Congenital stationary night blindness in a patient with mild learning disability due to a compound heterozygous microdeletion of 15q13 and a missense mutation in TRPM1.

The complete form of congenital stationary night blindness (cCSNB) represents a non-progressive retinal disorder characterized by night vision problems and often congenital nystagmus, reduced vision, high myopia, strabismus and normal fundus appearance. Clinically this form of CSNB can be diagnosed by full-field electroretinogram. The mode of inheritance can be X-linked and autosomal recessive with mutations in genes coding for proteins mainly present at the dendritic tips of ON-bipolar cells. Mutations in NYX, GRM6, GPR179, LRIT3 and TRPM1 lead to this condition. The latter gene defect represents the major form underlying cCSNBC. It codes for the melastatin-related transient receptor 1 expressed in the inner nuclear layer of the retina, with the protein localized in ON-bipolar cells. To date, various homozygous or compound heterozygous mutations in TRPM1 have been reported. Small chromosomal rearrangements are frequent cause of mental retardation. In rare cases deletions can overlap with a mutation on the remaining chromosome and lead to a recessive disorder. Here, we describe a patient with mild neurological deficiencies and cCSNB caused by a microdeletion on 15q32 overlapping with a TRPM1 variant.

Assessing assistive technology requirements in children with written language disorders. A decision tree to guide counseling.

Children with a written language disorder are sometimes dependent upon help from others for their schoolwork. A computer can be a way to circumvent this difficulty. Various software programs and plug-in peripheral devices are available, some of which specifically target the needs of these young people. There is no consensus, however, with regard to how best to counsel parents and children with regard to these tools. Furthermore, written language disorders and existing technical supports are not always clearly understood. In many cases, healthcare and teaching professionals have only limited knowledge of the potentially specific advantages for patients with written language disorders. A child's full integration into daily activities and school life can be hampered by counseling that was inadequately tailored or by a lack of support in using this equipment. Joint consultations involving both an occupational and a speech therapist have been set up in our department to improve counseling with regard to technical supports. Using our daily practice as a basis, we have developed a decision tree that we see as a necessary tool for helping professionals make the most appropriate practical choices.

[Mathematical learning disability: A multiple origin? Examples of Turner and Fragile X syndromes]. / Troubles en mathématiques : une origine multiple ? L'exemple des syndromes de Turner et de l'X Fragile.

Problems in mathematics are a frequent major complaint in neuropediatric departments, for which there are two explanatory theoretical models: the hypothesis of a genetic and modular origin (with a number sense deficit) and a multidetermined origin. The purpose of this paper is to review the mathematical difficulties described in Turner syndrome and Fragile X syndrome, because a specific mathematical disorder is usually reported in these populations, supporting the existence of a number sense. Analysis of the literature reveals highly variable cognitive phenotypes in these populations, especially regarding mathematical abilities. Performance heterogeneity might be related to different factors such as the abilities needed to perform the task, the variability of definitions, the different tests used in the studies and the heterogeneity of the syndromes themselves. A number sense deficit is usually described in these syndromes, but variable cognitive impairments are also observed. The idea of a modular functioning is then debated and we argue for the necessity of a global cognitive evaluation approach.

[Evaluating a child after a febrile seizure: Insights on three important issues]. / Évaluation d'un enfant après une crise fébrile : focus sur trois problèmes de pratique clinique.

Febrile seizures (FS) are the most common seizures seen in the paediatric population in the out-of-hospital and emergency department settings, and they account for the majority of seizures seen in children younger than 5 years old. An FS is a seizure accompanied by fever, without central nervous system infection, occurring in children between 6 months and 5 years old. Five criteria have been used and taught to classify any FS as simple or complex FS. These factors do not bear the same significance for clinical practice, in particular, the decision to perform a lumbar puncture for cerebrospinal fluid analysis to rule out an intracranial infection. Moreover, epidemiological studies have illustrated that some factors are predictive of febrile seizure recurrence while others are predictive of epilepsy occurrence. On this basis, a workshop was organized to provide an answer to three clinical practice questions: when should a lumbar puncture be performed in a child who has experienced a seizure during a fever episode, is the prescription of a rescue drug required with a risk of a prolonged febrile seizure recurrence, when should a neurological consultation be requested (risk of later epilepsy)? Based on a review of the literature and on a 1-day workshop, we report here the conclusion of the working group. A lumbar puncture is required in any child with meningitis symptoms or septic signs or behaviour disturbance. A lumbar puncture should be discussed based on the clinical symptoms and their progression over time when a child has experienced a focal FS or repetitive FSs without signs of meningitis or sepsis or behaviour disturbance. The lumbar puncture is not necessary in case of simple FS without signs of meningitis, including in infants between 6 and 12 months old. An early clinical evaluation (at least 4 h after the first clinical assessment) could be helpful, in particular in infants younger than 12 months of age. A rescue drug might be prescribed when there is a high risk of prolonged FS (i.e., risk higher than 20%): age at FS<12months OR a history of a previous febrile status epilepticus OR if the first FS was a focal seizure OR abnormal development/neurological exam/MRI OR a family history of nonfebrile seizure. A neurological consultation should be requested for any child who has experienced a prolonged FS before the age of 1 year, for children who have experienced prolonged and focal FS or repetitive (within 24h) focal FS, for children who have experienced multiple complex (focal or prolonged or repetitive) FS, for children with an abnormal neurological exam or abnormal development experiencing a FS. Although childhood febrile seizures in most cases are benign, witnessing such seizures is always a terrifying experience for the child's parents. Most parents feel that their child is dying or could have severe brain injury related to the episode. Therefore, the group also suggests a post-FS visit with the primary care physician.

[Iron and Neurodevelopment]. / Fer et neurodéveloppement.

In the central nervous system, iron is a cofactor of many metabolic processes and synthesis of aminergic neurotransmitters. Iron plays an major function on brain development from the prenatal period to teenage years. The blood-brain barrier modulates concentration of iron in the brain. In case of iron deficiency in the child, the negative impact on the myelinogenesis and synaptogenesis are well proven, with negative effects on psychomotor and cognitive functions. Iron supplementation has a beneficial effect, even if there is no anemia. The consequences of iron deficiency are more harmful as deficiency is early. The main mechanisms involved about iron and brain are reviewed.

Impact of miglustat on evolution of atypical presentation of late-infantile-onset Niemann-Pick disease type C with early cognitive impairment, behavioral dysfunction, epilepsy, ophthalmoplegia, and cerebellar involvement: a case report.

BACKGROUND: Niemann-Pick disease type C is a rare inherited neurodegenerative disease involving impaired intracellular lipid trafficking and accumulation of glycolipids in various tissues, including the brain. Miglustat, a reversible inhibitor of glucosylceramide synthase, has been shown to be effective in the treatment of progressive neurological manifestations in pediatric and adult patients with Niemann-Pick disease type C, and has been used in that indication in Europe since 2010. CASE PRESENTATION: We describe the case of a 16-year-old white French boy with late-infantile-onset Niemann-Pick disease type C who had the unusual presentation of early-onset behavioral disturbance and learning difficulties (aged 5) alongside epileptic seizures. Over time he developed characteristic, progressive vertical ophthalmoplegia, ataxic gait, and cerebellar syndrome; at age 10 he was diagnosed as having Niemann-Pick disease type C based on filipin staining and genetic analysis (heterozygous I1061T/R934X NPC1 mutations). He was commenced on miglustat therapy aged 11 and over the course of approximately 3 years he showed a global improvement as well as improved cognitive and ambulatory function. During this period he remained seizure free on antiepileptic therapy, using valproate and lamotrigine. CONCLUSIONS: Miglustat improved the neurological status of our patient, including seizure control. Based on our findings in this patient and previous published data, we discuss the importance of effective seizure control in neurological improvement in Niemann-Pick disease type C, and the relevance of cerebellar involvement as a possible link between these clinical phenomena. Thus the therapeutic efficacy of miglustat could be hypothesized as a substrate reduction effect on Purkinje cells.

[Classification of children with specific language impairments: What can we think about them in 2016?] / Les classifications des troubles spécifiques du langage oral : qu'en penser en 2016 ?

Specific language impairments are characterized by a strong semiological heterogeneity. Numerous classifications have been used to bring out this heterogeneity and to create subgroups after outlining specific symptoms and deficits. However, semiological fixed profiles would not be adequate for these disorders related to neurodevelopmental trajectories. This heterogeneity is not only semiological: it is also found within underlying mechanisms, as well as in the etiopathogenesis, which is still not well understood today. The aim of this article is to introduce the main semiological classifications to highlight the fact that the symptomatic level alone is not sufficient to characterize specific language impairments.

[Multidisciplinary management of children with disabling chronic pain in a French pediatric rehabilitation center: Current management and perspectives]. / Prise en charge multidisciplinaire des enfants souffrant de douleurs chroniques invalidantes dans un centre de rééducation fonctionnelle pédiatrique français : analyse rétrospective d'une série et perspectives.

INTRODUCTION: Chronic pain in children and adolescents has a major impact on their life in terms of school, sleep as well as family and social life. Teenagers aged 13-15 and girls are at the highest risk. Zeltzer et al. established a bio-psychosocial model of chronic pain in 1998 to account for all its dimensions and advocated a multidisciplinary management plan. Programs based on their principles target specific symptoms such as anxiety and loss of function, while treating underlying factors and teaching coping skills to patients and their families. They aim for patients to regain autonomy rather than focusing on pain resolution. Such programs, with varied protocols, have existed outside of France for approximately 15 years. The efficacy of these multidisciplinary programs has been shown in studies in Germany, the United Kingdom, the United States, Canada, and Australia. To our knowledge, there are no French studies on this topic; therefore, our aim was to describe a French program. We hypothesized that the program would be effective in reducing chronic pain and its impact. METHODS: The aim of this study was to describe the multidisciplinary management of chronic pain in a French pediatric functional rehabilitation center. It is a public health establishment located in the suburbs of Lille, offering care for children aged 0-18 with various conditions. It has 52 hospital beds, can accommodate up to 22 day-hospital visits per day and has comprehensive technical facilities. This prospective study consisted in a chart review of all consecutive patients who were hospitalized in the functional rehabilitation center for chronic pain with significant disability since 2010. We reviewed the treatment protocol for each patient as well as the treatment results for the composite primary endpoint, comprising pain characteristics and the impact of pain on function and schooling after discharge. RESULTS: Twenty-nine patients, aged 9.4-17.8 years, 62.1% of whom were girls, were hospitalized for chronic pain with a significant impact on their daily life between 2010 and August 2014. The most common diagnosis was complex regional pain syndrome type 1 (CRPS1) (37.9%). Pain had major consequences, with total disability in 69% of cases and 100% of children taking pain medications. In 65.5% of cases, patients were hospitalized in an inpatient setting, and 34.5% attended an outpatient program. Treatment lasted from 1 to 68 weeks (mean, 24.3; standard deviation [SD], 21.6). Patients received a combination of medical care, physical therapy (100%), occupational therapy (37.9%), psychological counseling (100%), pain medications (96.6%), and schooling (96.6%). Pain improved significantly in 89.7% of patients (95% confidence interval [95% CI] [0.73-0.98]) and pain medication consumption decreased significantly in 72.4% of children (95% CI [0.53-0.87]). Patients who had stopped walking could ambulate again in 91.7% of cases (95% CI [0.73-0.99]) and 86.4% of patients who had been missing school were back at school full time (95% CI [0.65-0.97]). There were no significant differences for these results between inpatient and outpatient management programs. Improvements were maintained at 3-6 months after discharge in 83.3% of cases. CONCLUSION: The multidisciplinary pain management program in this French pediatric functional rehabilitation center shows results comparable to the programs described in other countries. Chronic pain should be evaluated with standardized and validated tools, such as the measurement of the pain-related disability with the Functional Disability Index.

[Lemierre syndrome revealed by torticollis]. / Syndrome de Lemierre révélé par un torticolis.

Classical Lemierre syndrome is a rare and severe disease with thrombosis of the internal jugular vein and metastatic infections. We report on a case of Lemierre-like syndrome secondary to mastoiditis, with a favorable outcome, in a healthy infant presenting with torticollis. Early diagnosis and treatment with antibiotics are necessary to decrease mortality.

[Muscle biopsy in children: Usefulness in 2012]. / Intérêt de la biopsie musculaire chez l'enfant en 2012.

Muscle biopsy is a mainstay diagnostic tool for investigating neuromuscular disorders in children. We report the yield of pediatric muscle biopsy in a population of 415 children by a retrospective study of 419 biopsies performed between 1/01/2000 and 31/12/2009 in a neuropediatric department, including mitochondrial respiratory chain analysis for 87 children. Two hundred and fifty-five biopsies were from boys (61%) 164 from girls (39%). Their mean age at biopsy was 6.5years; 155 (37%) biopsies were obtained before the child was 5years old. Final histopathological diagnoses were: congenital myopathy (n=193, including 15 structural congenital myopathies); progressive muscular dystrophy (n=75 [18%] including 57 dystrophinopathies); congenital muscular dystrophy (n=17, including six primary merosinopathies); dermatomyositis (n=11); spinal muscular atrophy (n=9, including six atypical spinal muscular atrophies); metabolic myopathy (n=32, including 19 mitochondrial myopathies); encephalomyopathy (n=53 [13%], including 27 with a mitochondrial respiratory chain defect). Pathological diagnosis remained undetermined in 16 cases. In 184 patients (44%), the muscle biopsy revealed specific histopathological anomalies (dystrophic process; specific ultrastructural abnormalities; perifascicular atrophy; neurogenic atrophy; metabolic anomalies) enabling a precise etiological diagnosis. For 85% of progressive muscular dystrophies, the biopsy resulted in a genetic diagnosis after identification of the protein defect. In 15% of the congenital myopathies, histopathological anomalies focused attention on one or several genes. Concerning dystrophinopathies, quantification of dystrophin deficiency on the biopsy specimen contributed to the definition of the clinical phenotype: Duchenne, or Becker. In children with a myopathy, muscle biopsy is often indispensable to establish the etiological diagnosis. Based on the results from this series, muscle biopsy can provide a precise orientation in 45% of patients, leading to a genetic hypothesis.

A novel microdeletion syndrome at 3q13.31 characterised by developmental delay, postnatal overgrowth, hypoplastic male genitals, and characteristic facial features.

BACKGROUND: Congenital deletions affecting 3q11q23 have rarely been reported and only five cases have been molecularly characterised. Genotype-phenotype correlation has been hampered by the variable sizes and breakpoints of the deletions. In this study, 14 novel patients with deletions in 3q11q23 were investigated and compared with 13 previously reported patients. METHODS: Clinical data were collected from 14 novel patients that had been investigated by high resolution microarray techniques. Molecular investigation and updated clinical information of one cytogenetically previously reported patient were also included. RESULTS: The molecular investigation identified deletions in the region 3q12.3q21.3 with different boundaries and variable sizes. The smallest studied deletion was 580 kb, located in 3q13.31. Genotype-phenotype comparison in 24 patients sharing this shortest region of overlapping deletion revealed several common major characteristics including significant developmental delay, muscular hypotonia, a high arched palate, and recognisable facial features including a short philtrum and protruding lips. Abnormal genitalia were found in the majority of males, several having micropenis. Finally, a postnatal growth pattern above the mean was apparent. The 580 kb deleted region includes five RefSeq genes and two of them are strong candidate genes for the developmental delay: DRD3 and ZBTB20. CONCLUSION: A newly recognised 3q13.31 microdeletion syndrome is delineated which is of diagnostic and prognostic value. Furthermore, two genes are suggested to be responsible for the main phenotype.

[Characteristics of tuberous sclerosis in children]. / Spécificités de la sclérose tubéreuse de Bourneville chez l'enfant.

Tuberous sclerosis complex is a genetic multisystem disease characterized by hamartic development of many organs, most notably the brain, heart, kidneys, lungs, and skin. This autosomic dominant disorder results from mutations in one of two genes, TSC1 and TSC2, coding for hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation. The clinical presentation is highly variable and most features of tuberous sclerosis become evident only in childhood after the child is several years of age, limiting their usefulness for early diagnosis. The aim of this article is to define the pediatric clinical manifestations of tuberous sclerosis in correlation with patient age. Sometimes, a prenatal diagnosis can be made based on fetal ultrasound and MRI, which show cardiac and brain lesions. However, newborns are most often asymptomatic. In the 1st year, seizures are the most common symptoms, with a high incidence of infantile spasms. In children between 2 and 10 years of age, neurological symptoms are the most frequent with epilepsy, mental retardation, and autism, but extraneurological manifestations can be diagnosed. In adolescents, most features of tuberous sclerosis become evident and renal and pulmonary manifestations must be sought. The knowledge of age-dependent clinical features of tuberous sclerosis can provide an earlier diagnosis and improve the management of these patients with a special role for multidisciplinary consultation.

Delineation of 15q13.3 microdeletions.

The increasing use of array-comparative genomic hybridization (array-CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4-BP5 microdeletion out of a series of 4625 patients screened by array-CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical approximately 1.5 Mb BP4-BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.

[Use of ketogenic diet in children in France from 2001 to 2008]. / Evolution de la prescription du régime cétogène en France chez l'enfant entre 2001 et 2008.

INTRODUCTION: The ketogenic diet is an adequate treatment for drug-resistant epilepsy and certain inborn metabolic disorders. The efficacy of the ketogenic diet for the treatment of epilepsy is now well established. In France, and more widely in Europe, there is currently no consensus concerning appropriate initiation of the ketogenic diet and subsequent patient management. METHODS: Using the same questionnaire in 2005 and 2008, we retrospectively recorded the practices of child neurology departments of the French university hospitals during three study periods (2001-2002, 2002-2003 and 2005-2008). The aim was to evaluate the number of ketogenic diets started and how the ketogenic diet was initiated. RESULTS: The ketogenic diet was widely used by pediatric neurologists. The number of patients on a ketogenic diet increased over time. Diet initiation protocols also changed over time, being modified adequately with advances in knowledge of the ketogenic diet. CONCLUSION: The French pediatric neurologists appear to have a good understanding of the ketogenic diet.

The prevalence of premonitory symptoms in paediatric migraine: a questionnaire study in 103 children and adolescents.

The prevalence and characterization of premonitory symptoms have not been rigorously studied in children and adolescents. Using a questionnaire, we retrospectively studied the prevalence of 15 predefined premonitory symptoms in a clinic-based population. In 103 children and adolescents fulfilling the International Classification of Headache Disorders, 2nd edn criteria for paediatric migraine, at least one premonitory symptom was reported by 69 (67%). The most frequently reported premonitory symptoms were face changes, fatigue and irritability. The mean number of premonitory symptoms reported per subject was 1.8 (median 2.2). Age, migraine subtype (with or without aura) and mean attack frequency per month had no effect on the mean number of premonitory symptoms reported per subject. In conclusion, premonitory symptoms are frequently reported by children and adolescents with migraine. Face changes seem to be a premonitory symptom peculiar to paediatric migraine.

The value of electromyography in the aetiological diagnosis of hypotonia in infants and toddlers.

INTRODUCTION: During the first two years of life, hypotonia may be the only symptom of a central or peripheral nervous system disorder. We propose to assess the sensitivity of electroneuromyography (ENMG) in the aetiological diagnosis of hypotonia of neuromuscular origin in infants and toddlers. METHOD: This is a retrospective, single-centre study with revision of the files of the 37 children aged between zero and 24 months who, between 1994 and 2006, underwent an ENMG in the etiological approach of their hypotonia and had a final diagnosis of neuromuscular disease. RESULTS: All the 13 patients with spinal muscular atrophy or Charcot Marie-Tooth disease displayed neurogenic alterations on the electromyography (EMG). Among the 24 children ultimately diagnosed with myopathies, five only displayed myogenic alterations when tested before the age of two. Sixteen had normal EMG results and three showed neurogenic alterations. DISCUSSION AND CONCLUSION: In infants presenting with hypotonia, ENMG is useful for the diagnosis of peripheral neuropathy. Normal ENMG is relatively common for confirmed muscle disorders in infants whereas myogenic alterations seem more unusual, so that muscle biopsy appears unquestionable. In a few cases, early onset myopathies may present with a neurogenic ENMG pattern. Such a result should not invalidate the clinically presumed diagnosis of myopathy and would indicate on the contrary the need for a muscle biopsy.

[Management of convulsive status epilepticus in infants and children]. / Prise en charge d'un état de mal épileptique de l'enfant (nouveau-né exclu).

Convulsive status epilepticus in childhood is a life threatening condition with serious risk of neurological sequelae which constitutes a medical emergency. Clinical and experimental data suggest that prolonged seizures can have immediate and long-term adverse consequences on the immature and developing brain. So the child who presents with a continuous generalized convulsive seizure lasting greater than five minutes should be promptly treated. The outcome is mainly determined by the underlying etiology, age and duration of status epilepticus. In children the mortality from status epilepticus ranges from 3 to 5% and the morbidity is two-fold higher. Mortality and morbidity are highest with status epilepticus associated with central nervous system infections, which is the most important cause of status epilepticus. There are few evidence-based data to guide management decisions for the child with status epilepticus. Immediate goals are stabilization of airways, breathing and circulation and termination of seizures. Benzodiazepines remain the first-line drugs recommended for prompt termination of seizures. As intravenous lorazepam is not available in France, we suggest clonazepam as the best choice for initial therapy. Rectal diazepam or buccal midazolam remain important options. Intravenous phenytoin/fosphenytoin and phenobarbital are the second-line drugs. Phenytoin is being increasingly substituted by fosphenytoin, but pediatric data are scarce and fosphenytoin is not authorized for use in France below five years old. In children, phenytoin is often preferred to phenobarbital, even though no comparative studies have demonstrated a better efficacy. To manage status epilepticus refractory to a benzodiazepine and administration of phenytoin and/or phenobarbital, many pediatricians today prefer high-dose midazolam infusion rather than thiopental to minimize serious side effects from barbiturate anesthesia. There is no benefit/risk ratio to support the use of propofol for children with refractory status epilepticus.