Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome.

Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.

Fragile X syndrome: economic burden and health-related quality of life of patients and caregivers in France.

BACKGROUND: Fragile X syndrome (FXS) is the main hereditary cause of intellectual disability. Although the associated burden appears to be considerable, to date no study has comprehensively assessed the cost incurred because of FXS, including its specific impact on health-related quality of life and the burden on caregivers using standardised quantitative tools. The aim of this article is to provide data in order to increase awareness of the repercussions of FXS on patients and caregivers as well as on the health and social care systems in France. METHODS: A retrospective cross-sectional study was carried out on 145 patients recruited through Le Goëland X-Fragile and Mosaïques, the French FXS patient associations. Data on their demographic characteristics and resource use were obtained from an online questionnaire, and costs were estimated by a bottom-up approach. The EQ-5D health questionnaire was used to measure patients' and caregivers' health-related quality of life. Perceived burden of care was measured using the Zarit Caregiver Burden Interview. The Barthel index, a non-utility-based assessment, was used to measure patients' level of dependence. RESULTS: The annual total direct cost of FXS was estimated at €25 800 per patient. The main contributors were informal care provided by the main caregiver (€10 500) and social services (€8400). Healthcare costs, estimated at €2700, represented only a minor share. Mean EQ-5D utility scores were 0.49 for patients and 0.75 for caregivers. The mean burden for caregivers as measured by the Zarit Caregiver Burden Interview was 39.9. CONCLUSIONS: Fragile X syndrome requires significant resources that are mainly of a non-medical nature and are higher for children than for adults. Compared with related diseases, it constitutes a particularly high burden for caregivers. Using a bottom-up approach and a wide range of standardised measures, this study underscores the need for greater awareness of the burden of FXS as well as an assessment of new and existing interventions to address it.

Simplified gyral pattern in severe developmental microcephalies? New insights from allometric modeling for spatial and spectral analysis of gyrification.

The strong positive-allometric relationship between brain size, cortical extension and gyrification complexity, recently highlighted in the general population, could be modified by brain developmental disorders. Indeed, in case of brain growth insufficiency, the pathophysiological relevance of the "simplified gyral pattern" phenotype is strongly disputed since almost no genotype-phenotype correlations have been found in primary microcephalies. Using surface scaling analysis and newly-developed spectral analysis of gyrification (Spangy), we tested whether the gyral simplification in groups of severe microcephalies related to ASPM, PQBP1 or fetal-alcohol-syndrome could be fully explained by brain size reduction according to the allometric scaling law established in typically-developing control groups, or whether an additional disease effect was to be suspected. We found the surface area reductions to be fully explained by scaling effect, leading to predictable folding intensities measured by gyrification indices. As for folding pattern assessed by spectral analysis, scaling effect also accounted for the majority of the variations, but an additional negative or positive disease effect was found in the case of ASPM and PQBP1-linked microcephalies, respectively. Our results point out the necessity of taking allometric scaling into account when studying the gyrification variability in pathological conditions. They also show that the quantitative analysis of gyrification complexity through spectral analysis can enable distinguishing between even (predictable, non-specific) and uneven (unpredictable, maybe disease-specific) gyral simplifications.

Distortion of the anterior part of the interhemispheric fissure: significance and implications for prenatal diagnosis.

In order to illustrate the significance of a new anatomical finding, distortion of the interhemispheric fissure (DIHF) associated with impacted medial borders of the frontal lobes, we report a retrospective observational study of 13 fetuses in which DIHF was identified on prenatal imaging. In 10 cases there were associated anatomical anomalies, including mainly midline anomalies (syntelencephaly (n=2), lobar holoprosencephaly (n=1), Aicardi syndrome (n=2)), but also schizencephaly (n=1), cortical dysplasia (n=1) and more complex cerebral malformations (n=3), including neural tube defect in two cases. Chromosomal anomaly was identified in two cases, including 6p deletion in a case without associated central nervous system anomalies and a complex mosaicism in one of the cases with syntelencephaly. In two cases, the finding was apparently isolated on both pre- and postnatal imaging, and the children were doing well at follow-up, aged 4 and 5 years. The presence of DIHF on prenatal imaging may help in the diagnosis of cerebral anomalies, especially those involving the midline. If DIHF is apparently isolated on prenatal ultrasound, magnetic resonance imaging is recommended for careful analysis of gyration and midline, especially optic and olfactory structures. Karyotyping is also recommended.

A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation.

X-linked forms of mental retardation (MR) affect approximately 1 in 600 males and are likely to be highly heterogeneous. They can be categorized into syndromic (MRXS) and nonspecific (MRX) forms. In MRX forms, affected patients have no distinctive clinical or biochemical features. At least five MRX genes have been identified by positional cloning, but each accounts for only 0.5%-1.0% of MRX cases. Here we show that the gene TM4SF2 at Xp11.4 is inactivated by the X breakpoint of an X;2 balanced translocation in a patient with MR. Further investigation led to identification of TM4SF2 mutations in 2 of 33 other MRX families. RNA in situ hybridization showed that TM4SF2 is highly expressed in the central nervous system, including the cerebral cortex and hippocampus. TM4SF2 encodes a member of the tetraspanin family of proteins, which are known to contribute in molecular complexes including beta-1 integrins. We speculate that through this interaction, TM4SF2 might have a role in the control of neurite outgrowth.

The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males.

Since the first reports of polyglutamine-binding protein 1 (PQBP1) mutations in Renpenning syndrome and related disorders, the spectrum of PQBP1-linked clinical manifestations has been outlined from rare published case reports. The phenotypic description is often obtained from medical archives, and therefore, heterogeneous. Moreover, some aspects such as brain imaging or cognitive and behavioral functioning are rarely described. In this study, 13 PQBP1-mutated French patients were subjected to a standardized clinical, cognitive and behavioral assessment. Physical measurements of their relatives were also collected. We report on a recognizable clinical and radiological phenotype. All patients presented with microcephaly, leanness and mild short stature, relative to familial measurements. Three new clinical features are described: upper back progressive muscular atrophy, metacarpophalangeal ankylosis of the thumb and velar dysfunction. The specific facial dysmorphic features included at least four of the following signs: long triangular face, large ridged nose, half-depilated eyebrows, dysplastic or protruding ears and rough slightly sparse hair. An over-aged appearance was noticed in elderly patients. Cortical gyrification was normal based on available magnetic brain imaging of six patients. PQBP1-linked microcephaly (or Renpenning syndrome) is an X-linked mental retardation syndrome, which has clinically recognizable features.

Implicit procedural learning in fragile X and Down syndrome.

BACKGROUND: Procedural learning refers to rule-based motor skill learning and storage. It involves the cerebellum, striatum and motor areas of the frontal lobe network. Fragile X syndrome, which has been linked with anatomical abnormalities within the striatum, may result in implicit procedural learning deficit. METHODS: To address this issue, a serial reaction time (RT) task including six blocks of trials was performed by 14 individuals with fragile X syndrome, 12 individuals with Down syndrome and 12 mental age-matched control subjects. The first (B1) and fifth (B5) blocks were random whereas the others (B2, B3, B4 and B6) consisted of a repeated 10-step sequence. Results were analysed by Kruskal-Wallis one-way analysis of variance and Wilcoxon signed-rank test. RESULTS: For patients with fragile X syndrome, the RT was highly suggestive of preserved implicit learning as a significant difference was observed between blocks B5 and B6 (P = 0.009). However, the difference of RT between B4 and B5 did not reach significance, possibly due to a subgroup of individuals who did not learn. In contrast, in the Down syndrome group, RT decreased significantly between B4 and B5 (W = 2; P = 0.003) but not between the last ordered block (B6) and the last random block (B5), suggesting a weakness in procedural learning which was sensitive to the interfering random block. CONCLUSION: implicit learning is variable in genetic syndromes and therefore relatively independent of general intellectual capacities. The results are discussed together with previous reports.

Neurological outcome and risk of recurrence depending on the anterior vs. posterior arterial distribution in children with stroke.

We report the outcome of 46 previously healthy children with arterial ischemic stroke. After a mean follow-up of 26 months, five (11%) children suffered a recurrence and 28 (61%) were left with sequelae. The prevalence and the severity of the sequelae were similar irrespective of whether the localization of the accident was anterior or posterior. However, a recurrence was significantly more frequent in the posterior than in the anterior group (4/14 vs. 1/32; p=0.025). These observations may lead to the establishment of therapeutic guidelines according to the localization of the infarct.

[Long-term follow-up of bacterial meningitis - sequels in children and adults: incidence, type, and assessment issues]. / Quel suivi à long terme pour quels patients ? Séquelles des méningites bactériennes chez l'enfant et chez l'adulte : incidence, types, modes d'évaluation.

Bacterial meningitis remains a major cause of death and neurological and hearing sequels. In adults, the death rate ranges from 16 to 37% in meningitis due to Pneumococcus pneumoniae and neurological sequels occur in 30 to 52% of survivors. In childhood, the prognosis is better, with a death rate ranging from 2 to 15%, higher for Pneumococcus pneumoniae. Seventy-five percent of children survive without any sequel, 15% with hearing disorders (up to 30% with Pneumococcus), and rarely (3-4%) present with mental retardation, motor deficit, or epilepsy. In addition to the type of germ, the risk of sequels is six times higher in case of Pneumococcus, several factors of poor prognosis are described on admission: degree of coma, neurological deficit, cranial nerve palsy, high protein level, high erythrocytes count and low leukocytes count in CSF (less than 600 or 1000 leukocytes per microliter). Any neurological complication such as epilepsy, stroke, brain edema, hydrocephalus, or hemodynamic failure will be correlated to a poor outcome. Hearing must be tested within 15 days, followed by audiologic consultation and MRI focused on labyrinths to detect early onset cochlear ossification. One year after meningitis, behavior and cognitive skills must be assessed, including IQ, memory, attention and executive functions, adaptive abilities, to set up specific educative and teaching strategies.

Abnormal Sylvian fissure on prenatal cerebral imaging: significance and correlation with neuropathological and postnatal data.

OBJECTIVE: To illustrate and determine the significance of abnormal Sylvian fissure development (or abnormal operculization) in cases in which prenatal cerebral imaging is suggestive of underlying cortical dysplasia. METHODS: This was a retrospective study of 15 fetuses at 24-34 weeks in which abnormal operculization was identified on prenatal cerebral imaging and for which follow-up data were available. The imaging findings were correlated to macro- and microscopic neuropathological data (n = 11) or to postnatal clinical and imaging findings (n = 4). RESULTS: On microscopic examination of fetuses from 11 terminated pregnancies, abnormal operculization was associated with cortical dysplasia in four cases and the cortex was normal in seven. Abnormal operculization was associated with cortical dysplasia in only one of the four liveborn infants. Cases of abnormal Sylvian fissure development with normal cortical architecture were classified, according to associated anomalies of the central nervous system, into one of five groups: those with neural tube defects, microcephaly or frontal hypoplasia, glutaric aciduria, other cerebral abnormalities, and extracerebral anomalies. CONCLUSION: Abnormal operculization on prenatal imaging does not systematically reflect underlying cortical dysplasia. It may be related to extracortical factors such as abnormal cerebral volume or other developmental anomalies of the central nervous system. An understanding of the significance of abnormal Sylvian fissure development could be useful in integrating its analysis into a more general one of the whole central nervous system.

Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia.

Fried syndrome, first described in 1972, is a rare X-linked mental retardation that has been mapped by linkage to Xp22. Clinical characteristics include mental retardation, mild facial dysmorphism, calcifications of basal ganglia and hydrocephalus. A large four-generation family in which the affected males have striking clinical features of Fried syndrome were investigated for linkage to X-chromosome markers; the results showed that the gene for this condition lies within the interval DXS7109-DXS7593 in Xp22.2. In total, 60 candidate genes located in this region, including AP1S2, which was recently shown to be involved in mental retardation, were screened for mutations. A mutation in the third intron of AP1S2 was found in all affected male subjects in this large French family. The mutation resulted in skipping of exon 3, predicting a protein with three novel amino-acids and with termination at codon 64. In addition, the first known large Scottish family affected by Fried syndrome was reinvestigated, and a new nonsense mutation, p.Gln66X, was found in exon 3. Using CT, both affected patients from the French family who were analysed had marked calcifications of the basal ganglia, as previously observed in the first Scottish family, suggesting that the presence of distinctive basal ganglia calcification is an essential parameter to recognise this syndromic disorder. It may be possible to use this feature to identify families with X-linked mental retardation that should be screened for mutations in AP1S2.

[Acute hemiparesis revealing a neuroborreliosis in a child]. / Hémiparésie aiguë révélatrice d'une neuroborréliose chronique chez un enfant.

We report on a 11-year-old boy who had 2 acute hemiparesis episodes over a period of 1 month. He suffered from headache and fatigue since 1 year. He could not remember neither a tick bite nor a local erythematous skin lesion. The diagnosis of neuroborreliosis was based on intrathecal production of specifics antibodies. Furthermore, the CSF/blood glucose ratio was decreased (0.14), which was rarely described. Cranial MRI showed left capsulothalamic inflammation and a vasculitis. The patient was successfully treated by ceftriaxone. Neuroborreliosis should be considered in all children with stroke-like episode, even in the absence of a history of a tick bite.

[Quality of life of very disabled children: a questionnaire about the role of health status and tube feeding]. / Qualité de vie de l'enfant polyhandicapé: questionnaire portant sur l'influence de l'état de santé et de l'alimentation entérale.

UNLABELLED: To resort to gastrostomy feeding is a difficult decision to take in children with severe disability, the objective being better quality of life. OBJECTIVES: To describe quality of life in children with severe disability and to look for factors which influence this quality of life, in particular gastrostomy. METHOD: Descriptive study in 28 patients, aged 1 to 18 years, with severe motor and mental disability, with or without gastrostomy. The studied factors were: health and nutritional status and quality of life. The quality of life was evaluated with QUALIN questionnaire, specifically designed for infants. RESULTS: This questionnaire was pertinent and well accepted by the family. Quality of life was influenced by capacity of communication (P=0.006), quality of sleeping (P=0.004), digestive problems (P<0.05) and age (P=0.031). CONCLUSION: Gastrostomy did not impair quality of life. Its benefit was estimated as high as 8.71/10 in average by parents.

[Developmental approach of executive functions: From infancy to adolescence]. / Approche développementale des fonctions exécutives : du bébé à l'adolescence.

Given the importance of the relationship between executive function (EF) and many aspects of child development - including the development of reasoning, emotion regulation, school performance, and wider self-regulation itself - research on the development of EF from infancy to the end of adolescence has become one of the scientific priorities of the last decade. Improving our knowledge on the maturative trajectory of EF and the functional weight of different internal and environmental factors, supposed to optimize their efficiency, can only promote a better understanding of EF and its role in the normal development of the child as well as of those at risk of poor outcome either because of neurodevelopmental disorders or psychopathological disorders. This article aims to update the recent literature in this area. It appears that executive function grows very gradually and evolves from a relatively simple and unitary model in young children to a more complex one - differentiated, integrated, and tripartite - in adolescence.

[Update on the genetics of X-linked mental retardation]. / Actualités sur la génétique des retards mentaux liés au chromosome X.

Mutations in X-linked genes are likely to account for the observation that more males than females are affected with mental retardation. Causative mutations have been identified in both syndromic XLMR and in the genetically heterogeneous non-syndromic forms of XLMR, without a clear clinical phenotype other than cognitive deficit. Progress in genome analysis and the establishment of large collaborations between clinical and molecular research teams, especially the European XLMR consortium, have led to the identification of 20 non-syndromic XLMR genes and 25 syndromic XLMR genes. Given the extensive heterogeneity of non syndromic XLMR, different strategies are used for the identification of new genes: linkage analysis, studies of balanced chromosomal rearrangements (X-autosome translocations, microdeletions) and candidate genes strategies by mutation screening in regions of the X chromosome known to be involved in neuronal development and function. Delineating the monogenic causes of XLMR and their molecular and cellular consequences will provide insight into the mechanisms that are required for normal development of cognitive function in humans. Non syndromic XLMR proteins include 5 distinct classes: transmembrane receptors, small GTPases effectors or regulators, enzymes and translational regulators.

[Creatine deficiency syndromes]. / Les syndromes de déficit en créatine.

INTRODUCTION: Creatine deficiency syndromes are a newly described group of inborn errors of metabolism affecting creatine metabolism. Three diseases have been described: deficiency of arginine: glycine amidinotransferase (AGAT), deficiency of guanidinoacetate methyltransferase (GAMT) and creatine transporter defect (CRTR). STATE OF ART: These syndromes are characterized by a depletion of creatine/phosphocreatine in the brain. Clinically, most of the patients develop a variable mental retardation and a severe speech delay associated with epilepsy, extra-pyramidal syndrome and behavior disturbances. These diseases are often diagnosed during infancy but a few adult cases have been reported recently. Diagnosis is established by measurement of guanidinoacetate and creatine in biologic fluids and in vivo proton magnetic resonance spectroscopy by the total lack of intra-cerebral creatine/phosphocreatine demonstrating. GAMT and AGAT deficiencies are treatable by oral creatine supplementation whereas patients with CRTR do not respond to the treatment. CONCLUSION: Better knowledge of these syndromes is necessary to optimize diagnosis and patient management of these rare but potentially treatable disorders.

Pineal region tumors: Clinical symptoms and syndromes.

The present paper investigates the clinical picture and the different clinical signs that reveal pineal region tumors or appear during the course of the follow-up. Biological malignancy and tumor extension determine the semiology and its setting up mode. Typical endocrine signs, dominated by abnormal puberty development, are frequently a part of the clinical scene. Bifocal or ectopic localization in the hypothalamic-pituitary region is accompanied by other endocrine signs such as ante- or post-pituitary insufficiencies which occur several months or even years after the first neurological signs appear. Due to a mass syndrome and obstructive hydrocephalus, intracranial hypertension signs are frequent but unspecific. A careful ophthalmologic examination is essential to search upward gaze paralysis and other signs of the Parinaud's tetrad or pentad. Midbrain dysfunction, including extrinsic aqueduct stenosis, are also prevalent. Except for abnormal pubertal signs, hyper-melatoninemia (secretory tumors) or a-hypo-melatoninemia (tumors destructing pineal) generally remains dormant. Some patients present sleep problems such as narcolepsy or sleepiness during the daytime as well as behavioral problems. This suggests a hypothalamic extension rather than a true consequence of melatonin secretion anomalies. Similarly, some patients may present signs of a "pinealectomized" syndrome, including (cluster) headaches, tiredness, eventually responsive to melatonin.

[Smith-Magenis syndrome is an association of behavioral and sleep/wake circadian rhythm disorders]. / Le syndrome de Smith-Magenis, une association unique de troubles du comportement et du cycle veille/sommeil.

Smith-Magenis syndrome (SMS) is a genetic disorder characterized by the association of facial dysmorphism, oral speech delay, as well as behavioral and sleep/wake circadian rhythm disorders. Most SMS cases (90%) are due to a 17p11.2 deletion encompassing the RAI1 gene; other cases stem from mutations of the RAI1 gene. Behavioral issues may include frequent outbursts, attention deficit/hyperactivity disorders, self-injuries with onychotillomania and polyembolokoilamania (insertion of objects into bodily orifices), etc. It is noteworthy that the longer the speech delay and the more severe the sleep disorders, the more severe the behavioral issues are. Typical sleep/wake circadian rhythm disorders associate excessive daytime sleepiness with nocturnal agitation. They are related to an inversion of the physiological melatonin secretion cycle. Yet, with an adapted therapeutic strategy, circadian rhythm disorders can radically improve. Usually an association of beta-blockers in the morning (stops daily melatonin secretion) and melatonin in the evening (mimics the evening deficient peak) is used. Once the sleep disorders are controlled, effective treatment of the remaining psychiatric features is needed. Unfortunately, as for many orphan diseases, objective guidelines have not been drawn up. However, efforts should be focused on improving communication skills. In the same vein, attention deficit/hyperactivity disorders, aggressiveness, and anxiety should be identified and specifically treated. This whole appropriate medical management is underpinned by the diagnosis of SMS. Diagnostic strategies include fluorescent in situ hybridization (FISH) or array comparative genomic hybridization (array CGH) when a microdeletion is sought and Sanger sequencing when a point mutation is suspected. Thus, the diagnosis of SMS can be made from a simple blood sample and should be questioned in subjects of any age presenting with an association of facial dysmorphism, speech delay with behavioral and sleep/wake circadian rhythm disorders, and other anomalies including short stature and mild dysmorphic features.