Pediatric neurolisteriosis: A diagnosis to consider even in the absence of immunodeficiency.

Neurolisteriosis is known to affect vulnerable groups, for example neonates or children with immunodeficiency. This is a key point of the current clinical guidelines regarding pediatric meningitis. We report a rare case of neurolisteriosis in an immunocompetent infant, without the typical signs of listeriosis, which led to a delay in administering the appropriate antibiotherapy. This case illustrates the clinical heterogeneity of neurolisteriosis and the relevance of appropriate polymerase chain reaction (PCR) tests when the clinical presentation differs from the current guidelines. This case also reminds us that raw or unpasteurized milk-based food products pose a risk even in immunocompetent infants or children.

[Congenital myasthenic syndromes in childhood: Drug therapeutic strategies]. / Syndromes myasthéniques congénitaux de l'enfant : stratégies thérapeutiques médicamenteuses.

Congenital myasthenia syndromes (CMS) are a group of genetic disorders responsible for neuromuscular junction dysfunction. Usually beginning before 2 years of age, they are revealed by fatigability and muscle weakness, especially after stress, and often prevent the child's normal development. Over recent years, major advances in therapeutic strategies have been made following the discovery of numerous mutations responsible for CMS and the understanding of their pathogenic role. Here we report a pediatric CMS case caused by a mutation of the ɛ subunit of the acetylcholine receptor. The initial treatment with acetylcholinesterase inhibitor rapidly showed its limits in terms of both effectiveness and tolerance. The association with 3.4 diaminopyridine (DAP), a new drug available to treat such conditions, has transformed the motor outcome of our patient and allowed psychomotor development. In addition to 3.4 DAP, other molecules adapted to other types of CMS are now available. Three major groups of CMS can be distinguished depending on whether the deficit is at the presynaptic, synaptic, or postsynaptic level of the neuromuscular junction. Depending on the type of CMS, therapeutic management may include acetylcholinesterase inhibitors, 3.4 DAP, fluoxetine, quinidine sulfate, or ephedrine. With the case report, we provide a recent review of the literature on such new therapeutic options, their indications and restrictions, their mechanism of action, and prescription modalities. Knowing the precise CMS type and the appropriate therapeutic options available is essential for the proper management of such chronic and severe but relatively treatable childhood disorders.

[N-methyl-D-aspartate receptor antibody encephalitis: value of immunomodulatory therapy]. / Encéphalite à anticorps anti-récepteurs N-méthyl-D-aspartate (NMDA-R) : place des immunomodulateurs.

INTRODUCTION: Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is little known to pediatricians and likely underdiagnosed. The child's vital and cognitive prognosis is at stake. The use of immunomodulatory drugs, such as rituximab has led to spectacular results, but many questions remain about its mode of action in this type of pathology. CASE REPORT: We report the case of a 6-year-old girl with no medical history, admitted for status epilepticus preceded by behavior symptoms and sleep disorders. Gradually, the child became bedridden, mute, and animated by predominantly orofacial dyskinesia. Examinations were normal (cerebrospinal fluid [CSF] analysis, brain MRI). The diagnosis was established by the presence of NMDA-R antibodies in the CSF. After exclusion of a tumor-associated syndrome, treatment was started initially by intravenous immunoglobulins, then by plasma exchange, and finally rituximab. The patient was cured with rituximab despite an unusually early recovery of the B-cell pool. DISCUSSION: Anti-N-methyl-D-aspartate receptor (NMDA-R) encephalitis is a severe but potentially reversible neurologic disorder only recently described, even in childhood. It may be reversible without sequelae if diagnosed and treated early. The use of immunomodulatory therapy, such as rituximab seemingly improves the outcome. Immunological monitoring is needed to better understand its mechanism of action in autoimmune diseases of the nervous system in childhood.

Twenty-five novel mutations including duplications in the ATP7A gene.

Twenty-five novel mutations including duplications in the ATP7A gene. Menkes disease (MD) and occipital horn syndrome (OHS) are allelic X-linked recessive copper deficiency disorders resulting from ATP7A gene mutations. MD is a severe condition leading to progressive neurological degeneration and death in early childhood, whereas OHS has a milder phenotype with mainly connective tissue abnormalities. Until now, molecular analyses have revealed only deletions and point mutations in both diseases. This study reports new molecular data in a series of 40 patients referred for either MD or OHS. We describe 23 point mutations (9 missense mutations, 7 splice site variants, 4 nonsense mutations, and 3 small insertions or deletions) and 7 intragenic deletions. Of these, 18 point mutations and 3 deletions are novel. Furthermore, our finding of four whole exon duplications enlarges the mutation spectrum in the ATP7A gene. ATP7A alterations were found in 85% of cases. Of these alterations, two thirds were point mutations and the remaining one third consisted of large rearrangements. We found that 66.6% of point mutations resulted in impaired ATP7A transcript splicing, a phenomenon more frequent than expected. This finding enabled us to confirm the pathogenic role of ATP7A mutations, particularly in missense and splice site variants.

Basal ganglia neuroprotection with anticonvulsants after energy stress: a comparative study.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model provides a valuable paradigm of the energy deficiency disorders found in childhood. In such disorders, anticonvulsants may provide neuroprotection by modulating cellular energy consumption and by exerting favorable pleiotropic effects on neuronal survival. To verify such hypothesis, we tested the effects of levetiracetam, vigabatrin, gabapentine, pregabaline, tiagabine, clonazepam and lamotrigine on neuroprotection in the MPTP mouse model. The membrane dopamine transporter (DAT) density, which provides a reliable index of dopaminergic neurons survival in the basal ganglia, was assessed by semi-quantitative autoradiography of the striatum. Unlike all other anticonvulsants tested, lamotrigine provided a significant and dose-dependent neuroprotection in these experimental conditions. Lamotrigine, a widely used and well-tolerated molecule in children, could provide neuroprotection in various energy deficiency disorders.

MPTP intoxication in mice: a useful model of Leigh syndrome to study mitochondrial diseases in childhood.

The basal ganglia, which are interconnected in the striato-nigral dopaminergic network, are affected in several childhood diseases including Leigh syndrome (LS). LS is the most common mitochondrial disorder affecting children and usually arise from inhibition of the respiratory chain. This vulnerability is attributed to a particular susceptibility to energetic stress, with mitochondrial inhibition as a common pathogenic pathway. In this study we developed a LS model for neuroprotection trials in mice by using the complex I inhibitor MPTP. We first verified that MPTP significantly inhibits the mitochondrial complex I in the brain (p = 0.018). This model also reproduced the biochemical and pathological features of LS: MPTP increased plasmatic lactate levels (p = 0.023) and triggered basal ganglia degeneration, as evaluated through dopamine transporter (DAT) autoradiography, tyrosine hydroxylase (TH) immunohistochemistry, and dopamine dosage. Striatal DAT levels were markedly decreased after MPTP treatment (p = 0.003). TH immunoreactivity was reduced in the striatum and substantia nigra (p = 0.005), and striatal dopamine was significantly reduced (p < 0.01). Taken together, these results confirm that acute MPTP intoxication in young mice provides a reproducible pharmacological paradigm of LS, thus opening new avenues for neuroprotection research.

[Clinical variability and diagnosis steps in childhood mitochondrial disease]. / Variabilité clinique et conduite diagnostique des cytopathies mitochondriales : à propos d'une série de 18 cas pédiatriques.

OBJECTIVES: Mitochondrial respiratory chain deficiencies are known for their high clinical variability. Difficult to diagnose, the prevalence of these diseases is probably underestimated. METHODS: We report 18 children diagnosed with respiratory chain deficiency at the Tours University Hospital over the past 10 years. RESULTS: Three clinical profiles can be distinguished depending on the age at onset of the first symptoms: the neonatal period (4 cases), between 1 month and 2 years of age (10 cases), and after 10 years (4 cases). However, no clinical feature appears specific of any age group. In contrast, respiratory chain analysis on liver biopsy was very informative for all our patients at any age and with any clinical presentation, even with predominant neurological symptoms. CONCLUSIONS: These biochemical analyses support the diagnosis of mitochondrial disorders in view of molecular analysis, which nevertheless frequently remains inconclusive. These investigations should benefit from the new molecular screening technologies based on DNA chips that can identify the genomic mutations responsible for these severe and relatively frequent diseases.

[Long-chain 3-hydroxyacyl CoA dehydrogenase deficiency and choroidal neovascularization]. / Néovascularisation choroïdienne au cours d'un déficit en Long-Chain 3-Hydroxyacyl CoA Dehydrogenase (LCHAD).

We report the case of a 9-year-old girl with a long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency. This enzyme participates in mitochondrial fatty acid B-oxidation. Genetic fatty acid oxidation defects induce cellular energetic deficiency, and thus early life-threatening manifestations. An appropriate diet prevents these severe disorders. Nevertheless, LCHAD deficiency is the only B-oxidation enzymatic disorder that induces a chorioretinopathy, predominating at the posterior pole. We describe the first case of bilateral macular choroidal neovascularization. One eye presented a fibrovascular lesion. The other eye presented an active neovascularization stabilized by two dynamic phototherapies. The specificity of choroidal degeneration related to LCHAD deficiency remains unknown. Reviewing of literature and biochemical mechanisms suggests that fatty acid oxidative stress rather than a mitochondrial energetic defect is involved. For practical purposes, this report emphasizes the importance of ophthalmological follow-up of these patients.

[Neurofibromatosis type 1 complications in the pediatric age: follow-up of a hundred cases]. / Complications de la neurofibromatose de type 1 chez l'enfant: à propos d'une série de 100 cas.

UNLABELLED: Neurofibromatosis 1 (NF1) is a frequent genetic disease. Diagnostic criterias were established in 1988. The patients can exhibit various and unpredictable complications. OBJECTIVES: To check the efficiency of a coordinated follow-up in specialized multidisciplinary centers providing a higher quality of management and to have a better knowledge of the complications including their true frequencies. POPULATION AND METHODS: We report a serie of 100 NF1 children who were followed-up during 4 years in a specialized center at the Tours University Hospital. Three hospital check-up at 2-5, 6-7, 14-15 years of age were performed as well as an annual physical examination. RESULTS: In our serie, the mean age was 7.8 years old with a sex ratio of 1. The mean age at diagnosis was 3.8 years old and the main diagnosis criteria were the café-au-lait spots and the family history for 80% of the patients. The optic nerve glioma has a low frequency of 5%. Learning disabilities clearly represent the most frequent complication (46% of the patients). CONCLUSION: An early detection of these difficulties is a priority for the appropriate management of these children.

[Benefit of the extended-release methylphenidate formulations: a comparative study in childhood]. / Apports des formes de méthylphénidate à libération prolongée: étude comparative chez l'enfant.

UNLABELLED: Methylphenidate (MPH) is a potential therapeutic tool for Attention Deficit with Hyperactivity Disorders (ADHD). In addition to the immediate-release formulation, Ritalin, two extended-release formulations, Ritalin LA and Concerta are available and allow a once-daily administration. We compared the respective benefits of both formulations for the patients and their family in terms of efficacy, handling and tolerance. PATIENTS AND METHODS: This prospective study was based on 30 children aged 6 to 15 years. All patients had a confirmed ADHD and were efficiently treated with Ritalin. The children were consecutively treated with Ritalin LA and Concerta, with a comparable MPH daily dosage, during 2 months for each molecule. The 3 drugs were evaluated individually and comparatively through a battery of questionnaires submitted to the parents and the teachers of each child. RESULTS: Extended-release MPH efficacy was comparable to the immediate-release formulation, Ritalin. For both of them, the once-daily administration appeared beneficial. Concerta was finally prescribed in 18 children, Ritalin LA in 8 cases and Ritalin in 4 cases. In each case the medical choice was consistent with the parents preference. Concerta was appreciated for its persisting efficacy in late afternoon during homework. Concerta and Ritalin LA did not induce significant adverse effects, especially regarding alimentation and sleep. CONCLUSIONS: MPH therapy in ADHD carries an excellent risk/benefit ratio without addictive induced behaviours. The extended-release MPH formulations provide an improvement for the patients in keeping with Ritalin efficacy through a once-daily administration. Regardless of its formulation, MPH indications and guidelines must be respected.

[Diagnostic strategies for ischemic strokes in childhood]. / Stratégie diagnostique dans les accidents vasculaires cérébraux ischémiques de l'enfant.

Ischemic strokes represent a rare condition in childhood, mostly revealed by a motor deficit. In the pediatric age, strokes are different than in adulthood where atherosclerosis is the major cause. The etiologies of stroke in childhood are rather multiple and each of them is rare. In nearly half of the pediatric cases no cause can be found and usually no recurrence occurs. The aim of this presentation is to propose a diagnosis strategy for ischemic strokes in children. An extensive search should be performed in every children presenting a stroke episode even if the initial outcome appears favorable. Such investigations could improve our understanding and therapeutic strategies of stroke in childhood, a condition where the cognitive and functional prognosis can be severely compromised.

[Diagnostic strategies for ischemic strokes in childhood]. / Stratégie diagnostique dans les accidents vasculaires cérébraux ischémiques de l'enfant.

Ischemic strokes represent a rare condition in childhood, mostly revealed by a motor deficit. In the pediatric age, strokes are different than in adulthood where atherosclerosis is the major cause. The etiologies of stroke in childhood are rather multiple and each of them is rare. In nearly half of the pediatric cases no cause can be found and usually no recurrence occurs. The aim of this presentation is to propose a diagnosis strategy for ischemic strokes in children. An extensive search should be performed in every children presenting a stroke episode even if the initial outcome appears favorable. Such investigations could improve our understanding and therapeutic strategies of stroke in childhood, a condition where the cognitive and functional prognosis can be severely compromised.

Striatal and pontocerebellar hypoperfusion in Hallervorden-Spatz syndrome.

Hallervorden-Spatz syndrome is a group of rare and severe disorders marked by extrapyramidal symptoms and iron accumulation in the globi pallidi, usually visible by magnetic resonance imaging. To assist in determining the functional correlates of these structural abnormalities, positron emission tomography was used to measure regional cerebral blood flows and dopaminergic function in a patient with Hallervorden-Spatz syndrome that manifested as progressive generalized dystonia, optic atrophy, and bilateral pallidal "eye of the tiger" sign. Voxel-by-voxel analysis of positron emission tomography images revealed no pallidal abnormalities but demonstrated significant hypoperfusion of the head of the right caudate nucleus, pons, and cerebellar vermis. Dopaminergic function of the basal ganglia, which was assessed based on visual- analysis of fixation of 18F-labeled fluoro-levodopa, was normal. These data suggest that Hallervorden-Spatz syndrome pathogenesis is not confined to the globi pallidi, and these data also may help to generate new pathogenic hypothesis.

Wolcott-Rallison syndrome: a case with endocrine and exocrine pancreatic deficiency and pancreatic hypotrophy.

Clinical analysis and genetic investigations of new cases of Wolcott-Rallison syndrome are needed to evaluate the role of the gene(s) directly or indirectly implicated in pancreas development and in the aetiology of the syndrome.

Infantile spasms and Menkes disease.

Epileptic seizures are a common feature in Menkes disease, an X-linked genetic disorder of copper metabolism. Details of type of seizures are rarely reported. We report the evolution of infantile spasms in two patients with Menkes disease and the relation with subcutaneous administration of copper-histidine.

Hyperinsulinemic hypoglycemia as a presenting sign in phosphomannose isomerase deficiency: A new manifestation of carbohydrate-deficient glycoprotein syndrome treatable with mannose.

We report the case of a patient with carbohydrate-deficient glycoprotein syndrome type Ib who developed normally until 3 months of age, when she was referred to the hospital for evaluation of hypoglycemia that was found to be related to hyperinsulinism. She also had vomiting episodes, hepatomegaly, and intractable diarrhea, which evoked the diagnosis of carbohydrate-deficient glycoprotein syndrome. Oral mannose treatment at a dose of 0.17 g/kg body weight 6 times/d was followed by a clinical improvement and normalization of blood glucose, aminotransferases, and coagulation factor levels. Hyperinsulinemic hypoglycemia should be considered as a leading sign of carbohydrate-deficient glycoprotein syndrome type Ib, especially when it is associated with enteropathy and abnormal liver tests.

X-linked nonspecific mental retardation (MRX16) mapping to distal Xq28: linkage study and neuropsychological data in a large family.

A genetic linkage study was performed on a large four-generation family with variable nonspecific X-linked mental retardation (MRX16), speech abnormalities, and retardation of all milestones. Significant linkage was found in the Xq28 region with loci DXS52, DXS15, BGN, and DXS1108 with maximum LOD scores of 4.86, 4.01, 4.83, and 5.43, respectively, at theta = 0.00. Recombination was observed at the locus DXS1113, thus mapping the gene in an 8-Mb interval between this marker and the Xq telomere. Linkage intervals of three other MRX families overlap with this interval in Xq28 where the RABGDIA gene, mutated in the MRX41 and MRX48 families, is also located. In MRX3, MRX28, but also in MRX16, no alteration of RABGDIA has been found, thus suggesting the existence of at least two MRX genes in distal Xq28.

Abnormal iron deposition associated with lipid peroxidation in transgenic mice expressing interleukin-6 in the brain.

Transgenic mice, named GFAP-IL6, that express interleukin-6 in astrocytes in the central nervous system (CNS) have a constitutive blood-brain barrier (BBB) defect and develop a progressive neurodegenerative disease. Based on ultrastructural observations showing electron-dense pigment in the brain of the GFAP-IL6 mice, we hypothesized that iron metabolism was altered in the brains of these animals. Enhanced histochemical methods revealed abnormal iron deposition in the cerebellum from 1 month of age that worsened with progression of the disease. Immunohistochemical analysis of iron-binding proteins (IBP) showed increased ferritin immunoreactivity and a decreased signal from the transferrin receptor in symptomatic animals. Atomic absorption spectroscopy revealed a 40% increase of total iron concentration in the cerebellum at the symptomatic stage. In order to obtain evidence that accumulation of this oxidizing metal was toxic, we looked for the presence of oxidative damage. Using the MAL-2 antibody, extensive lipid peroxidation (LP) was detected in the neocortex and the cerebellum in symptomatic animals. Ultrastructural analysis indicated lipofuscin deposition at the sites of neuro-axonal degeneration and abnormal iron deposition. These results suggest that the IL6-induced BBB defect precipitates iron accumulation in the GFAP-IL6 mouse brain and that subsequent IBP regulation mediates protective responses. As these defenses become overwhelmed, the iron overload seems to promote LP, which may contribute to the neurodegeneration that ensues. This transgenic mouse model of IL6-mediated neurodegeneration provides a unique opportunity to examine several aspects of iron metabolism in the brain, including its entry at the site of the BBB, its distribution through the IBP, and its mechanisms of toxicity.