to obtain sufficient recoveries for all tested compounds, we developed a sample preparation protocol including a step of urea removal followed by two extraction steps using two solvents of different polarity and selectivity. Recoveries with the proposed method reached more than 80% for all targeted compounds and the linearity was satisfactory up to 50µmol/L. The CVs of the within-run and within-laboratory precisions were less than 8% for all tested compounds. The limits of quantification (LOQs) were 0.6µmol/L for MMA, 0.4µmol/L for 3-OHMGA, 0.7µmol/L for PhPA, and 1µmol/L for QUIN. The LOQs of these metabolites obtained by a classical GC-MS method under the same chromatographic conditions were 5µmol/L for MMA, 4µmol/L for 3-OHMGA, 6µmol/L for PhPA while QUIN was below the limit of detection. As compared to 1D-GC, these results highlight the enhanced detectability of urine metabolites by the 2D-GC technique. Our results also show that for each new detected compound it is necessary to develop and validate an appropriate sample preparation procedure.

[A difficult transition from childhood to adult healthcare: the case of epilepsy]. / Le difficile passage à l'âge adulte en matière de soins : l'exemple de l'épilepsie.

OBJECTIVE: The purpose of this study was to analyze modalities of the transition from pediatric to adult epilepsy care and patients' acquisition of autonomy. METHOD: This study was conducted using semidirected interviews composed of three major parts: the patient's criteria of transition toward adult healthcare (factors taken into account, anticipation, the patient's opinion, etc.), conditions (teamwork with the neurologists, transmission of the medical record, continuity of health care, etc.), and the role played by social workers and psychologists. We interviewed 10 doctors belonging to six major Parisian hospital units involved in the monitoring of children and adolescents with epilepsy and working in Pediatric Neurology Departments of the Île-de-France region. RESULTS: For most of the doctors, reaching 18 years of age was the major argument taken into account to consider transition to adult care. According to the doctors interviewed, parents are generally worried when their child has to find another doctor (7/10). According to eight out of 10 doctors, the neurologist is selected to take over. The doctors recognize the importance of psychologists and social workers even if they are not always included. The process by which the patient gains autonomy depends a great deal on the role played by the pediatricians and parents, although some parents are very protective. This behavior weakens the patient's capacity for autonomy and it varies according to the degree of his or her physical and/or neurological disabilities. Furthermore, developing autonomy requires interdisciplinary work that is not yet fully in place. CONCLUSION: The lack of structures well-adapted to the uniqueness of each patient and the lack of coordination between the various institutions do not favor the acquisition of autonomy. A network that could efficiently respond to the needs of epileptic patients as well as medical care tailored to adolescents would be the answer to this dilemma.

Multiple congenital anomalies in two boys with mutation in HCFC1 and cobalamin disorder.

The cobalamin type C deficiency is a rare condition that results from impaired biosynthesis of both methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). Hemizygous mutations of the HCFC1 gene explain the majority of clinically and biologically compatible cblC patients without MMACHC mutations (OMIM 309541). We report a family with two maternal half-brothers with multiple congenital anomalies and HCFC1 gene mutation in the second Kelch domain. Both presented with dysmorphic features (flat profile, cleft lip for one), increased nuchal translucency, prenatal onset microcephaly and hypospadias. Additionally to early onset intractable epilepsy and profound neurocognitive impairment, this familial observation suggests that HCFC1 gene should be considered in boys with midline malformations, even without proven cobalamin C deficiency.

GLUT1 deficiency syndrome: an update.

INTRODUCTION: Glucose transporter type 1 deficiency syndrome is caused by heterozygous, mostly de novo, mutations in the SLC2A1 gene encoding the glucose transporter GLUT1. Mutations in this gene limit brain glucose availability and lead to cerebral energy deficiency. STATE OF THE ART: The phenotype is characterized by the variable association of mental retardation, acquired microcephaly, complex motor disorders, and paroxysmal manifestations including seizures and non-epileptic paroxysmal episodes. Clinical severity varies from mild motor dysfunction to severe neurological disability. In patients with mild phenotypes, paroxysmal manifestations may be the sole manifestations of the disease. In particular, the diagnosis should be considered in patients with paroxysmal exercise-induced dyskinesia or with early-onset generalized epilepsy. Low CSF level of glucose, relative to blood level, is the best biochemical clue to the diagnosis although not constantly found. Molecular analysis of the SLC2A1 gene confirms the diagnosis. Ketogenic diet is the cornerstone of the treatment and implicates a close monitoring by a multidisciplinary team including trained dieticians. Non-specific drugs may be used as add-on symptomatic treatments but their effects are often disappointing. CONCLUSION: Glucose transporter type 1 deficiency syndrome is likely under diagnosed due to its complex and pleiotropic phenotype. Proper identification of the affected patients is important for clinical practice since the disease is treatable.

[Diagnostic investigations for an unexplained developmental disability]. / Stratégie d'exploration d'une déficience intellectuelle inexpliquée.

Developmental disability/mental retardation is a major public health problem and a common cause of consultation in pediatrics, neuropediatrics, and genetics. Etiologies of mental retardation are highly heterogeneous. Diagnostic strategies have been explored in a small number of consensus publications, essentially from English-speaking countries. In these publications, the utility of the conventional karyotype, fragile X screening, metabolic workup, and brain imaging were discussed. Recently, investigations in mental disabilities have been dramatically modified by molecular cytogenetics and the emergence of new metabolic pathologies. Based on the published experiments, the Reference centers for rare disease network "mental deficiencies with rare causes" elaborated an updated protocol for the investigation of nonsyndromal mental disability that takes into account recent innovations in genetics and genomics. Whenever local facilities make it possible, we recommend array CGH investigation as the first step or, when CGH is not available, a combination of classic karyotype with systematic screening of telomeric and interstitial rearrangements by MLPA, fragile X screening in both sexes, and a reorientation of metabolic screening toward certain diseases that have recently been described: congenital disorders of glycosylation (CDG), thyroid hormone carrier deficiency, and creatine metabolism deficiency. We recommend MRI imaging only if head size is abnormal, if neurological examination is abnormal, or regression occurs if walking is not achieved by 2 years, or if development is severely delayed.

Correlation between pre- and postnatal cerebral magnetic resonance imaging.

OBJECTIVES: To evaluate the diagnostic accuracy of fetal cerebral magnetic resonance imaging (MRI) on a large cohort and to compare pre- and postnatal MRI data. METHODS: This prospective study included all cases referred to our unit for fetal cerebral MRI examination between June 2006 and December 2009 and which underwent at least one postnatal MRI examination. Cases in which there was termination of pregnancy, fetal death or stillbirth were excluded. The pre- and postnatal diagnoses established by MRI were compared and divided into five subgroups: same diagnosis on pre- and postnatal MRI (Group 1); same diagnosis but different appearance related to the natural course of the disease (Group 2); different diagnosis (related to limitations of fetal MRI) (Group 3); same diagnosis but with additional findings discovered on postnatal MRI examination (Group 4); or same diagnosis but different appearance related to the natural course of the disease (as in Group 2) and associated with additional findings discovered on postnatal MRI examination (Group 5). The prognostic impact of a possible disagreement between pre- and postnatal findings was evaluated. RESULTS: One hundred fetuses were included. Fetal MRI was performed at a mean gestational age of 33 (range, 24-39) weeks and postnatal MRI at a mean age of 3.5 months. There were 53 cases classified as Group 1, 32 in Group 2, four in Group 3, 10 in Group 4 and one in Group 5. Thus, in 15 cases (Groups 3-5), there were discrepancies between pre- and postnatal findings (mostly related to corpus callosum anatomy, cortical and migration disorders). The discrepancy was judged to have a prognostic impact in 9/15 cases. Two postnatal MRI examinations were performed in eight cases, in one of which the second examination showed subependymal heterotopia which were not detectable on the first examination. CONCLUSION: Pre- and postnatal MRI data showed good agreement in 85% of cases. There was disagreement with a prognostic impact in 9% of cases.

Severe neonatal episodic laryngospasm due to de novo SCN4A mutations: a new treatable disorder.

BACKGROUND: Myotonia is unusual in infants, and not well-known. METHODS: We describe neonatal life-threatening features of myotonia caused by de novo mutations in the muscle sodium channel gene SCN4A. RESULTS: Three male neonates initially displayed episodic laryngospasms, with face and limb myotonia appearing later. We found SCN4A de novo mutations in these neonates: p.Gly1306Glu in 2 unrelated cases and a novel mutation p.Ala799Ser in the third. Two patients survived their respiratory attacks and were efficiently treated by sodium channel blockers (mexiletine, carbamazepine) following diagnosis of myotonia. CONCLUSION: Severe neonatal episodic laryngospasm is a new phenotype caused by a sodium channelopathy, which can be alleviated by channel blockers.