Neuropsychological Disorders in Moderate Hyperphenylalaninemia: Literature Review.

Moderate hyperphenylalaninemia (mHPA) is a hydroxylase deficiency corresponding to phenylalanine levels, at newborn screening, below 360 µmol/l. The neurological impact of mHPA is usually considered to be very low, but few studies have investigated the neuropsychological profile of mHPA patients.A systematic review of the neuropsychological aspects of mHPA was therefore conducted.The results showed a preservation of cognitive functions (intelligence, memory, visuoperception…). However, several indicators point to executive difficulties in this population. In regard to the important impact of executive functions in daily life, it is essential to conduct other studies in mHPA patients by proposing an integrative approach.

A rare chest tumor in a 7-year old girl with a neurodegenerative disease.

We report the case of a 7-year-old girl with a history of San Filippo disease who presented with gingivitis and painful chest tumefaction. Microbiology of this tumefaction identified Aggregatibacter actinomycetemcomitans (AA), a slowly growing, commensal, Gram negative bacillus that is a very unusual cause of thoracic infection. We discuss this case in the light of available literature of pediatric cases of AA thoracic infection. Conclusion: a tumor-like chest mass in a patient with multiple disabilities should evoke an invasive AA infection.

Use of a book to disclose a diagnosis of Duchenne muscular dystrophy to a young child: A pilot study.

Disclosing the diagnosis of Duchenne muscular dystrophy, a progressive genetic disease, to children requires taking the time to talk with them and to identify the emotions that they experience on a daily basis. At the Reference Center for Neuromuscular Diseases of Children in Marseille, to accompany the disclosure of the diagnosis to the child, we have created a book to facilitate communication and dialog in the parent-child relationship. A single-center and prospective study was conducted of nine children and nine families to evaluate the usefulness of this tool. The results show that the book was appreciated by families and mainly recommended by children and their parents. Children's understanding of the disease improved, especially for the 6-8-year-old age group. The children's mental state was better at school after using the tool. The book offered them support to express their mood. As an accompaniment, this mediator tool helps parents and children alike. Caregivers use it as a support for the children to have a place to share their thoughts and emotions, from the very beginning of the follow-up. It helps build the child-parent-caregiver triad.

Pediatric hospital care organization: Cross-sectional enquiry in four regions in France.

OBJECTIVE: The aim of this study was to characterize conventional pediatric care capacities in French public hospitals and identify the main difficulties in guiding upcoming health policies. The secondary objective was to assess the quality of care by the implementation of the European Charter of the Rights of Children in Hospital. METHOD: Multicenter cross-sectional study using a questionnaire survey sent by e-mail to the heads of conventional pediatric departments in four French regions identified on the French Hospital Federation's website. The survey was conducted between 25 September and 25 October 2018. RESULTS: Fifty-six of 113 heads of departments participated in the survey. The mean annual number of admissions per unit in 2017 was 2066 (SD, 1433), with a median length of stay of 2.7 days (range, 1-10). Children were admitted up to age 18 years in 76% of the departments, and 83% of the departments had an individualized pediatric emergency department. The nurse care load was very high, specifically during the night shift (9.5 patients/nurse). Inpatient education and academic teaching were unavailable in 38% of the departments. Overall, 89% of department heads declared knowing the European Charter of the Rights of Children in Hospital, and a copy of it was posted in all units in 57% (95% confidence interval, 44-70) of the services/departments. At all times and in all departments, parents were allowed to be with their children, and for 34% (95% CI, 21-47) of the departments, an accommodation for parents was available close to the hospital. CONCLUSION: Public hospital pediatric departments lack sufficient medical and nonmedical caregivers. Department heads were well aware of the European Charter, and it was well disseminated but should be updated to address today's challenges in pediatrics. An area of improvement would be to include parents in their child's care more effectively.

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.

New ethical challenges in the management of rare pediatric diseases with innovative therapies.

INTRODUCTION: Rare diseases, despite their low individual prevalence, affect a large number of children. Their management has considerably improved recently due to new treatments, modifying the diseases evolution without being totally curative. Since this raises many ethical dilemmas, we present a study about respecting the principles of medical ethics in the management of rare diseases in pediatrics. MATERIAL AND METHODS: We carried out a qualitative study in a French pediatric neurology department. In our study, we included health caregivers and parents of children being monitored for rare diseases and benefiting from innovative therapies. We conducted semi-structured interviews and, after transcription, we performed computerized and manual analysis. RESULTS: A total of 26 participants were included. Six main themes were addressed: rare diseases, science and medical research, general disease management, specific innovative treatments, neonatal screening, and cost of these treatments. Discussions centered on the children. Particular importance was given to the notions of information and the physician/family relationship. A major place is given to the treatment objectives and the improvement of quality of life. We also noted a sense of satisfaction with the current overall management of these diseases. CONCLUSION: Our study suggests that our current practice, including the use of innovative therapies, respects the four main ethical principles, from the points of view of both caregivers and parents.

The phenotype caused by recessive variations in SLC25A22: Report of a new case and literature review.

We describe the clinical, electroencephalography (EEG), and developmental features of a patient with developmental and epileptic encephalopathy due to a homozygous pathogenic variation of mitochondrial glutamate/H+ symporter SLC25A22. Epilepsy began during the first week of life with focal onset seizures. Interictal EEG revealed a suppression-burst pattern with extensive periods of non-activity. The prospective follow-up confirmed developmental encephalopathy as well as ongoing active epilepsy and almost no sign of development at 8 years of age. We confirm in the following paper that SLC25A22 recessive variations may cause a severe developmental and epileptic encephalopathy characterized by a suppression-burst pattern. On the basis of an in-depth literature review, we also provide an overview of this rare genetic cause of neonatal onset epilepsy.

Clinical phenotype associated with TANGO2 gene mutation.

The clinical picture associated with a Transport and Golgi Organization 2 (TANGO2) gene bi-allelic mutation is represented by encephalopathy and rhabdomyolysis marked by cardiac rhythm disorders and neurological regression. The presentation of encephalopathy is diverse and can range from isolated language delay and cognitive impairment in a child to multiple disabilities and spastic quadriparesis. Hypothyroidism has also been frequently reported. This article presents the clinical phenotype of seven children with a TANGO2 bi-allelic mutation. The mutation was found by sequencing a panel of genes associated with rhabdomyolysis. While the clinical picture represents generalized cases, there is phenotypic variability in, for example, the degree of disability for each patient. A TANGO2 gene mutation, nevertheless, represents a serious illness with a limited life expectancy due to an unpredictable risk of cardiac rhythm disorder and death, particularly during rhabdomyolysis. Although the natural history of the disease presents an evolution of rhabdomyolysis triggered by infections or effort, an early diagnosis is difficult due in part to the fact that there is a lack of specific biochemical marker or identifying symptoms in the early presentation of the disease. Clinicians must therefore consider the TANGO2 gene when confronted with rhabdomyolysis in a patient suffering from an early developmental disorder. In the meantime, management of the disease remains purely symptomatic.

Ethical aspects in the care of a child with infantile spinal muscular atrophy (SMA).

The pediatrician has a privileged relationship with a child with infantile spinal muscular atrophy (SMA). At all times, he/she must be the child's mentor, promoting a comprehensive approach and support in order to ensure the best possible solution for the patient's autonomy. In all circumstances, an ethical stance is essential. After a reminder on the notions of ethics of care, we will address various ethical questions encountered through three critical situations during the care of a child with infantile spinal muscular atrophy: the announcement of the diagnosis, the transmission of information on innovative therapies, and palliative care and end-of-life support. © 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Pediatric emergency room visits for neurological conditions: Description and use of pediatric neurologist advice.

INTRODUCTION AND OBJECTIVE: Information on the spectrum and frequencies of pediatric neurological presentations to emergency departments is vital to optimize quality of care. The objective of this study was to determine the incidence of pediatric neurological emergencies and to analyze the impact of specialist neurological advice in emergency care. PATIENTS AND METHODS: We performed a retrospective descriptive study of pediatric emergency room visits for neurological reasons at the Timone University Hospital in Marseille over a 6-month period (from October 2017 to March 2018). RESULTS: Of the 14,572 emergencies analyzed, 370 (2.5%) were for neurological conditions. These were most commonly seizures (56.7% of cases), headache (19.7%), and motor or sensory deficits (5.1%). The most frequent diagnosis was epileptic seizure (30%), followed by febrile seizure (26.1%) and migraine (15%). Around two in every five patients (37.6%) required hospitalization. Neurological emergencies requiring critical care occurred at a frequency of about one per month (1.6% of cases). A pediatric neurologist was consulted in 37.3% of cases, resulting in a modification of the diagnosis or treatment in 66% of these referrals. CONCLUSION: The results of this study suggest that a formal referral system between the emergency department and pediatric neurologists would be useful.

Mutations in NBAS and SCYL1, genetic causes of recurrent liver failure in children: Three case reports and a literature review.

Acute liver failure (ALF) in childhood is a life-threatening emergency. ALF is often caused by drug toxicity, autoimmune hepatitis, inherited metabolic diseases, and infections. However, despite thorough investigations, a cause cannot be determined in approximately 50% of cases. Here, we report three cases with recurrent ALF caused by NBAS and SCYL1 pathogenic variants. These patients did not present with any other phenotypic sign usually associated with NBAS and SCYL1 pathogenic variants. Two of them underwent liver transplantation and are healthy without recurrence of ALF. We propose NBAS and SCYL1 genetic analysis in children with unexplained fever-triggered recurrent ALF even without a typical phenotype.

Transition from paediatric to adult care in adolescents with neurological diseases and handicap.

The transfer of adolescents from paediatric care to adult health facilities is often difficult for the patients and their families and can lead to a breakdown in medical follow-up and therefore serious complications. Existing recommendations for the successful transition of patients with chronic disorders do not specifically address patients with handicap. Preparations for the transfer must be made well in advance. They must aim to achieve the autonomisation of adolescents by making them responsible and providing them with the knowledge that will enable them to manage their care themselves, the know-how to react appropriately if there is any change in their condition, and to move comfortably within the adult health system. This requires the active participation of the patient, his or her family and the paediatric and adult care teams. It involves multidisciplinary management plus the production and maintenance of an educational therapy programme. Finally, the identification of doctors trained in handicap, relevant sub-specialists and even expert patients could enable improvements in the continuum of complete and appropriate care for these patients within adult medicine.

Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is a hereditary sensory-motor neuropathy characterized by a strong clinical and genetic heterogeneity. Over the past few years, with the occurrence of whole-exome sequencing (WES) or whole-genome sequencing (WGS), the molecular diagnosis rate has been improved by allowing the screening of more than 80 genes at one time. In CMT, except the recurrent PMP22 duplication accounting for about 60% of pathogenic variations, pathogenic copy number variations (CNVs) are rarely reported and only a few studies screening specifically CNVs have been performed. The aim of the present study was to screen for CNVs in the most prevalent genes associated with CMT in a cohort of 200 patients negative for the PMP22 duplication. CNVs were screened using the Exome Depth software on next generation sequencing (NGS) data obtained by targeted capture and sequencing of a panel of 81 CMT associated genes. Deleterious CNVs were identified in four patients (2%), in four genes: GDAP1, LRSAM1, GAN, and FGD4. All CNVs were confirmed by high-resolution oligonucleotide array Comparative Genomic Hybridization (aCGH) and/or quantitative PCR. By identifying four new CNVs in four different genes, we demonstrate that, although they are rare mutational events in CMT, CNVs might contribute significantly to mutational spectrum of Charcot-Marie-Tooth disease and should be searched in routine NGS diagnosis. This strategy increases the molecular diagnosis rate of patients with neuropathy.

The medical and social outcome in 2016 of infants who were victims of shaken baby syndrome between 2005 and 2013.

INTRODUCTION: There are few studies that have investigated the long-term outcome of children who have been victims of shaken baby syndrome (SBS). However, the consequences appear to be significant and the data available from a social point of view are scarce. The main objective of this study was to define the medical and social outcome in 2016 of the infants who were victims of SBS and admitted to one of the Marseille university hospitals. The number of patients followed by a specialized team was evaluated along with their clinical state, living conditions, and whether a social support system such as the Child welfare system had been put into place. METHOD: The study was retrospective and descriptive. Patients under 1 year of age who were hospitalized between January 2005 and December 2013 and manifested clinical and paraclinical characteristics enabling the diagnosis of SBS were included in the study. The diagnosis was certain, probable, or possible according to the definitions given by the consensus of the 2011 shaken baby health authority conference (HAS). RESULTS: Eighty babies qualified for the study, three of whom died in intensive care. Only ten of these patients (12.9%) had regular (annual) neuropediatric check-up during the whole study period. Thirty-seven patients (48%) had an annual neuropediatric check-up during the first 2 years only following the diagnosis. Only 12 of the children (15.6%) were still being followed after the age of 6. The children were followed up on average for 2.5 years (29.6 months). In 24 cases (31%), the last medical visit revealed an abnormal neurological examination including multiple disabilities due to spastic quadriplegia and severe intellectual deficit, which led to total dependency in half of these cases. Forty-four patients (57%) had a normal neurological examination. Concerning the babies' social outcome, 50 patients (64.9%) had returned home, 12 (15.6%) benefited, from educational assistance at the patient's home (AEMO) following the ruling of a children's judge, and 19 (24.7%) were still placed in foster care (ASE). The average foster care placement lasted 34.7 months. DISCUSSION AND CONCLUSION: Long-term medical follow-up for children having sustained serious head injury as a result of abuse is inadequate. Sequelae such as multiple disabilities are less frequent than described in the literature. According to this study, a longer-term follow-up is necessary for children suffering from sequelae such as learning disabilities than what is actually possible in our center.

Retrospective study of 75 children with peripheral inherited neuropathy: Genotype-phenotype correlations.

INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with an impact on patients' quality of life and wide genetic heterogeneity. Next-generation sequencing (NGS) has extended the molecular diagnosis. This study aims to describe a cohort of patients with CMT onset in childhood to explore genotype-phenotype correlations. MATERIAL AND METHODS: This is a retrospective and single-center study. Between 1992 and 2016, patients with CMT diagnosed in childhood and a molecular diagnosis were included. The follow-up was done at the Marseille Timone Teaching hospital and symptoms were retrieved over time in the patients' files, as well as from molecular data and an electrodiagnostic exam. We distinguished three groups: PMP22 compared CMT (CMT1A), MFN2 compared CMT (CMT2A2) and "all genes except PMP22". RESULTS: Seventy-five patients were included with 11 different genes involved, PMP22 being the most frequent (61.3%), then MFN2 (14.7%) and other sporadic mutations in various genes. Limitations in walking tended to occur earlier and more often, and distal strength impairment tended to progress further in CMT2A2 and "others genes than PMP22". The mean age at diagnosis was 8.4 years with a mean age when parents first expressed concern of 4.1 years. Only three patients lost their ability to walk. We describe two cases of digenism and one case of GAN mutation with a CMT-like presentation. An electromyogram was not systemically performed. CONCLUSION: There is a wide genetic and clinical heterogeneity in CMT. We tend to describe more severe patterns in CMT2A2 and less progressive presentations in CMT1A considering distal strength impairment and limitations walking. Prospective studies with more objective principal judgement criteria would be necessary to confirm these observations.

Muscle Shortening and Spastic Cocontraction in Gastrocnemius Medialis and Peroneus Longus in Very Young Hemiparetic Children.

OBJECTIVES: Muscle shortening and spastic cocontraction in ankle plantar flexors may alter gait since early childhood in cerebral palsy (CP). We evaluated gastrosoleus complex (GSC) length, and gastrocnemius medialis (GM) and peroneus longus (PL) activity during swing phase, in very young hemiparetic children with equinovalgus. METHODS: This was an observational, retrospective, and monocentric outpatient study in a pediatric hospital. Ten very young hemiparetic children (age 3 ± 1 yrs) were enrolled. These CP children were assessed for muscle extensibility (Tardieu scale XV1) in GSC (angle of arrest during slow-speed passive ankle dorsiflexion with the knee extended) and monitored for GM and PL electromyography (EMG) during the swing phase of gait. The swing phase was divided into three periods (T1, T2, and T3), in which we measured a cocontraction index (CCI), ratio of the Root Mean Square EMG (RMS-EMG) from each muscle during that period to the peak 500 ms RMS-EMG obtained from voluntary plantar flexion during standing on tiptoes (from several 5-second series, the highest RMS value was computed over 500 ms around the peak). RESULTS: On the paretic side: (i) the mean XV1-GSC was 100° (8°) (median (SD)) versus 106° (3°) on the nonparetic side (p = 0.032, Mann-Whitney); (ii) XV1-GSC diminished with age between ages of 2 and 5 (Spearman, ρ = 0.019); (iii) CCIGM and CCIPL during swing phase were higher than on the nonparetic side (CCIGM, 0.32 (0.20) versus 0.15 (0.09), p < 0.01; CCIPL, 0.52 (0.30) versus 0.24 (0.17), p < 0.01), with an early difference significant for PL from T1 (p = 0.03). CONCLUSIONS: In very young hemiparetic children, the paretic GSC may rapidly shorten in the first years of life. GM and PL cocontraction during swing phase are excessive, which contributes to dynamic equinovalgus. Muscle extensibility (XV1) may have to be monitored and preserved in the first years of life in children with CP. Additional measurements of cocontraction may further help target treatments with botulinum toxin, especially in peroneus longus.

Transition from pediatric to adult care in adolescents with hereditary metabolic diseases: Specific guidelines from the French network for rare inherited metabolic diseases (G2M).

Inherited metabolic diseases (IMD) form a heterogeneous group of genetic disorders that surface primarily during childhood and result in significant morbidity and mortality. A prevalence of 1 in 2500-5000 live births is often reported. The transfer of adolescents from pediatric care to adult health facilities is often difficult for patients and their families and can lead to a breakdown in medical follow-up and therefore serious complications. Existing recommendations for the successful transition of patients with chronic disorders do not specifically address patients with IMDs associated with dietary treatment. Here, the French network for rare inherited metabolic diseases (G2M) presents its reflections and recommendations for a successful transition. Preparations for the transfer must be made well in advance. The transfer must aim for adolescents gaining autonomy by making them responsible and providing them with the knowledge that will enable them to manage their care themselves, know how to react appropriately if there is any change in their condition, and move comfortably within the adult healthcare system. This requires the active participation of the patient, his or her family, and pediatric and adult care teams. It involves multidisciplinary management plus the production and maintenance of an educational therapy program. Finally, the identification of physicians and dietitians trained in IMDs, relevant subspecialists, and even expert patients could improve the continuum of complete and appropriate care for these patients within adult medicine.

Infant botulism: Two case reports and electroneuromyogram findings.

Botulism is an uncommon severe neuromuscular disorder. We report two recent cases of confirmed infant botulism diagnosed in an 11-week and a 5-month-old infant along with electroneuromyogram (ENMG) findings. Then, we discuss the EMG features of infant botulism. In severe forms of infant botulism, presence of these features might help decide to use botulinum immune globulin. To our knowledge, case 1 is the first case reported in France based on confirmed dust contamination.