The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome.

Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.

MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

The Iberian legacy into a young genetic xeroderma pigmentosum cluster in central Brazil.

In central Brazil, in the municipality of Faina (state of Goiás), the small and isolated village of Araras comprises a genetic cluster of xeroderma pigmentosum (XP) patients. The high level of consanguinity and the geographical isolation gave rise to a high frequency of XP patients. Recently, two founder events were identified affecting that community, with two independent mutations at the POLH gene, c.764 + 1 G > A (intron 6) and c.907 C > T; p.Arg303* (exon 8). These deleterious mutations lead to the xeroderma pigmentosum variant syndrome (XP-V). Previous reports identified both mutations in other countries: the intron 6 mutation in six patients (four families) from Northern Spain (Basque Country and Cantabria) and the exon 8 mutation in two patients from different families in Europe, one of them from Kosovo. In order to investigate the ancestry of the XP patients and the age for these mutations at Araras, we generated genotyping information for 22 XP-V patients from Brazil (16), Spain (6) and Kosovo (1). The local genomic ancestry and the shared haplotype segments among the patients showed that the intron 6 mutation at Araras is associated with an Iberian genetic legacy. All patients from Goiás, homozygotes for intron 6 mutation, share with the Spanish patients identical-by-descent (IBD) genomic segments comprising the mutation. The entrance date for the Iberian haplotype at the village was calculated to be approximately 200 years old. This result is in agreement with the historical arrival of Iberian individuals at the Goiás state (BR). Patients from Goiás and the three families from Spain share 1.8 cM (family 14), 1.7 cM (family 15), and a more significant segment of 4.7 cM within family 13. On the other hand, the patients carrying the exon 8 mutation do not share any specific genetic segment, indicating an old genetic distance between them or even no common ancestry.

Trends and geographic inequalities in the prevalence of Down syndrome in Europe, 1980-1999.

BACKGROUND: EUROCAT is a network of population-based registries for the epidemiologic surveillance of congenital anomalies covering approximately one quarter of births in the European Union. Down syndrome constitutes approximately 8% of cases of registered congenital anomaly in Europe, with over 7000 affected pregnancies in the 15 current member states of the European Union each year. In this paper, we aim to examine trends in the live birth prevalence of Down syndrome in Europe in the light of trends in maternal age and in prenatal diagnosis. METHODS: Descriptive analysis of data from 24 EUROCAT registries, covering 8.3 million births 1980-99. Cases include live births, stillbirths and terminations of pregnancy following prenatal diagnosis. RESULTS: Since 1980, the proportion of births to mothers of 35 years of age and over has risen quite dramatically from 8 to 14% for the European Union as a whole, with steeper rises in some regions. By 1995-1999, the proportion of "older" mothers varied between regions from 10% to 25%, and the total prevalence (including terminations of pregnancy) of Down syndrome varied from 1 to 3 per 1000 births. Some European regions have shown a more than twofold increase in total prevalence of Down syndrome since 1980. The proportion of cases of Down syndrome which were prenatally diagnosed followed by termination of pregnancy in 1995-1999 varied from 0% in the three regions of Ireland and Malta where termination of pregnancy is illegal, to less than 50% in 14 further regions, to 77% in Paris. The extent to which terminations of pregnancy were concen trated among older mothers varied between regions. The live birth prevalence has since 1980 increasingly diverged from the rising total prevalence, in some areas remaining approximately stable, in others decreasing over time. CONCLUSION: The rise in average maternal age in Europe has brought with it an increase in the number of pregnancies affected by Down syndrome. The widespread practice of prenatal screening and termination of pregnancy has in most of the regions covered by EUROCAT counteracted the effect of maternal age in its effect on live birth prevalence. Under the joint influences of maternal age and prenatal screening the pattern of geographic inequalities in Down syndrome live birth prevalence in Europe has also been changed.

Multilocular hydrocephalus: ultrasound studies of origin and development.

Multilocular hydrocephalus is a complication of neonatal hydrocephalus. Its main feature is the presence of multiple cysts inside the ventricles, which requires a specific therapeutic approach. The case of a preterm infant with intracranial hemorrhage grade II-III and central nervous system infection is reported. The cysts developed at the subependymal layer in the posterior area of the patient's thalamus. Their growth and development were charted by ultrasound imaging for several weeks. These types of cysts may grow to occupy the totality of the lateral ventricles, isolating the temporal horns. Of all the reviewed pathogenic mechanisms, we support the hypothesis of an inflammatory vasculitis at the subependymal level, with the subsequent infarct giving rise to the cysts. The osmotic pressure within the cavities, rather than intraventricular fluid, would account for the enlargement of the cysts.

[Neuropediatric clinical practice in a tertiary hospital of Basque Country]. / La práctica clínica neuropediátrica en un hospital terciario del País Vasco.

INTRODUCTION: In our country, studies on the neuropediatric practice are scarce, in spite of their importance for planning of spending and resources, and definition of quality criteria. OBJECTIVE: To study the clinical workload of the main neuropediatric clinical problems. METHODS: Prospective, longitudinal, descriptive study of doctor-patient encounters, according to diagnosis, in the Child Neurology Division of a tertiaty hospital. RESULTS: 3,200 visits, of which 83% were ambulatory. 24 ambulatory visits per 1,000 inhabitants younger than 15 years, and year. Diagnosis demanding larger clinical activity for out-patients were: epilepsy/seizures (38%), mental retardation (17%), headaches (17%), hyperactivity/conduct disorders (12%), and cerebral palsy/permanent motor sequela (10%). Among in-patients: epilepsy/seizures (47%), mental retardation (10%), brain tumors/neurological complications of oncology disorders (8%), cerebral palsy/motor sequela (8%), and neurological complications of prematurity (7%). Among new out-patients, headaches is the most frequent diagnosis, followed by epilepsy; among new in-patients, epilepsy holds the first place, followed by neurological complications of prematurity and brain trauma. The index follow-up/first visit is much larger for the real neurologic patient than for functional disorders so frequent among new referrals. CONCLUSIONS: The neuropediatric practice comprises essentially epilepsy, cognitive and conduct disorders, and headaches. Unfortunately, our practice is in part being defined by the pressure exerted by the primary medical care and by hospital management practices.

[Can acute disseminated encephalomyelitis progress in a deferred way?]. / ¿Puede la encefalomielitis aguda diseminada cursar de forma diferida?

OBJECTIVE: To report on the heterogeneity with regard to the clinical course of the acute disseminated encephalomyelitis (ADEM). CASE REPORT: A 5 year old boy suffered of acute disseminated encephalomyelitis of unknown origin. This child suffered two episodes of different neurologic symptoms separated by several weeks. Based on the clinical manifestations and typical appearance of magnetic resonance imaging findings and the absence of oligoclonal bands in CSF immunoglobulins, multiple sclerosis (MS) was ruled out. CONCLUSION: We postulate that the recurrent symptoms in our patient could be explained as a multiphasic disseminated encephalomyelitis (MDEM). Favourable outcome after simultaneous treatment with methylprednisolone and intravenous immunoglobulin is emphasized in this report.

Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation.

Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech. Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males.

Prenatal diagnosis of severe structural congenital malformations in Europe.

OBJECTIVES: To assess at a population-based level the frequency with which severe structural congenital malformations are detected prenatally in Europe and the gestational age at detection, and to describe regional variation in these indicators. METHODS: In the period 1995-1999, data were obtained from 17 European population-based registries of congenital malformations (EUROCAT). Included were all live births, fetal deaths and terminations of pregnancy diagnosed with one or more of the following malformations: anencephalus, encephalocele, spina bifida, hydrocephalus, transposition of great arteries, hypoplastic left heart, limb reduction defect, bilateral renal agenesis, diaphragmatic hernia, omphalocele and gastroschisis. RESULTS: The 17 registries reported 4366 cases diagnosed with the 11 severe structural malformations and of these 2300 were live births (53%), 181 were fetal deaths (4%) and 1863 were terminations of pregnancy (43%); in 22 cases pregnancy outcome was unknown. The overall prenatal detection rate was 64% (range, 25-88% across regions). The proportion of terminations of pregnancy varied between regions from 15% to 59% of all cases. Gestational age at discovery for prenatally diagnosed cases was less than 24 weeks for 68% (range, 36-88%) of cases. There was a significant relationship between high prenatal detection rate and early diagnosis (P < 0.0001). For individual malformations, the prenatal detection rate was highest for anencephalus (469/498, 94%) and lowest for transposition of the great arteries (89/324, 27%). Termination of pregnancy was performed in more than half of the prenatally diagnosed cases, except for those with transposition of the great arteries, diaphragmatic hernia and gastroschisis, in which 30-40% of the pregnancies with a prenatal diagnosis were terminated. CONCLUSION: European countries currently vary widely in the provision and uptake of prenatal screening and its quality, as well as the "culture" in terms of decision to continue the pregnancy. This inevitably contributes to variation between countries in perinatal and infant mortality and in childhood prevalence and cost to health services of congenital anomalies.