Effects of an intervention program to improve mental health and epilepsy care in Madagascar.

BACKGROUND: Despite the high prevalence of mental disorders and epilepsy in low- and middle-income countries, nearly 80% of patients are not treated. In Madagascar, initiatives to improve access to epilepsy and mental health care, including public awareness and training of general practitioners (GPs), were carried out between 2013 and 2018. Our study's main objective was to assess the effectiveness of these initiatives, two to five years post-intervention. METHODS: This quasi-experimental study (intervention vs. control areas) included five surveys assessing: general population's Knowledge Attitudes and Practices (KAP), GPs' KAP , number of epilepsy and mental health consultations at different levels of the healthcare system, diagnostic accuracy, and treatments' availability. OUTCOMES: In the general population, KAP scores were higher in intervention areas for epilepsy (11.4/20 vs. 10.3/20; p = 0.003). For mental disorders, regardless of the area, KAP scores were low, especially for schizophrenia (1.1/20 and 0.1/20). Among GPs, KAP scores were higher in intervention areas for schizophrenia (6.0/10 vs. 4.5/10; p = 0.008) and epilepsy (6.9/10 vs. 6.2/10; p = 0.044). Overall, there was a greater proportion of mental health and epilepsy consultations in intervention areas (4.5% vs 2.3%). Although low, concordance between GPs' and psychiatrists' diagnoses was higher in intervention areas. There was a greater variety of anti-epileptic and psychotropic medications available in intervention areas. INTERPRETATION: This research has helped to better understand the effectiveness of initiatives implemented in Madagascar to improve epilepsy and mental health care and to identify barriers which will need to be addressed. FUNDING: Sanofi Global Health, as part of the Fight Against STigma Program.

Knowledge, attitudes, and practices of health sciences students regarding epilepsy at the end of their curriculum in Benin.

OBJECTIVE: The main objective of this study was to evaluate the knowledge, attitudes, and practices (KAP) of health sciences students regarding epilepsy at the end of their curriculum in Benin. METHODS: We conducted a cross-sectional survey among medical, pharmacy, nursing, and midwife students in their last year of health sciences training in the University of Abomey-Calavi in Benin. Students completed a self-administered questionnaire, containing items addressing demographics, epilepsy treatment, diagnosis, clinical practice, and social tolerance regarding a person with epilepsy (PWE). RESULTS: The response rate to our survey was 87.7% (n = 164). The sample consisted of 64 medical students, 22 pharmacy students, 43 nursing students, and 35 midwife students. They were divided into 95 female subjects and 69 males; sex ratio was 0.7. The mean age of participants was 23.6 ±â€¯1.8 years. The mean scores for epilepsy knowledge, practices, and attitudes were respectively 7.6 ±â€¯1.7 out of a maximum score of 11, 3.9 ±â€¯1.8 out of 8, and 9.6 ±â€¯0.8 out of 10. The KAP overall score was 21.1 ±â€¯3.4 out of a maximum score of 29.0. The variables associated with the overall KAP score were training school, gender, having heard about epilepsy before health sciences studies (p = 0.017), and having a relative with epilepsy (p = 0.001). Male students and medical school students had significantly better overall KAP score than female students or the other training schools respectively (p < 0.001). SIGNIFICANCE: These findings support the need to improve the health sciences students' knowledge of epilepsy, in particular, during their training.

BLAST paradigm: A new test to assess brief attentional fluctuations in children with epilepsy, ADHD, and normally developing children.

BACKGROUND: Pure attentional deficits are still underdiagnosed in children with epilepsy. While attention-deficit hyperactivity disorder (ADHD) is historically the most studied cause of attentional disorders, an important number of children with epilepsy and attentional complaints do not fully meet the DSM-V (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition) criteria for ADHD and may be excluded from specific care. Clinical tools currently available are insufficient to detect more subtle but clinically relevant attentional fluctuations. OBJECTIVE/METHODS: The recently developed Bron-Lyon Attention Stability Test (BLAST) was used to evaluate brief attentional fluctuations with a high temporal precision. Drawing on two new attentional indices, we evaluated spontaneous fluctuations of response accuracy and timing, underlying attentional stability. The main objective was to assess attentional stability in children with i) epilepsy with comorbid ADHD, ii) epilepsy without comorbid ADHD, iii) ADHD not medicated and without epilepsy, and iv) normal development. Further objectives were to assess the main determinants of attentional stability in those groups, including the effect of factors related to the epileptic condition. RESULTS: In 122 children with epilepsy (67 with comorbid ADHD), 52 children with ADHD, and 53 healthy controls, we demonstrated lower attentional stability in both the groups with epilepsy and ADHD compared with healthy children. In children with epilepsy, BLAST scores were negatively associated with earlier seizure onset and AED (antiepileptic drug) polytherapy, while the seizure frequency, epilepsy duration, or type did not influence BLAST scores. CONCLUSIONS: This study demonstrates that attentional stability is impaired in children with epilepsy and/or ADHD. Bron-Lyon Attention Stability Test seems to be a sensitive test to detect attentional stability deficit in children with epilepsy and with attentional complaints who did not meet all criteria of ADHD. We propose that BLAST could be a useful clinical neuropsychological tool to assess attentional disorders in children.

Co-morbidities of mental disorders and chronic physical diseases in developing and emerging countries: a meta-analysis.

BACKGROUND: As the data on the association of mental disorders and chronic physical diseases in developing and emerging countries is heterogeneous, this study aims to produce the first meta-analysis of these comorbidities. METHODOLOGY: The meta-analysis protocol was registered in PROSPERO (N°CRD42017056521) and was performed in accordance with PRISMA guidelines. Initially, an article search was conducted on Medline, Embase, Lilacs and the Institut d'Epidémiologie et de Neurologie Tropicale database [Institute of Epidemiology and Tropical Neurology], as well as manually, with no restriction on language or date focusing on mental disorders, chronic diseases and neurotropic diseases. Two independent investigators assessed the quality of the studies which met the inclusion criteria using the Downs and Black assessment grid. The pooled estimates were calculated out using a random-effects method with CMA software Version 3.0. A meta-regression was then performed, and the significance level was set at 0.05. RESULTS: Of the 2604 articles identified, 40 articles involving 21,747 subjects met the inclusion criteria for co-morbidities between mental disorders and chronic physical diseases. Thirty-one articles were included in the meta-analysis of prevalence studies and 9 articles in that of the analytical studies. The pooled prevalence of mental disorders in patients with chronic physical diseases was 36.6% (95% CI, 31.4-42.1) and the pooled odds ratio was 3.1 (95% CI, 1.7-5.2). There was heterogeneity in all the estimates and in some cases, this was explained by the quality of the studies. CONCLUSION: Some estimates regarding the prevalence of mental disorders in people with chronic physical diseases living in developing and emerging countries were similar to those in developed countries. Mental disorders are a burden in these countries. In order to respond effectively and efficiently to the morbidity and mortality associated with them, mental health care could be integrated with physical care.

Associations of mental disorders and neurotropic parasitic diseases: a meta-analysis in developing and emerging countries.

BACKGROUND: Although they are declining worldwide, neurotropic parasitic diseases are still common in developing and emerging countries. The aim of this study was to estimate the pooled prevalence and pooled association measures of comorbidities between mental disorders (anxiety, depression, bipolar disorder, and schizophrenia) and neurotropic parasitic diseases (malaria, cysticercosis, toxoplasmosis, human African trypanosomiasis, Chagas disease, and human toxocariasis) in developing and emerging countries. METHODS: As the first meta-analysis on this topic, this study was performed in accordance with PRISMA guidelines. The protocol was registered in PROSPERO (N°CRD42017056521). The Medline, Embase, Lilacs, and Institute of Epidemiology and Tropical Neurology databases were used to search for articles without any restriction in language or date. We evaluated the quality of studies independently by two investigators using the Downs and Black assessment grid and pooled estimates using the random-effects method from CMA (Comprehensive Meta Analysis) Version 3.0. RESULTS: In total, 18 studies published between 1997 and 2016 met our inclusion criteria. We found that the prevalence of anxiety and depression in people suffering from Chagas disease and/or neurocysticercosis was 44.9% (95% CI, 34.4-55.9). In 16 pooled studies that included 1782 people with mental disorders and 1776 controls, toxoplasmosis and/or toxocariasis were associated with increased risk of schizophrenia and/or bipolar disorders (odds ratio = 2.3; 95% CI, 1.7-3.2). Finally, toxocariasis and/or toxoplasmosis were associated with an increased risk of the onset of schizophrenia (odds ratio = 2.4; 95% CI, 1.7-3.4). CONCLUSION: Our pooled estimates show that the associations between diseases studied are relatively high in developing and emerging countries. This meta-analysis supports the hypothesis that toxoplasmosis could be the cause of schizophrenia. These findings could prove useful to researchers who want to further explore and understand the associations studied.

Epilepsy-associated levels of perceived stigma, their associations with treatment, and related factors: A cross-sectional study in urban and rural areas in Ecuador.

BACKGROUND: Epilepsy is felt to be a stigmatizing condition. Stigma has been considered one of the major factors contributing to the burden of epilepsy and to the treatment gap. Stigma has a negative effect on the management of people with epilepsy (PWE). Furthermore, lack of information and inappropriate beliefs are still the factors that most contribute to stigma and discrimination. In this study, we assessed the level of perceived stigma in urban and rural areas and we report their association with in antiepileptic drug (AED) use, effects on seeking medical care, and stigma-associated factors. METHODS: A cross-sectional study in urban and rural areas in Ecuador from January 2015 until May 2016. People with a confirmed diagnosis of epilepsy were included using three sources of information. The survey was implemented through a questionnaire to determine perceived stigma and evaluate the factors associated. The perceived stigma was measured using the revised Jacoby's stigma scale to detect differences in levels of stigmatization. Access to treatment was evaluated through self-report of AED use, and attainment of medical care and stigma-associated factors were assessed. Furthermore, a multivariate analysis adjusted for possible confounders was performed using stigma as the outcome variable. RESULTS: A total of 243 PWE were interviewed, 65.8% reported feeling stigmatized and 39.1% reported a high stigmatized level. We found a significant difference in high stigma perception in the urban area compared to the rural area. However, the lack of use of AEDs was significantly higher in the rural areas. No significant correlation was found between use of AEDs and the levels of perceived stigma. PWE who did not talk about their condition and those who did not feel well informed about their epilepsy had significantly higher perceived stigma levels. Additionally, the multivariate analysis demonstrated that area, educational level, type of seizure, talk about epilepsy, and information were associated with perceived stigma. CONCLUSION: The stigma perception was relevant in all PWE. We found a higher stigma level perception in the urban compared to rural area. Moreover, the lack of treatment was a serious problem mainly in rural areas. Even though we did not find that perceived stigma was associated with AED use, our study pointed out the influence of educational level and information related to stigmatization. Consequently, a coordinated effort to reduce stigma should include strategies focused on PWE education and information about their condition.

Impact of an educational comic book on epilepsy-related knowledge, awareness, and attitudes among school children in Ethiopia.

INTRODUCTION: Epilepsy is of worldwide public health importance because it is common, often accompanied by physical and cognitive disabilities, and is widely stigmatized. The incidence of epilepsy in Ethiopia was reported to be 64/100,000 population and a prevalence of 520/100,000 population. A minority of subjects is treated, and religious and sociocultural beliefs influence the nature of treatment and care. One approach to support the development of positive attitudes toward individuals with disabilities is through the use of comics. Comics have been effective in creating awareness and educating about epilepsy. MATERIAL AND METHODS: We conducted a cross-sectional study among randomly selected students from two preparatory schools (one from a city and the other from a rural area) in June 2014. We collected information using a structured KAP questionnaire before and after reading a comic book. The comic book relevance was assessed by 40 health professionals. RESULT: One hundred sixteen students from urban and 110 from rural high schools were enrolled in the present study with an age distribution of 31.9% in 16-17years, 48.7% in 18-19years, and 19.5% in 20+years. Thirty percent of the urban school was male compared with sixty-five percent of the rural school. The comic book was recommended as useful educational material to be distributed among school children by 90% of interviewed health professionals (internists, neurologist, psychiatrists, residents, GPs, and nurses). CONCLUSION: The comic book was appreciated by the Ethiopian high school students. After brief exposure to the comic book, students could extract a great deal of information, it could change misconceptions and provide correct information about epilepsy, and can be an effective approach to epilepsy awareness creation. Health professionals found the comic book to be very informative and recommended its distribution to students, teachers, nurses, libraries, and community/religious leaders. Illustrations were Ethiopian-oriented.

Evaluating the feasibility of prehospital point-of-care EEG: The prehospital implementation of rapid EEG (PHIRE) study.

Background: Point-of-care electroencephalography (EEG) devices can be rapidly applied and do not require specialized technologists, creating new opportunities to use EEG during prehospital care. We evaluated the feasibility of point-of-care EEG during ambulance transport for 911 calls. Methods: This mixed-methods study was conducted between May 28, 2022 and October 28, 2023. Emergency Medical Services (EMS) clinicians identified eligible individuals, provided emergent treatment, applied EEG, and obtained an EEG recording during ambulance transport. Eligible patients were aged 6 years or older and evaluated for seizure, stroke, or altered mental status. EMS clinicians completed a survey and a brief phone interview following every enrollment. Two epileptologists reviewed EEG recordings for interpretability and artifact. Results: There were 34 prehospital encounters in which EEG was applied. Patients had a mean age of 69 years, and 15 (44%) were female. EEG recordings had a median duration of 10 min 30 s. It took EMS clinicians an average of 2.5 min to apply the device and begin EEG recording. There were 14 (47%) recordings where clinicians achieved a high-quality connection for all 10 electrodes and 32 (94%) recordings that were sufficient in quality to interpret. There were 24 (71%) recordings with six or more channels free of artifact for 5 min or more. All clinicians agreed or strongly agreed that the device was easy to use. Conclusion: Among real-world prehospital encounters for patients with neurologic symptoms, point-of-care EEG was rapidly applied and yielded EEG recordings that could be used for clinical interpretation, demonstrating the feasibility of point-of-care EEG in future prehospital care.

Epilepsy in Asia: a Cambodian experience.

Epilepsy is particularly challenging for resource-poor countries and in turn for Asia which is likely to have greater challenges in terms of treatment cost and deficit, premature mortality, health transitions, population and poverty size, etc. Here we present an example of working in one of the resource-poor 'least-talked-about' populations to demonstrate that finding financial means and achieving cross-country cooperation over a long period of time is possible even in countries with currently limited resources. Conducting such cooperation could be a model for other initiatives. Scientific, capacity-building, and political tools should be employed to generate local representative data and influence government policies. These measures can be of immediate benefit for patients in these countries.

Comprehensive evaluation of the psychosocial parameters of epilepsy: a representative population-based study in Prey Veng (Cambodia).

PURPOSE: We conducted a population-based study of epilepsy in Prey Veng (Cambodia) to explore self-esteem, fear, discrimination, knowledge-attitude-practice (KAP), social-support, stigma, coping strategies, seizure-provoking factors, and patient-derived factors associated with quality of life (QOL). METHODS: The results are based on a cohort of 96 cases and matched controls (n = 192), randomly selected from the same source population. Various questionnaires were developed and validated for internal consistency (by split-half, Spearman-Brown prophecy, Kuder-Richardson 20), content clarity and soundness. Summary, descriptive statistics, classical tests of hypothesis were conducted. Uncorrected chi-square was used. Group comparison was done to determine statistically significant factors, for each domain, by conducting logistic regression; 95% confidence interval (CI) with 5% (two-sided) statistical significance was used. KEY FINDINGS: All questionnaires had high internal consistency. Stress was relevant in 14.0% cases, concealment in 6.2%, denial in 8.3%, negative feelings in public in 3.0%. Mean self-esteem was 7.5, range 0-8, related to seizure frequency. Mean discrimination was least during social interactions. Coping strategies were positive (e.g. look for treatment). Postictal headache, anger, no nearby health facility, etc. were associated with QOL. SIGNIFICANCE: The reliability of our questionnaires was high. A positive social environment was noted with many infrequent social and personal prejudices. Not all populations should (by default) be considered as stigmatized or equipped with poor KAP. We addressed themes that have been incompletely evaluated, and our approach could therefore become a model for other projects.

Functionalized calcium carbonate as a novel pharmaceutical excipient for the preparation of orally dispersible tablets.

PURPOSE: To overcome the limitation of insufficient hardness during the production of rapidly disintegrating orally dispersible tablets (ODTs). Furthermore, we investigated the properties and usefulness of functionalized calcium carbonate (FCC) as a new pharmaceutical excipient for the production of ODTs. METHODS: A highly sensitive tensiometer-based method was developed to measure kinetics of weight loss during tablet disintegration. With this method we were able to determine the residence time of tablets placed on a basket immersed into a test medium. The shapes of tensiometer plots allowed us to categorize substances into four different types of disintegration. RESULTS: At the same volume and hardness, the tablet formulations with FCC showed a significantly higher porosity (over 60%) than all other formulations. Residence time depended mainly on the tablet composition rather than on porosity. When combined with disintegrants, FCC formulations exhibited favorable disintegration properties, comparable to those of the marketed drug risperidone oro (disintegration time ca. 10 s). CONCLUSIONS: Oral dosage forms--based on the new pharmaceutical excipient FCC--can be designed to have a short disintegration time combined with good mechanical strength. Due to these properties, FCC can be used for the preparation of ODTs.

Effect of Sub-Inhibitory Concentrations of Nitrofurantoin, Ciprofloxacin, and Trimethoprim on In Vitro Biofilm Formation in Uropathogenic Escherichia coli (UPEC).

The purpose of this study was to determine the effect of sublethal concentrations of nitrofurantoin, ciprofloxacin, and trimethoprim on biofilm formation in 57 uropathogenic Escherichia coli strains (UPEC). The minimum inhibitory concentration of nitrofurantoin, ciprofloxacin, and trimethoprim was determined and the biofilm formation for each isolate with and without sub-lethal concentrations of each antibiotic was then quantified. The statistical significance of changes in biofilm formation was ascertained by way of a Dunnett's test. A total of 22.8% of strains were induced to form stronger biofilms by nitrofurantoin, 12% by ciprofloxacin, and 19% by trimethoprim; conversely 36.8% of strains had inhibited biofilm formation with nitrofurantoin, 52.6% with ciprofloxacin, and 38.5% with trimethoprim. A key finding was that even in cases where the isolate was resistant to an antibiotic as defined by EUCAST, many were induced to form a stronger biofilm when grown with sub-MIC concentrations of antibiotics, especially trimethoprim, where six of the 22 trimethoprim resistant strains were induced to form stronger biofilms. These findings suggest that the use of empirical treatment with trimethoprim without first establishing susceptibility may in fact potentiate infection in cases where a patient who is suffering from a urinary tract infection (UTI) caused by trimethoprim resistant UPEC is administered trimethoprim. This emphasizes the need for laboratory-guided treatment of UTI.

First-ever, door-to-door cross-sectional representative study in Prey Veng province (Cambodia).

PURPOSE: To estimate the lifetime prevalence of epilepsy in Prey Veng province (Cambodia). METHODS: Door-to-door screening was performed using a random cluster survey whereby all people >1 year of age were screened for epilepsy by using a validated and standardized questionnaire for epilepsy in tropical countries. Suspected epilepsy patients identified by the questionnaire were revisited and examined by epileptologists. The confirmation of epilepsy was based on an in-depth clinical examination. Electroencephalograms were recorded at the community dispensary. KEY FINDINGS: Five hundred three potential epilepsy cases were identified from 16,510 screened subjects, and 96 were diagnosed to have epilepsy. An overall prevalence of 5.8 per 1,000 [95% confidence interval (CI) 4.6-7.0 per 1,000] was obtained. Generalized epilepsy (76%) was more common than partial epilepsy (12.5%). Three cases were of generalized myoclonic epilepsy (3.1%) and one case each (1.0%) were of absence and olfactory partial epilepsy. Six cases (5.2%) had more than one seizure type [one case with absence + generalized tonic-clonic (GTC), one case each with GTC + partial seizures with secondary generalization and absence + generalized myoclonic seizures and absence + simple partial seizures, and two cases with GTC + complex partial seizures]. Electroencephalography (EEG) studies revealed spike and wave discharges in 43.8%, focal spikes in 21.0%, generalized slow waves in 19.2%, and generalized slowing of background in 15.7%. SIGNIFICANCE: This is the first population-based study in Cambodia that had epilepsy as a primary objective, and compared to Western and neighboring countries it shows a lower prevalence.

Angiotensin II for Near Drowning: A Case Series.

This case series describes the effect of angiotensin II administration on hemodynamics in patients with parenchymal lung injury due to submersion injury. CASE SUMMARY: A 33-year-old female and a 72-year-old female were both brought to the emergency department after incidents of near drowning. Upon arrival to the emergency department, both patients were hemodynamically unstable and were eventually intubated for airway protection. Imaging done by conventional chest radiograph for both patients revealed bilateral pulmonary edema. Due to their hemodynamic status, vasopressors were initiated for both patients and were quickly titrated, leading to the initiation of angiotensin II. In one patient, angiotensin II was initiated early in shock and resulted in rapid improvement of hemodynamics. In the other patient, angiotensin II was initiated later and a more muted response was observed. CONCLUSIONS: In patients with near drowning, angiotensin II appeared to improve hemodynamic status rapidly. This is the first case series to report the use of this new vasoactive agent in this population and poses noteworthy mechanistic considerations.

Knowledge, attitudes and practices in mental health of health professionals at the end of their curriculum in Burkina Faso: A pilot study.

Aim: To study the knowledge, attitudes and practices regarding mental health amongst health professionals at the end of their curriculum in Burkina Faso. Design: A descriptive and cross-sectional study was adopted. Methods: A simple random sampling was used to select 420 health students in Burkina Faso. Self-administered questionnaires on sociodemographic profile, knowledge, attitudes and practices about mental health were distributed. Results: The response rate to the questionnaires was 93%. Our study sample included 391 students amongst whom 35% (138/391) were nurse students, 32% (125/391) medical students, 26% (100/391) midwife students and 7% (28/391) were pharmacy students. A quarter of our sample had completed an internship in psychiatry. Medical students' average knowledge, attitudes and practices in mental health were significantly higher than that of other students. Medical students had more time dedicated to mental health lectures and more opportunities for a mental health internship, unlike nurse students.

Comorbidities of epilepsy in low and middle-income countries: systematic review and meta-analysis.

Epilepsy is a major public health concern in low and middle-income countries (LMICs) and comorbidities aggravate the burden associated with the disease. The epidemiology of these comorbidities has not been well described, although, identifying the main comorbidities of epilepsy, and their relative importance, is crucial for improving the quality of care. Comorbidities were defined as disorders coexisting with or preceding epilepsy, or else compounded or directly attributed to epilepsy or to its treatment. A meta-analysis of the proportion of main comorbidities by subcontinent as well as overall was also conducted. Out of the 2,300 papers identified, 109 from 39 countries were included in this systematic review. Four groups of comorbidities were identified: parasitic and infectious diseases (44% of comorbid conditions), somatic comorbidities (37%), psychosocial (11%), as well as psychiatric comorbidities (8%). Heterogeneity was statistically significant for most variables then random effect models were used. The most frequently studied comorbidities were: neurocysticercosis (comorbid proportion: 23%, 95% CI: 18-29), head trauma (comorbid proportion: 9%, 95% CI: 5-15) malnutrition (comorbid proportion: 16%, 95% CI: 28-40), stroke (comorbid proportion: 1.3%, 95% CI: 0.2-7.0), and discrimination for education (comorbid proportion: 34%, 95% CI: 28-40). Many comorbidities of epilepsy were identified in LMICs, most of them being infectious.

Attention and Executive Disorders in Neurofibromatosis 1: Comparison Between NF1 With ADHD Symptomatology (NF1 + ADHD) and ADHD Per Se.

Objective: To compare children with Neurofibromatosis type 1 and associated ADHD symptomatology (NF1 + ADHD) with children having received a diagnosis of ADHD without NF1. The idea was that performance differences in tasks of attention between these two groups would be attributable not to the ADHD symptomatology, but to NF1 alone. Method: One group of children with NF1 + ADHD (N = 32), one group of children with ADHD (N = 31), and one group of healthy controls (N = 40) participated in a set of computerized tasks assessing intensive, selective, and executive aspects of attention. Results: Differences were found between the two groups of patients in respect of several aspects of attention. Children with NF1 + ADHD did not always perform worse than children with ADHD. Several double dissociations can be established between the two groups of patients. Conclusion: ADHD symptomatology in NF1 does not contribute to all attention deficits, and ADHD cannot account for all attention impairments in NF1.

Mutation screening of the MECP2 gene in a large cohort of 613 fragile-X negative patients with mental retardation.

Mental retardation affects 2 to 3% of the population and is marked by significant etiological heterogeneity, including genetic and non genetic causes. FRAXA (FMR1) trinucleotide expansion is widely searched in routine screening, but found in only about 2% of the patients tested. Mutations of the MECP2 (methyl-CpG-binding protein) gene mainly cause Rett syndrome but were also shown to be involved in mental retardation. This study aimed to estimate the frequency of MECP2 gene mutations in a large group of mentally retarded patients without FRAXA expansion. Screening by heteroduplex analysis and SSCP followed by DNA sequencing of shifted bands were performed on 613 patients, including 442 males and 171 females. Eleven sequence variants were found, including nine polymorphisms. The two others may be pathogenetic. The first one, the double nucleotide substitution c.1162_1163delinsTA leading to a premature stop codon (p.Pro388X) was found in a female patient with random X-inactivation, presenting with borderline mental impairment without any features of Rett syndrome. The second one, the c.679C>G substitution, changing a glutamine to a glutamate in the transcriptional repression functional domain (p.Gln227Glu), was found in a female patient with a moderately biased X-chromosome inactivation profile and presenting with mild intellectual delay and minor psychotic features. The low mutation rate suggests that a large-scale routine screening for MECP2 in mentally retarded subjects is not cost-effective in clinical practice. Screening may be improved by a pre-selection based on clinical features that remain to be established.

Asperger syndrome and early-onset schizophrenia associated with a novel MECP2 deleterious missense variant.

Methyl-CpG-binding protein 2 (MECP2) deleterious variants, which are responsible for Rett syndrome in girls, are involved in a wide spectrum of developmental disabilities in males. A neuropsychiatric phenotype without intellectual disability is uncommon in patients with MECP2 deleterious variants. We report on two dizygotic twins with an MECP2-related psychiatric disorder without intellectual disability. Neuropsychological and psychiatric phenotype assessments were performed, and a genetic analysis was carried out. Both patients fulfilled the Pervasive Developmental Disorder criteria on Autism Diagnostic Observation Schedule and Asperger syndrome criteria on Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). One patient developed early-onset schizophrenia (DSM-IV criteria) with two acute psychotic episodes, the latest one following corticosteroids and sodium valproate intake, with major hyperammonemia. A novel MECP2 gene transversion c.491 G>T [p.(Ser164Ile)] was found in both twins. Pathogenicity of this variant was considered on the basis of strong clinical and molecular data. The underlying molecular basis of neuropsychiatric disorders may have important consequences on genetic counseling and therapeutic strategies.