3q27.3 microdeletional syndrome: a recognisable clinical entity associating dysmorphic features, marfanoid habitus, intellectual disability and psychosis with mood disorder.

BACKGROUND: Since the advent of array-CGH, numerous new microdeletional syndromes have been delineated while others remain to be described. Although 3q29 subtelomeric deletion is a well-described syndrome, there is no report on 3q interstitial deletions. METHODS: We report for the first time seven patients with interstitial deletions at the 3q27.3q28 locus gathered through the Decipher database, and suggest this locus as a new microdeletional syndrome. RESULTS: The patients shared a recognisable facial dysmorphism and marfanoid habitus, associated with psychosis and mild to severe intellectual disability (ID). Most of the patients had no delay in gross psychomotor acquisition, but had severe impaired communicative and adaptive skills. Two small regions of overlap were defined. The first one, located on the 3q27.3 locus and common to all patients, was associated with psychotic troubles and mood disorders as well as recognisable facial dysmorphism. This region comprised several candidate genes including SST, considered a candidate for the neuropsychiatric findings because of its implication in interneuronal migration and differentiation processes. A familial case with a smaller deletion allowed us to define a second region of overlap at the 3q27.3q28 locus for marfanoid habitus and severe ID. Indeed, the common morphological findings in the first four patients included skeletal features from the marfanoid spectrum: scoliosis (4/4), long and thin habitus with leanness (average Body Mass Index of 15 (18.5

Expanding the clinical phenotype of patients with a ZDHHC9 mutation.

In 2007, 250 families with X-linked intellectual disability (XLID) were screened for mutations in genes on the X-chromosome, and in 4 of these families, mutations in the ZDHHC9 gene were identified. The ID was either isolated or associated with a marfanoid habitus. ZDHHC9 encodes a palmitoyl transferase that catalyzes the posttranslational modification of NRAS and HRAS. Since this first description, no additional patient with a ZDHHC9 mutation has been reported in the literature. Here, we describe a large family in which we identified a novel pathogenic ZDHHC9 nonsense mutation (p.Arg298*) by parallel sequencing of all X-chromosome exons. The mutation cosegregated with the clinical phenotype in this family. An 18-year-old patient and his 40-year-old maternal uncle were evaluated. Clinical examination showed normal growth parameters, lingual fasciculation, limited extension of the elbows and metacarpophalangeal joints, and acrocyanosis. There was neither facial dysmorphism nor marfanoid habitus. Brain MRI detected a dysplastic corpus callosum. Neuropsychological testing showed mild intellectual disability. They both displayed generalized anxiety disorder, and the younger patient also suffered from significant behavior impairment that required attention or treatment. Speech evaluation detected satisfactory spoken language since both were able to provide information and to understand conversations of everyday life. Occupational therapy examination showed impaired visual-spatial and visual-motor performance with poor drawing/graphic skills. These manifestations are not specific enough to guide ZDHHC9 screening in patients with ID, and emphasize the value of next generation sequencing for making a molecular diagnosis and genetic counseling in families with XLID.

ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia.

Mutations in the ARX gene cause both nonsyndromic and several forms of syndromic mental retardation (MR). Two polyalanine (polyA) expansions of ARX are recurrent mutations. The most common one, the c.428_451dup, is associated with a wide spectrum of phenotypes, ranging from the most severe West syndrome to Partington syndrome (MR and hand dystonia), and even nonsyndromic X-linked mental retardation (NS-XLMR). Studies of patients not selected for specific clinical signs showed that the c.428_451dup is relatively frequent in families harboring X-linked MR (7.5%), but less common in familial cases compatible with X-linked NR (1%), and very rare in sporadic cases (0.1%). The c.333_334ins(GCG)7 expansion is less frequent and mainly associated with West syndrome. We screened for both ARX polyA expansions in 98 unrelated patients selected for the presence of NR associated with different types of epilepsy and/or with hand dystonia. We also studied two families with an initial diagnosis of NS-XLMR, one of which was identified as showing linkage to the ARX locus. The c.428_451dup was identified in three patients and the c.333_334ins(GCG)7 in one; all of the patients were from families with two affected brothers. We also found the c.428_451dup in the family linked to ARX, and clinical re-evaluation showed subtle, previously undetected signs. Our study illustrates that ARX polyA expansions are primarily associated with syndromic MR and shows a higher yield (18% in our cohort) when these mutations are screened in familial cases of MR with epilepsy and/or dystonia.

Hypokalemia is associated with lengthening of QT interval in psychiatric patients on admission.

Several studies have revealed a relatively high frequency of hypokalemia in the general psychiatric population. This may be explained by adrenergic stimulation observed in the acute phase of psychiatric disorders. Little is known about the effects of hypokalemia on cardiac repolarisation in these circumstances. The current study was designed to determine if the hypokalemia observed among patients with acute psychiatric disorders can cause significant QT interval prolongation, and thus increase the risk of ventricular arrhythmia. Electrocardiograms were obtained in 282 non-selected patients admitted to a psychiatric unit. Heart-rate adjusted QT intervals (QTc) were compared to serum potassium levels and to other risk factors for QT prolongation (bradycardia, age, gender, and administration of antipsychotics). Hypokalemia, diagnosed in more than 11% of the patients, was associated with a significantly longer QTc interval (means 423.5+/-40 ms vs 408.5+/-31 ms), as was female sex. Multiple linear regression analysis on the studied risk factors revealed that only hypokalemia and female sex were independently associated with lengthening of the QT interval. According to our results, hypokalemia seems to be one of the most important risk factors for QT prolongation. We therefore strongly recommend that psychiatric patients should be screened for hypokalemia on admission.

[In chronic hepatitis C, delays between diagnosis and treatment are linked to the doctor-patient relationship]. / Dans l'hépatite chronique C, les délais entre diagnostic et traitement sont liés à la relation médecins-patients.

An epidemiological survey conducted in Côte d'Or and Doubs in 2004 showed that out of 1,251 patients carrying HCV, only 1 in 4 was treated whereas 1 in 6 evades medical care after diagnosis. A study carried out in Burgundy in 2006-2008 aimed to identify the key factors underlying insufficiency in medical care of hepatitis C. Semi-structured in-depth interviews were conducted with 25 medical doctors. They covered the frequency with which doctors were confronted with hepatitis C and the difficulties encountered in its management. The interviews with patients explored the circumstances of diagnosis, therapeutic route, perceptions regarding infection and its treatment and relationships with healthcare providers. The study showed a variability in delays between diagnosis and treatment that can be explained by the functioning of the doctor-patient relationship, and the choices of medical strategies. To prevent more efficiently hepatitis C complications, treatment acceptance by patients needs to be improved and doctors' hesitations in prescribing it lessened. Efforts should also be made to reduce the iatrogenic side effects of the treatment, and improve general practitioners' training with respect to viral hepatitis, and interaction between the medical specialities involved, in order to develop greater consensus in therapeutic strategies to be adopted.

[Antipsychotic drugs and cardiovascular safety: need for monitoring the QT interval]. / Risque cardiovasculaire des antipsychotiques, une surveillance nécessaire de l'intervalle QT.

Torsades de pointes (TdP), a form of ventricular arrhythmia that can cause ventricular fibrillation and sudden death, may occur during prolongation of the QT interval. QT prolongation has recently been reported with antipsychotic drugs. Physicians should be able to obtain a corrected measurement of the QT interval. QT is measured from the beginning of the QRS complex to the end of the T wave (QTm). This value must then be corrected to take heartbeat into account. The most common formula in current use is Bazett's. In practice, a QTc interval value greater than 500 ms indicates an increased risk of TdP. Safe combinations of antipsychotic drugs have been recommended by the French drug agency (Agence française de sécurité sanitaire des produits de santé). Many other drugs, including psychotropic drugs such as tricyclic antidepressants, can prolong the QT interval. Combinations of these medications with one another, with antipsychotic medications, or with other concomitant factors, such as hypokalemia, also increase the risk. TdP is most often diagnosed only after observing QT prolongation. This underlines the need to monitor QT intervals attentively to prevent the risk of cardiac arrhythmia in patients treated with antipsychotic drugs.

[Post-stroke depression, another handicap]. / Dépression après un accident vasculaire cérébral, un handicap supplémentaire.

INTRODUCTION: Post-stroke depression is a severe complication affecting 30-50% of patients during the first year. Experienced medical and paramedical staff in stroke units, using validated scales, can now identify initial signs of depression in the first days after stroke onset. METHODS: This review of the literature is based on a Medline search for the terms stroke, depression, and epidemiology. It discusses problems of pathophysiology, diagnosis, prognosis, and therapeutics. RESULTS: Depression is an emergency in stroke patients because it impedes rehabilitation and family and social insertion. Early diagnosis is difficult, but possible with clinical somatic and cognitive symptoms. Post-stroke depression may also be a marker of pending cognitive decline. Management requires both antidepressants and psychotherapy. CONCLUSION: There is a pressing need for further research to improve clinical practice in this area of stroke care.

A de novo microdeletion of SEMA5A in a boy with autism spectrum disorder and intellectual disability.

Semaphorins are a large family of secreted and membrane-associated proteins necessary for wiring of the brain. Semaphorin 5A (SEMA5A) acts as a bifunctional guidance cue, exerting both attractive and inhibitory effects on developing axons. Previous studies have suggested that SEMA5A could be a susceptibility gene for autism spectrum disorders (ASDs). We first identified a de novo translocation t(5;22)(p15.3;q11.21) in a patient with ASD and intellectual disability (ID). At the translocation breakpoint on chromosome 5, we observed a 861-kb deletion encompassing the end of the SEMA5A gene. We delineated the breakpoint by NGS and observed that no gene was disrupted on chromosome 22. We then used Sanger sequencing to search for deleterious variants affecting SEMA5A in 142 patients with ASD. We also identified two independent heterozygous variants located in a conserved functional domain of the protein. Both variants were maternally inherited and predicted as deleterious. Our genetic screens identified the first case of a de novo SEMA5A microdeletion in a patient with ASD and ID. Although our study alone cannot formally associate SEMA5A with susceptibility to ASD, it provides additional evidence that Semaphorin dysfunction could lead to ASD and ID. Further studies on Semaphorins are warranted to better understand the role of this family of genes in susceptibility to neurodevelopmental disorders.

[Specificity of stroke in the elderly: clinical characteristics and impact on care]. / Particularités de l'accident vasculaire cérébral du sujet âgé et impact sur la prise en charge.

Stroke in the elderly differs from stroke in younger adults in several points. It represents the most frequent consequence of atherothrombotic disease associated with hypertension, diabetes and hypercholesterolemia. It is also the main complication of cardiac arrhythmia. From a clinical point of view, epileptic seizure is frequently observed at the onset, and prognosis is darkened by a high risk of dementia occurrence (20%). Management of stroke in acute phase requires intensive care, which has been shown to decrease mortality and handicap by 20% in Stroke Units. Fibrinolysis with rt-PA can be carried out till 80 years. Primary and secondary prevention are still very efficacious in old patients and decrease not only the risk of stroke, but also the risk of dementia. Moreover, influenzae vaccination has been shown to decrease the risk of stroke in the following year in subjects over 65 years.

20 ans après: a second mutation in MAOA identified by targeted high-throughput sequencing in a family with altered behavior and cognition.

Intellectual disability (ID) is characterized by an extraordinary genetic heterogeneity, with >250 genes that have been implicated in monogenic forms of ID. Because this complexity precluded systematic testing for mutations and because clinical features are often non-specific, for some of these genes only few cases or families have been unambiguously documented. It is the case of the X-linked gene encoding monoamine oxidase A (MAOA), for which only one nonsense mutation has been identified in Brunner syndrome, characterized in a single family by mild non-dysmorphic ID and impulsive, violent and aggressive behaviors. We have performed targeted high-throughput sequencing of 220 genes, including MAOA, in patients with undiagnosed ID. We identified a c.797_798delinsTT (p.C266F) missense mutation in MAOA in a boy with autism spectrum disorder, attention deficit and autoaggressive behavior. Two maternal uncles carry the mutation and have severe ID, with a history of maltreatment in early childhood. This novel missense mutation decreases MAOA enzymatic activity, leading to abnormal levels of urinary monoamines. The identification of this new point mutation confirms, for the first time since 1993, the monogenic implication of the MAOA gene in ID of various degrees, autism and behavioral disturbances. The variable expressivity of the mutation observed in male patients of this family may involve gene-environment interactions, and the identification of a perturbation in monoamine metabolism should be taken into account when prescribing psychoactive drugs in such patients.

Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation.

CONTEXT: Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia. OBJECTIVES: To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category. DESIGN: Case-control study. SETTING: Academic research. PARTICIPANTS: We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls. MAIN OUTCOME MEASURES: Collective and individual frequencies of the analyzed CNVs in cases compared with controls. RESULTS: Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes. CONCLUSIONS: Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.

Brain injured patients versus multiple trauma patients: some neurobehavioral and psychopathological aspects.

BACKGROUND: The study aims to describe the neurobehavioral and psychopathological disorders in road crash victims with cerebral lesions compared with multiple trauma sufferers with no brain damage. METHODS: This study compares the neuropsychological and psychopathological developments of two groups of road crash victims (25 severe brain injuries (SBI) and 25 multiple traumas (MULT)) on the basis of the Neurobehavioral Scale, the SCL 90-R and the State/Trait Anxiety Scale. RESULTS: On the basis of the Neurobehavioral Scale, it was clear that the SBI patients suffered from significantly more disorders of type factor 1 (self-appraisal and flexible thinking), factor II (withdrawal), factor III (mood swings, irritability, disinhibition, excitement), factor IV (attention, slower motor responses, and mental fatigue), factor V (articulatory problems, problems of oral expression, and oral comprehension) and nonfactored disorders (exaggerated somatic concerns). On the SCL 90-R scale, we observed a higher level of obsessive symptoms in the SBI patients, whereas there was no significant difference between the two groups on the State/Trait Anxiety Scale. Unexpected results indicated that the multiple trauma patients suffered from memory troubles (60%), concept disorganization (32%), loss of initiative (36%), irritability (52%), unusual thought content (40%), mood swings (40%), attention difficulties (24%), suspiciousness (48%), and feelings of guilt (36%). CONCLUSION: Even though multiple trauma sufferers do not receive a psychologic assessment of their cerebral functioning, and do not benefit from any rehabilitation, they exhibit neurobehavioral and psychopathological disorders which need to be taken into account when designing rehabilitation programs. This study points toward new therapeutic methods for the treatment of multiple trauma sufferers.