RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes.

Pontocerebellar hypoplasias (PCH) are characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. We report five patients referred for PCH, showing atypical clinical and magnetic resonance imaging (MRI) features suggestive of defects in the Reelin pathway. We screened for mutations in RELN or VLDLR and compared the phenotype of these patients with that of previously reported patients. All patients had profound cerebellar hypoplasia on MRI with peculiar cerebellar morphology, associated with flattened pons and neocortical abnormalities. Patient 1 had profound motor and intellectual disability with moderate lissencephaly suggestive of RELN mutations and was shown to harbor a splicing homozygous RELN mutation. The four other patients had a milder phenotype consistent with CARMQ1 (cerebellar ataxia and mental retardation with or without quadrupedal locomotion). These patients showed mild simplification or thickening of cortical gyration and had VLDLR mutations. Reelin signaling regulates neuronal migration in the developing mammalian brain. VLDLR is a key component of the Reelin pathway. Our patients had a very small and dysplatic cerebellar vermis that should suggest the involvement of these genes. Moreover, differences in clinical severity, involvement of the cerebellar hemispheres, together with the severity of the neocortical defect, enables RELN-mutated patients to be distinguished from VLDLR-mutated patients.

Xq27 FRAXA locus is a strong candidate for dyslexia: evidence from a genome-wide scan in French families.

Dyslexia is a frequent neurodevelopmental learning disorder. To date, nine susceptibility loci have been identified, one of them being DYX9, located in Xq27. We performed the first French SNP linkage study followed by candidate gene investigation in dyslexia by studying 12 multiplex families (58 subjects) with at least two children affected, according to categorical restrictive criteria for phenotype definition. Significant results emerged on Xq27.3 within DYX9. The maximum multipoint LOD score reached 3,884 between rs12558359 and rs454992. Within this region, seven candidate genes were investigated for mutations in exonic sequences (CXORF1, CXORF51, SLITRK2, FMR1, FMR2, ASFMR1, FMR1NB), all having a role during brain development. We further looked for 5'UTR trinucleotide repeats in FMR1 and FMR2 genes. No mutation or polymorphism co-segregating with dyslexia was found. This finding in French families with Dyslexia showed significant linkage on Xq27.3 enclosing FRAXA, and consequently confirmed the DYX9 region as a robust susceptibility locus. We reduced the previously described interval from 6.8 (DXS1227-DXS8091) to 4 Mb also disclosing a higher LOD score.

[Psychocognitive and psychiatric disorders associated with developmental dyslexia: A clinical and scientific issue]. / Les troubles psychiatriques et psychocognitifs associés à la dyslexie de développement : un enjeu clinique et scientifique.

INTRODUCTION: Dyslexia is a complex neurodevelopemental disorder that affects 5 to 10% of school-age children. This condition consists in a specific learning disability with a neurological origin. These learning difficulties are unexpected in relation to other cognitive abilities and the provision of efficient classroom instruction. A range of neurobiological investigations suggests that disruption of the parieto-temporo-occipital systems underlies a failure of skilled reading to develop. The observation that dyslexia is both a familial and heritable problem was made early on and was confirmed by twin studies. They also suggested that both genetic and environmental factors are involved. Several loci have been implicated in dyslexia, notably on chromosomes 2, 3, 6, 15 and 18 and some candidate genes have been proposed, but no functional mutation has yet been identified. LITERATURE REVIEW: Dyslexia seldom appears isolated and dyslexic people are very likely to present other kinds of learning disabilities or psychiatric disorders. Specific language impairment, often with a mild outcome, is the most frequently associated with dyslexia. Indeed, late language development is often reported by dyslexic patients and also occurs more frequently among their siblings. Genetic linkage studies suggest some common genetic factor underlying this comorbidity. Dyscalculia is associated with dyslexia in 25% of cases, but most people with dyscalculia do not have any sign of dyslexia. The question of whether dyscalculia associated with dyslexia and dyscalculia itself rely on the same cognitive impairment is still controversial. Impaired motor development is also a common feature that affects nearly 50% of dyslexics and dyslexia is frequent among dyspraxic patients. This association raises the discussion on the role of motor impairment in dyslexia's physiopathology and the cerebellar theory of dyslexia. Beyond its link with other learning disorders, the study of dyslexia's comorbidity highlights psychopathological issues. ADHD is the most frequent psychiatric disorder associated with dyslexia. Underpinnings of this link between the two disorders seem to rely on common cognitive and genetic factors. Some authors have proposed a candidate gene ADRA2A to determine the condition including ADHD and dyslexia. In addition, dyslexics are exposed to a higher risk of anxiodepressive and behavioural disorders. Dyslexic children experience three times more behavioural disorders and one third of children with behavioural problems turn out to be affected by dyslexia. The literature study reveals inconsistent findings about depressed mood among dyslexics, but evidence of a persistent increase in the rate of anxiety disorders. The authors put forward the impact of environmental factors to explain these psychiatric comorbidities. CONCLUSION: This review emphasizes dyslexia's comorbidities because they represent an important issue, both from a scientific and clinical point of view. Indeed, for clinicians, children showing multiple learning disabilities have specific reeducation and educational needs and dyslexics have a higher risk of emotional and behavioural disorders. On the other hand, dyslexia's comorbidity study provides a powerful method for researchers to investigate the still unknown physiopathology of dyslexia.

The FHM1 mutation S218L: a severe clinical phenotype? A case report and review of the literature.

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura that is characterized by motor weakness during attacks. FHM1 is associated with mutations in the CACNA1A gene located on chromosome 19. We report a severe, prolonged HM attack in a young pregnant patient who had the S218L FHM1. This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma. The case history we report suggests a specific, severe phenotype and the co-occurrence of HM and epilepsy related to the S218L FHM1 mutation.

[Enzyme replacement therapy in a boy with infantile Pompe disease: cardiac follow-up]. / Enzymothérapie substitutive chez un nourrisson atteint de maladie de Pompe : évolution cardiologique.

Pompe disease is an autosomal recessive glycogen storage disorder caused by acid-alpha-glucosidase deficiency. The infantile form is usually fatal by 1 year of age in the absence of specific therapy. We report the cardiac follow-up of a 4-month-old boy treated with enzyme replacement therapy (ERT) for 8 months. The patient had no cardiac failure at the age of 1 year. Before starting ERT, ECG showed a shortened PR interval, with huge QRS complexes and biventricular hypertrophy; echocardiography demonstrated major hypertrophic cardiomyopathy. The QRS voltage (SV1+RV6) decreased from 13 to 2.9 mV after 32 weeks of ERT, suggesting a progressive reduction of cardiac hypertrophy and intracellular glycogen excess. The PR interval increased from 60 to 90 ms. A block of the right bundle branch appeared after 13 weeks of treatment. The indexed left ventricular mass decreased from 240 to 90 g/m2 after 30 weeks of ERT. The left ventricular ejection fraction decreased transitorily between the 5th and the 15 th weeks of treatment. In summary, ERT is an efficient therapeutic approach for the cardiomyopathy of infantile Pompe disease. However, the possible occurrence of a right bundle branch block and a transitory alteration in the ejection fraction highlight the importance of cardiac follow-up.

[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.

[Thoracic outlet syndrome: an unusual postoperative complication]. / Le syndrome du défilé thoraco-brachial: une complication post-opératoire inhabituelle.

UNLABELLED: Introduction. Neurogenic Thoracic Outlet Syndrome (NTOS) is a chronic lower trunk brachial plexus entrapment caused by a cervical rib or a fibrous band. True NTOS is rare and progresses usually slowly. Case report. A 12-year-old girl complained of numbness and weakness of the right upper limb immediately after an orthopedic surgical procedure for scoliosis. Neurological and neurophysiological features were both consistent with a neurogenic thoracic outlet syndrome (NTOS). CONCLUSION: This observation illustrates the risk of NTOS after certain surgical procedures, especially when a prolonged prone position with abducted shoulders is required.

[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.

Retinoic acid therapy in "degenerative-like" neuro-langerhans cell histiocytosis: a prospective pilot study.

BACKGROUND: Degenerative-like neuro-Langerhans cell histiocytosis (DN-LCH) is a rare complication of LCH marked by progressive cerebellar ataxia. No treatment has so far been shown to slow this progression. PROCEDURE: All-trans retinoic acid (ATRA) was administered orally at a dose of 45 mg/m(2) daily for 6 weeks and then 2 weeks every month for 1 year. The endpoints were clinical status at 1 year (assessed with rating scales for ataxia and disability), adverse effects, and changes in neurological abnormalities on MRI. RESULTS: Ten patients were studied. The treatment was well tolerated. All the patients were clinically stable at the end of the study. No MRI changes were noted. CONCLUSIONS: DN-LCH appeared to be stable during ATRA therapy, but further studies are required to appreciate the possible long-term benefits of ATRA.

Continuous spikes and waves during slow sleep (CSWS): outcome in adulthood.

We report a longitudinal, electroencephalographic and neuropsychological analysis of epilepsy with continuous spikes and waves during slow sleep (CSWS) in a 19 year-old boy. The clinical course fluctuated, with temporary worsening or improvement of the paroxysmal abnormalities, epilepsy and cognitive functions. At the end of the follow-up period, seizures persisted. Evaluation of the boy's behaviour, language and cognitive function suggested a dysexecutive syndrome. We discuss the relationship between paroxysmal abnormalities and neuropsychological disorders.

Langerhans cell histiocytosis and the central nervous system in childhood: evolution and prognostic factors. Results of a collaborative study.

This retrospective study detailed clinical and radiologic involvement of the central nervous system related to Langerhans cell histiocytosis in 18 French children. We excluded cases of isolated hypothalamic-pituitary dysfunction or spinal involvement. Cerebellar symptoms were the most common clinical symptoms. Two different patterns of magnetic resonance or computed tomographic images were identified: demyelination and gliosis or atrophy, described as degenerative lesions, mostly located in the cerebellum in 10 children, or tumor-like lesions occurring in any part of the brain in 13 children. Six children had both types of lesion. The clinical cerebellar syndrome correlated with the specific imaging pattern suggestive of a cerebellar degenerative lesion, which did not show any changes after treatment. As suggested by this study and previous clinical and histologic reports, it is believed that brain involvement in the course of Langerhans cell histiocytosis might arise from different disease mechanisms: primary histiocyte proliferation and secondary atrophy or demyelination and gliosis of unknown origin. Treatment consequently should be adapted to the supposed mechanism of the lesion.

Neuropsychologic and adaptive functioning in adolescents and young adults shunted for congenital hydrocephalus.

The major aim of this study was to assess whether the syndrome of nonverbal learning disabilities described in hydrocephalic children is observed in adulthood. Eleven adults shunted for congenital hydrocephalus related to spina bifida and eight adults shunted for hydrocephalus related to aqueductal stenosis were administered an extensive neuropsychologic battery to investigate discrepancies between verbal and visuospatial cognition, verbal and visuospatial long-term memory, and psycho-social adaptive abilities. The results showed no discrepancies between Wechsler Performance IQ or Verbal IQ in either hydrocephalic group. Nevertheless, the subjects with spina bifida appeared more cognitively impaired than the subjects with aqueductal stenosis, who performed normally on the Wechsler Adult Intelligence Scale-Revised. Memory assessment using Signoret's Memory Battery revealed no discrepancy between verbal and visuospatial memory in the hydrocephalic group. Nevertheless, the subjects with spina bifida had poorer verbal and visuospatial memory performance than the subjects with aqueductal stenosis. There were no differences on the Vineland Adaptive Behavioral Scale between subjects with spina bifida and those with aqueductal stenosis in autonomy, socialization, and daily living skills. These results suggest that shunted congenital hydrocephalus is not characterized by nonverbal learning disabilities syndrome in adolescence or in adulthood.

Recurrence of the T666M calcium channel CACNA1A gene mutation in familial hemiplegic migraine with progressive cerebellar ataxia.

Familial hemiplegic migraine (HM) is an autosomal dominant migraine with aura. In 20% of HM families, HM is associated with a mild permanent cerebellar ataxia (PCA). The CACNA1A gene encoding the alpha1A subunit of P/Q-type voltage-gated calcium channels is involved in 50% of unselected HM families and in all families with HM/PCA. Four CACNA1A missense mutations have been identified in HM: two in pure HM and two in HM/PCA. Different CACNA1A mutations have been identified in other autosomal dominant conditions: mutations leading to a truncated protein in episodic ataxia type 2 (EA2), small expansions of a CAG trinucleotide in spinocerebellar ataxia type 6 and also in three families with EA2 features, and, finally, a missense mutation in a single family suffering from episodic ataxia and severe progressive PCA. We screened 16 families and 3 nonfamilial case patients affected by HM/PCA for specific CACNA1A mutations and found nine families and one nonfamilial case with the same T666M mutation, one new mutation (D715E) in one family, and no CAG repeat expansion. Both T666M and D715E substitutions were absent in 12 probands belonging to pure HM families whose disease appears to be linked to CACNA1A. Finally, haplotyping with neighboring markers suggested that T666M arose through recurrent mutational events. These data could indicate that the PCA observed in 20% of HM families results from specific pathophysiologic mechanisms.

Reading ability and processing in Duchenne muscular dystrophy and spinal muscular atrophy.

We analysed the reading abilities and processing of 21 children with Duchenne muscular dystrophy (DMD), 11 matched children suffering from spinal muscular atrophy (SMA) and 42 children receiving normal education. The principal result observed was that the DMD children exhibited a reading age which was significantly lower than the SMA children compared with their chronological age. These learning disabilities were not related to a deficit in non-verbal performance intelligence, but psycholinguistic evaluation showed a deficit in verbal intelligence, especially in the Similarities and Arithmetic WISC-R subtests, in phonological abilities, oral word repetition, and in digit span score. The results for the DMD children were heterogeneous, and ranged from normal to greater or lesser involvement. In an attempt to clarify the nature of this reading impairment in DMD children, the three groups (DMD, SMA, and normal control children) were tested by reading aloud a list of single words and non-words. The DMD children were significantly impaired in reading non-words, suggesting reading disability similar to dysphonetic dyslexia, the most frequent subtype of developmental dyslexia. These results are discussed in the light of psychometric data available for our DMD population and in the light of previous studies. The practical consequences of diagnosis on rehabilitation are very important. The precise description of the cognitive deficits seen in DMD is of value for future clinical and genetic studies.

Deafness and Mondini dysplasia in Kabuki (Niikawa-Kuroki) syndrome. Report of a case and review of the literature.

Report of a case and review of the literature: We report the case of a seven-year-old female kabuki patient suffering from severe bilateral deafness related to Mondini dysplasia and ossicular anomalies. A review of the literature in English confirms that hearing loss is a major component of Kabuki Syndrome (KS) with a frequency at around 32%. However the possible mechanisms have not been fully described and hearing loss is often attributed to otitis media, but one reported case had severe ossicular malformations, two had sensorineural deafness and three others had mixed deafness. Our observation is the first reported case of Mondini dysplasia in KS. Awareness by physicians of this problem has a major practical consequence as diagnosis of Mondini dysplasia implies searching for and surgical prevention and treatment of perilymphatic fistula in order to prevent meningitis.

Study of unilateral hemisphere performance in children with developmental dysphasia.

Hemisphere specialization for language was studied in 10 children with expressive developmental dysphasia (DD) (mean age 10 years 4 months) submitted to a dichotic listening task (in a word free-recall task and forced-attention task) and a finger tapping/vocalization dual-task paradigm. A nonsense shape dichaptic task was also introduced to control right hemispheric processing. Performances of dysphasic children were compared to those obtained from 15 normal children. The results showed that controls had a right ear advantage in free-recall (words) dichotic listening task and a significant right ear advantage in forced-right-attention task, with a change in ear asymmetry as a consequence of instruction. In the dysphasic group we observed a significant right ear advantage in the free-recall dichotic listening task and no change in ear asymmetry during forced right or forced left condition. Results in time sharing paradigm and nonsense dichaptic task are more difficult to interpret, because there was no interaction between group and condition. These results cannot support a complete left hemisphere dysfunction in developmental dysphasia.

Sleep EEG and developmental dysphasia: lack of a consistent relationship with paroxysmal EEG activity during sleep.

In order to clarify the relationship between developmental dysphasia and EEG abnormalities, paroxysmal activities during sleep were studied in a series of 24 children with expressive developmental dysphasia (mean age 8 years) and compared to a control group of 39 children (mean age 9 years). The children of both groups were selected excluding cases with prior history of neurological disease or epilepsy. In the control group, 37 children had normal sleep EEG while 2 children had paroxysmal abnormalities. In the dysphasic group, epileptic abnormalities were observed in 9 cases, rare in 4 cases and frequent in 5 cases (density: 2.5 to 66.2% of total sleep time). Nevertheless, paroxysmal abnormalities did not reach the frequency described in the Landau-Kleffner syndrome, and it is unlikely that EEG abnormalities could have produced dysphasia.