Sylvie Joriot

MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations

Background Over the last few years, array-comparative genomic hybridisation (CGH) has considerably improved our ability to detect cryptic unbalanced rearrangements in patients with syndromic mental retardation. Method Molecular karyotyping of six patients with syndromic mental retardation was carried out using whole-genome oligonucleotide array-CGH. Results 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb were detected in five unrelated patients with the following phenotypic similarities: severe mental retardation with absent speech, hypotonia and stereotypic movements. Facial dysmorphic features, epilepsy and/or cerebral malformations were also present in most of these patients. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, the gene for a protein known to act in brain as a neurogenesis effector, which regulates excitatory synapse number. In a patient with a similar phenotype, an MEF2C nonsense mutation was subsequently identified. Conclusion Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations.

Refinement of cortical dysgeneses spectrum associated with TUBA1A mutations

Objective: We have recently shown that de novo mutations in the TUBA1A gene are responsible for a wide spectrum of neuronal migration disorders. To better define the range of these abnormalities, we searched for additional mutations in a cohort of 100 patients with lissencephaly spectrum for whom no mutation was identified in DCX, LIS1 and ARX genes and compared these data to five previously described patients with TUBA1A mutations. Results: We detected de novo TUBA1A mutations in six patients and highlight the existence of a prominent form of TUBA1A related lissencephaly. In four patients, the mutations identified, c.1190T>C (p.L397P), c.1265G>A (p.R422H), c.1264C>T (p.R422C), c.1306G>T (p.G436R), have not been reported before and in two others, the mutation corresponds to a recurrent missense mutation, c.790C>T (p.R264C), likely to be a hot spot of mutation. All together, it emerges that the TUBA1A related lissencephaly spectrum ranges from perisylvian pachygyria, in the less severe form, to posteriorly predominant pachygyria in the most severe, associated with dysgenesis of the anterior limb of the internal capsule and mild to severe cerebellar hypoplasia. When compared with a large series of lissencephaly of other origins (ILS17, ILSX or unknown origin), these features appear to be specific to TUBA1A related lissencephaly. In addition, TUBA1A mutated patients share a common clinical phenotype that consists of congenital microcephaly, mental retardation and diplegia/tetraplegia. Conclusions: Our data highlight the presence of consistent and specific abnormalities that should allow the differentiation of TUBA1A related lissencephalies from those related to LIS1, DCX and ARX genes.

Comparison of seizure reduction and serum fatty acid levels after receiving the ketogenic and modified Atkins diet

The ketogenic diet (KD) and the modified Atkins diet are effective therapies for intractable epilepsy. We compared retrospectively the KD and modified Atkins diet in 27 children and also assessed serum long chain fatty acid profiles. After 3 months, using an intent-to-treat analysis, the KD was more successful, with >50% seizure reduction in 11/17 (65%) vs. 2/10 (20%) with the modified Atkins diet, p=0.03. After 6 months, however, the difference was no longer significant: 7/17 (41%) vs. 2/10 (20%) (p=0.24). We observed a preventive effect of both diets on the occurrence of status epilepticus. After 1 and 3 months of either diet, responders experienced a significant decrease in serum arachidonic acid concentration compared to non-responders. The KD and modified Atkins diet led to seizure reduction in this small pilot series, with slightly better results after 3 months with the KD, but not after 6 months. The decrease of serum arachidonic acid levels might be involved in the anticonvulsive effects of KD or modified Atkins diet.

Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient.

BackgroundPontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH).MethodsFourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected.ResultsWe observed a high frequency of patients with a CASK mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype.ConclusionThis study describes a new series of PCH female patients with CASK inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a de novo CASK mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre, CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling.

LIS1-Related Isolated Lissencephaly Spectrum of Mutations and Relationships With Malformation Severity

OBJECTIVE With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype. DESIGN Retrospective study. Subjects A total of 63 patients with posteriorly predominant lissencephaly. INTERVENTIONS Of the 63 patients, 40 were found to carry either LIS1 point mutations (77.5%) or small genomic deletions (20%), and 1 carried a somatic nonsense mutation. On the basis of the severity of neuromotor impairment, epilepsy, and radiological findings, correlations with the location and type of mutation were examined. RESULTS Most patients with LIS1 mutations demonstrated posterior agyria (grade 3a, 55.3%) with thin corpus callosum (50%) and prominent perivascular spaces (67.4%). By contrast, patients without LIS1 mutations tended to have less severe lissencephaly (grade 4a, 41.6%) and no additional brain abnormalities. The degree of neuromotor impairment was in accordance with the severity of lissencephaly, with a high incidence of tetraplegia (61.1%). Conversely, the severity of epilepsy was not determined with the same reliability because 82.9% had early onset of seizures and 48.7% had seizures more often than daily. In addition, neither the mutation type nor the location of the mutation were found to predict the severity of LIS1-related lissencephaly. CONCLUSION Our results confirm the homogeneity profile of patients with LIS1-related lissencephaly who demonstrate in a large proportion Dobyns lissencephaly grade 3a, and the absence of correlation with LIS1 mutations.

The location of DCX mutations predicts malformation severity in X-linked lissencephaly

Lissencephaly spectrum (LIS) is one of the most severe neuronal migration disorders that ranges from agyria/pachygyria to subcortical band heterotopia. Approximately 80% of patients with the LIS spectrum carry mutations in either the LIS1 or DCX (doublecortin) genes which have an opposite gradient of severity. The aim of the study was to evaluate in detail the phenotype of DCX-associated lissencephaly and to look for genotype–phenotype correlations. Of the 180 male patients with DCX-related lissencephaly, 33 males (24 familial cases and nine cases with de novo mutations) were found with hemizygous DCX mutations and were clinically and genetically assessed here. DCX mutation analysis revealed that the majority of mutations were missense (79.2%), clustered in the two evolutionary conserved domains, N-DC and C-DC, of DCX. The most prominent radiological phenotype was an anteriorly predominant pachygyria or agyria (54.5%) although DCX-associated lissencephaly encompasses a complete range of LIS grades. The severity of neurological impairment was in accordance with the degree of agyria with severe cognitive impairment in all patients, inability to walk independently in over half and refractory epilepsy in more than a third. For genotype–phenotype correlations, patients were divided in two groups according to the location of DCX missense mutations. Patients with mutations in the C-DC domain tended to have a less severe lissencephaly (grade 4–5 in 58.3%) compared with those in the N-DC domain (grade 4–5 in 36.3%) although, in this dataset, this was not statistically significant (p = 0.12). Our evaluation suggests a putative correlation between phenotype and genotype. These data provide further clues to deepen our understanding of the function of the DCX protein and may give new insights into the molecular mechanisms that could influence the consequence of the mutation in the N-DC versus the C-DC domain of DCX.

French General Practitioners' Management of Children's Migraine Headaches

Objectives.—This study sought to examine the treatment of children with migraine headaches in a prospective sample of children referred to a tertiary center for headaches.

Ultrasound diagnosis, management and prognosis in a consecutive series of 27 cases of fetal hydrops following maternal parvovirus B19 infection.

Introduction: Fetal hydrops caused by anemia from parvovirus B19 infection (FH-B19) is rare. Doppler measurement of the middle cerebral artery peak systolic velocity (PSV-MCA) improves its prenatal diagnosis, but its frequency and prognosis are still poorly known. Despite improved survival due to in utero transfusions, the possibility of late neurological sequelae makes prognosis uncertain. Objectives: To assess the frequency, management and prognosis of a consecutive series of FH-B19 observed over a 15-year period. Methods: Retrospective study of 27 cases of FH-B19, that is, 3/100,000 births, 24 of them discovered during routine second-trimester ultrasound. All but 1 case (96.2%) had at least four of the six ultrasound signs that Saltzman et al. [Obstet Gynecol 1989;74:106–111] suggested as indicators of anemia. Of the fetuses tested, 80% had a PSV-MCA >1.5 MoM, also indicative of anemia. Of the 19 fetuses treated by exchange transfusions, 11 were liveborn compared with 2 of the 6 not so treated (57.8 vs. 33.3%, NS). The survival rate was higher during the second half of the study period (23.1 vs. 71.4%, p < 0.02) for less severe anemia (p < 0.03) and for repeated transfusions (p = 0.03). In our series, 1 case of prenatal cerebral atrophy was identified on screening. All 13 liveborn children appeared healthy at the age of 1 year. Conclusion: In cases of fetal hydrops, Saltzman et al.’s ultrasound criteria and PSV-MCA measurement made it possible to determine the likelihood that anemia is the cause of the hydrops and to measure its intensity. Use of these techniques allowed us to choose the most appropriate treatment (transfusion or not, depending on the degree of anemia), and survival improved notably in our series.

The Richieri‐Costa and Pereira form of acrofacial dysostosis: First case in a non‐Brazilian infant

We report on a French boy with cleft mandible, pre/postaxial hand anomalies, and clubfoot born to consanguineous parents. These findings are comparable to those of previous cases of the autosomal recessive Richieri-Costa and Pereira syndrome of short stature, Robin sequence, cleft mandible, pre/postaxial hand anomalies, and clubfoot. This is the first case in a non-Brazilian infant.

Dix questions pratiques concernant l’intoxication aiguë au monoxyde de carbone chez la femme enceinte

BACKGROUND The poisoning of carbon monoxide (CO) is the leading cause of death by poisoning in France. Its consequences are potentially serious to the fetus. Literature is ancient and little known. PURPOSE AND METHOD Make an inventory of knowledge about carbon monoxide poisoning during pregnancy. RESULT The CO causes maternal then fetal tissue hypoxia primarily by binding to hemoglobin with which it has a high affinity. Its transplacental passage may cause fetal harm, predominantly in the brain. Severity seems correlated with maternal symptoms during exposure. In the absence of maternal symptoms, however, the available data are reassuring. Hyperbaric oxygen therapy may reduce the risk to the fetus. DISCUSSION Oxygen therapy should be offered in all cases of CO poisoning, especially if there are maternal symptoms during exposure. In addition, a fetal echography directed on the cephalic pole - even a fetal magnetic resonance imaging three weeks after exposure - should also be proposed.