Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.

DNA mutational events are increasingly being identified in autism spectrum disorder (ASD), but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA) is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement and interact with DNA mutations in the pathogenesis of the disorder.

Three sibs with microcephaly, clubfeet and agenesis of corpus callosum: a new genetic syndrome?

Clubfoot is a common birth deformity, and agenesis of the corpus callosum is one of the most prevalent brain malformations. We describe three sibs of Arab origin, who were born with clubfeet, agenesis of corpus callosum, and minor anomalies. Two of them were born with microcephaly. This phenotype may represent a novel autosomal recessive genetic condition.

X-linked mental retardation with alacrima and achalasia-Triple A syndrome or a new syndrome?

We describe a consanguineous Israeli Arab kindred with five males in two interrelated families with intellectual disabilities, alacrima, achalasia, and mild autonomic dysfunction. Adrenal function is normal. Their phenotype is similar to the phenotype observed in autosomal recessive Triple A syndrome except for the presence of mental retardation in all affected individuals. The pedigree is compatible with either X-linked or autosomal recessive inheritance. Sequencing of the AAAS gene causing autosomal recessive Triple A syndrome did not reveal mutations. Genotyping of affected family members identified a 16.4 Mb continuous segment of identical alleles shared by the patients between markers rs2748314 and rs5906782 on Xp11.23-p21, establishing linkage to chromosome X. This study further confirms genetic heterogeneity in Triple A syndrome and points to a clinically different subtype including significant cognitive impairment.

Fetal alcohol spectrum disorder in Israel.

BACKGROUND: Fetal alcohol spectrum disorder is a range of disabilities caused by gestational exposure to alcohol. FASD is the leading cause of preventable mental retardation and developmental disability in the United States, with an incidence of 1-10 per 1000 live births. FASD in Israel has yet to be examined systematically. OBJECTIVES: To evaluate professionals' experience, awareness and knowledge of FASD in Israel and their awareness of maternal consumption of alcohol, and to collect epidemiological data on the syndrome in Israel. METHODS: A short questionnaire was sent to all 43 program directors of genetic institutes (n = 14) and child developmental centers in Israel (n = 29). Four questions related to their experience and knowledge of FASD. The epidemiological survey included data from all 17 hospitals in Israel and from the two main health management organizations within the public health care system. RESULTS: The response rate was 98% (n = 42). A total of 38.1% of respondents reported having diagnosed at least one case of FASD and fewer than 10% of respondents stated that the knowledge regarding FASD among physicians in Israel was adequate. Developmental pediatricians were more likely to have diagnosed at least one case as compared to geneticists. During the period 1998-2007 the diagnosis of FASD appeared in the records of only 4 patients from the total number of 17 hospitals in Israel. During the same period only six patients were diagnosed at the HMO within the public health care system. CONCLUSIONS: Despite the accumulated knowledge on FASD in many countries and the increase in alcohol consumption in Israel, professionals' awareness of its potential damage is limited. Educational programs to increase physician awareness should accompany publicity campaigns warning the public of the dangers associated with alcohol consumption during pregnancy.

Time trends in reported autistic spectrum disorders in Israel, 1972-2004.

BACKGROUND: Studies from many countries have reported an increasing prevalence of autistic spectrum disorder in childhood. No comprehensive epidemiological studies of ASD have been performed in Israel. OBJECTIVES: To describe time trends in the reported number of patients with ASD in Israel and to characterize the demographic features of the reported patients. METHODS: We reviewed the charts of the National Insurance Institute of Israel from 1972 to 2004 for all children with a diagnosis of ASD receiving disability benefits. RESULTS: A total of 3509 children met the study criteria. Eighty percent were boys and 98% were Jewish. The incidence data showed an increase in the number of cases from zero in 1982-84 and 2 (1.2 per million capita under 18 years) in 1985 to a high of 428 cases in 2004 (190 per million). CONCLUSIONS: This is the first comprehensive study of the incidence of ASD in Israel. According to data derived from official health records, the rate of occurrence of ASD has substantially increased in the last 20 years. Further studies are needed to determine if this is a true increase or if the findings were confounded by external factors, such as recent improvements in diagnostic measures and social stigmas.

Autosomal recessive mental retardation syndrome with anterior maxillary protrusion and strabismus: MRAMS syndrome.

We report on a family in whom the combination of mental retardation (MR), anterior maxillary protrusion, and strabismus segregates. The healthy, consanguineous parents (first cousins) of Israeli-Arab descent had 11 children, 7 of whom (5 girls) were affected. They all had severe MR. Six of the seven had anterior maxillary protrusion with vertical maxillary excess, open bite, and prominent crowded teeth. None of the sibs with normal intelligence had jaw or dental anomalies. The child with MR but without a jaw anomaly was somewhat less severely retarded, had seizures and severe psychosis, which may point to his having a separate disorder. Biochemical and neurological studies, including brain MRI and standard cytogenetic studies, yielded normal results; fragile X was excluded, no subtelomeric rearrangements were detectable, and X-inactivation studies in the mother showed random inactivation. We have been unable to find a similar disorder in the literature, and suggest that this is a hitherto unreported autosomal recessive disorder, which we propose to name MRAMS (mental retardation, anterior maxillary protrusion, and strabismus).

Benign hereditary chorea: clinical, neuroimaging, and genetic findings.

Benign hereditary chorea is an autosomal dominant disease with an early onset of symptoms. In some families, symptoms tend to decrease in adulthood, suggesting that the disorder results from a developmental disturbance in the brain. Individuals with benign hereditary chorea, a nonprogressive disease, have normal or slightly below normal intelligence. The locus for benign hereditary chorea is on chromosome 14. Benign hereditary chorea is a result of mutations in the thyroid transcription factor 1 gene. Previous neuroimaging and pathological investigations of the brain showed no notable abnormalities in patients with this condition. In this study, 5 patients from 1 family with typical clinical features of benign hereditary chorea are presented. Clinical severity varied considerably in the family. Brain magnetic resonance imaging results were normal. Brain single photon emission computed tomography in 3 children, performed 1 hour after intravenous injection of 0.35 mCi/kg of body weight of technetium 99m ethyl cysteinate dimer, showed markedly decreased uptake in the right striatum and the right thalamus in 1 child. The oldest child had mildly reduced uptake in the right putamen and the left thalamus. Brain single photon emission computed tomographic findings in the youngest child were normal. Contrary to other reports of radionuclide brain imaging, notable brain single photon emission computed tomography changes were detected in 2 of 5 patients. Brain single photon emission computed tomography findings did not seem to correlate with the clinical status of the children.

Trauma-induced dystonia and camptocormia in a child.

A 14-year-old male sustained neck trauma during a fight at school. Torticollis developed immediately afterwards, followed by axial dystonia and camptocormia. Thorough evaluation for etiology or background disease, including psychiatric examination, was negative except for the recent trauma. Antidystonia medications, administered after significant worsening of the symptoms, led to improvement. Dystonia and camptocormia resulting from trauma are rare presentations in childhood and adolescence.

Task switching after cerebellar damage.

The authors of this study investigated task switching following cerebellar damage. The study group consisted of 7 children and adolescents (M age=13.8 years) who underwent surgical removal of a benign posterior fossa tumor. They were tested at a sufficient interval after surgery (M lag=6.13 years) for restoration of normal cognitive skills and intelligence. Although all showed normal learning of the task compared with control participants, when rapid behavioral changes were required (short preparation time), they exhibited behavioral rigidity manifested by enhanced switching cost. These results are in line with another study on serial reaction time with the same patients (A. Berger et al., in press). They have important implications for our understanding of the cognitive sequelae of early cerebellar damage as well as the involvement of the cerebellum in task switching.

Familial cognitive impairment with ataxia with oculomotor apraxia.

Ataxia with oculomotor apraxia is an autosomal recessive inherited disease characterized by childhood onset of progressive cerebellar ataxia, oculomotor apraxia, and progressive motor peripheral neuropathy. The mean age at onset is approximately 4.7 years, with oculomotor apraxia appearing a few years later. Diagnosis is based on molecular genetic analysis for mutations of the aprataxin (APTX) gene (chromosome 9p13.1; ataxia with oculomotor apraxia 1). Ataxia with oculomotor apraxia 2 is caused by an unknown gene mutation at locus 9q34. We describe two siblings, born to consanguineous parents, who had clinical features of cerebellar ataxia, tremor, dysarthria, oculomotor apraxia, and motor peripheral neuropathy. Brain magnetic resonance imaging showed cerebellar atrophy and mild brainstem atrophy. Electromyography showed signs of axonal neuropathy. The molecular genetic analysis demonstrated the APTX mutation W279X at locus 9p13.3 (ataxia with oculomotor apraxia 1 disease), and psychologic studies showed mild cognitive impairment. We suggest that mentation can be compromised in ataxia with oculomotor apraxia 1.

Methylphenidate treatment for attention-deficit/hyperactivity disorder in children and adolescents with velocardiofacial syndrome: an open-label study.

BACKGROUND: Velocardiofacial syndrome (VCFS) is a common microdeletion syndrome associated with psychiatric morbidity and developmental disabilities. Although attention-deficit/hyperactivity disorder (ADHD) is the most common psychiatric problem associated with VCFS, there are no reports on methylphenidate treatment in this patient population. Indeed, clinicians have commonly avoided the use of methylphenidate in children with VCFS because of concerns about ineffectiveness or psychotic exacerbation. METHOD: Forty subjects of mean +/- SD age 11.0 +/- 5.0 years with VCFS were assessed for DSM-IV diagnoses using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Present and Lifetime Version, and its extended ADHD module (K-SADS-P-ADHD). Those found to have comorbid ADHD were treated with methylphenidate, 0.3 mg/kg once daily. Treatment efficacy was evaluated after 4 weeks with the K-SADS-P-ADHD, the Conners' Abbreviated Teacher Questionnaire, and the Conners' Continuous Performance Test. Side effects were evaluated with a modified version of the Barkley Side Effects Rating Scale. RESULTS: Of the 18 subjects (45%) diagnosed with ADHD, 12 agreed to participate in the study. Their ADHD symptoms, both behavioral and cognitive, improved significantly with treatment. None of the patients showed clinical worsening or psychotic symptoms. Side effects were usually mild and did not warrant discontinuation of methylphenidate. The most common side effects were anorexia and depressive-like symptoms. CONCLUSION: This open-label study indicates that methylphenidate is effective and safe in patients with VCFS. Therefore, its current limited use in this population seems to be unjustified. Larger, controlled clinical and pharmacogenetic studies are needed to confirm these findings.

Isolated orofacial dyskinesia: a methylphenidate-induced movement disorder.

We report a case of orofacial dyskinesia in a 6-year-old female with attention-deficit-hyperactivity disorder who received a low dose of methylphenidate. The orofacial dyskinesia appeared immediately and subsided rapidly on the same day in an "on-off" fashion and on 3 separate days when methylphenidate was taken. To our knowledge this particular side effect has not been described previously and might represent an unusual type of brain response or sensitivity.

Pre-placement screening in international adoption.

BACKGROUND: The number of child adoptions from abroad is increasing, but the adverse living conditions of these children prior to the adoption raise questions on their medical and neurodevelopmental status, particularly since there are no guidelines for pre- or post-adoption medical evaluation. OBJECTIVES: To describe the condition of a cohort of young children who were candidates for adoption in East European orphanages and foster homes, and to determine those attributes associated with a family's decision to adopt or refuse a particular child. METHODS: Eighty-two young children, median age 11 months, were evaluated by Israeli pediatricians in Eastern Europe between 3 weeks and 6 months prior to their adoption. The evaluation consisted of comprehensive medical and neurodevelopmental testing on site using a battery of standardized assessment tools, and observation of free play and social interactive behaviors recorded on videotape. Laboratory tests included complete blood count, chemistries, serology screening, and metabolic and genetic testing. RESULTS: The children were growth-retarded. Medical problems were classified as resolved (pneumonia and diarrhea) in 32.8%; or ongoing, such as hepatitis B and C, failure to thrive, organomegaly, and visual and hearing disorders, in 14.8%. Neuromotor status was grossly abnormal in 13.4%. Twenty-two percent of the children were rejected for adoption by families in Israel. Factors associated with the adoption decision were performance skills on developmental testing (P = 0.0001), present medical status (P = 0.002), and weight (P = 0.016). CONCLUSIONS: Pre-placement comprehensive screening of children eligible for foreign adoption, which includes developmental screening, helps to identify a wide variety of strengths and impairments in a child's background before the adoption procedure is finalized. A family's decision to adopt or not was associated with the child's performance on Bayley Scales, weight, and current medical status, but not with language delays, serious past medical history or suspect family background.

[Growth and development aspects of international adoption].

With the increase in the number of children being adopted by Israeli families from abroad, the medical system has to face heretofore unfamiliar medical and developmental challenges. Many of the biological mothers of these children were substance abusers and suffered from a variety of illnesses and nutritional deficiencies during their pregnancy. Their infants and young children were placed in orphanages at a very young age. The ensuing emotional and environmental deprivation in many cases impacted negatively on their neurological, physical and emotional development. Whereas our previous survey dealt with the purely medical aspects of international adoption, the current review deals with the growth and developmental issues involved in raising these children.

[Parenthood--medical aspects of international adoption].

The unavailability of significant numbers of native-born children for adoption by local families has led to an upsurge in international adoptions throughout the Western world, including Israel. The sudden appearance here of large numbers of babies and young children from countries with a variety of indigenous infectious diseases has focused concern on the issue. It has also induced the Ministry of Health to issue guidelines to protect the well-being of the public at large, as well as to aid adoptive families in maintaining their own, as well as their newly adopted children's health. The great majority of community based primary caregivers are unfamiliar with the health issues surrounding internationally adopted children. These children merit special care and consideration. One possible solution, in addition to educational campaigns, and already implemented abroad, is the specialized training of physicians caring for large numbers of such children. [International Adoption, HIV, Hepatitis B, Hepatitis C, Tuberculosis, Syphilis].

Thiamine deficiency in infancy: long-term follow-up.

BACKGROUND: In 2003, several hundred Israeli infants risked thiamine deficiency after being fed a soy-based formula deficient in thiamine. Approximately 20 patients were seriously affected, and three of them died. We report the clinical presentation of acute encephalopathy in 11 children and the long-term sequelae of eight children who initially survived. PATIENTS: In the acute phase, six had bulbar signs, five had ophthalmologic signs and two had phrenic neuropathy. Three of the five patients with cardiac involvement had cardiomyopathy and died in the acute phase. One patient presented with a complete atrioventricular block. RESULTS: In the long-term, one patient, who was in a chronic vegetative state, died after 6 years. Seven children exhibited mental retardation and motor abnormalities, six developed severe epilepsy, two early kyphoscoliosis, and one patient remained with a complete atrioventricular block. CONCLUSIONS: Infants who survive severe infantile thiamine deficiency have serious residual motor and cognitive sequelae as well as epilepsy.

Prevalence of epilepsy and attention-deficit hyperactivity (ADHD) disorder: a population-based study.

Epilepsy and attention-deficit hyperactivity disorder (ADHD) were reported to co-occur at rates higher than expected for coincidental findings. This study investigated the prevalence of both disorders in community-based primary care practice. The central database of the second-largest health maintenance organization in Israel was searched for all children aged 6 to 13 years (n = 284 419; 51.5% males) diagnosed as having ADHD according to the physicians' records and/or the filling of at least 10 prescriptions for antiepileptic medications according to pharmacy records. The prevalence of epilepsy in the total population was 5 out of 1000 children, and the prevalence of ADHD was 12.6%. More than one-fourth (27.7%) of the epileptic children were also diagnosed as having ADHD. On multivariate analysis, children with ADHD had almost twice the risk of epilepsy than children without ADHD. This study supports hospital-based findings of a strong interrelationship between ADHD and epilepsy. The high rate of ADHD in Israeli children warrants further investigation.

Microcephaly-thin corpus callosum syndrome maps to 8q23.2-q24.12.

Postnatal microcephaly is defined as normal head circumference at birth, which progressively declines to more than 2 standard deviations below the average for the patient's age and sex. We describe four patients from three consanguineous families of Arab Bedouin origin who presented with autosomal recessive inheritance of progressive microcephaly, spasticity, thin corpus callosum, pyramidal signs, and intellectual disability. Homozygosity mapping (Human Mapping NspI 250K arrays, Affymetrix, Santa Clara, CA) placed the disease locus at 8q23.2-q24.12. The candidate region includes 22 known or predicted genes, including RAD21, which is related to the cohesion complex EIF3H, which is involved in translation initiation, and TAF2, which may be involved in intellectual disability. Identification of the causative gene in our reported family will shed light on the pathogenesis of this severe condition.

Alcohol consumption during pregnancy among women in Israel.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a range of disabilities caused by gestational exposure of the fetus to alcohol. Alcohol consumption in Israel has increased dramatically in the last decades. Our previous study revealed limited knowledge among Israeli medical professionals of the risks and potential long-term effects of FASD. OBJECTIVES: To evaluate the awareness and knowledge of women regarding the current recommendations on alcohol consumption during pregnancy, evaluate how many of the women received information regarding alcohol consumption during pregnancy from medical professionals, and their personal drinking habits during pregnancy. METHODS: A cross-sectional sample of new mothers in 3 large hospitals in Israel were asked to complete an ad hoc questionnaire on aspects of alcohol consumption during pregnancy. RESULTS: A total of 3815 women of mean age 30.4 years participated in the study; 82% were Jewish. Alcohol consumption during pregnancy was reported by 14.1%, including more than 17% of the Jewish women, 11.1% of the Christian women, and none of the Muslim women. Rates were higher among nonsecular and younger women and first-time mothers. 71.6% of the sample claimed that women should not drink alcohol at all during pregnancy, and 21.4% thought that it was permissible if limited to 2 drinks per week. Seventy-five percent had received no formal information from medical professionals regarding alcohol consumption during pregnancy. CONCLUSIONS: Alcohol consumption is frequent among pregnant women in Israel, especially young secular Jewish women with first pregnancies. Improved educational programs on the dangers of FASD are needed for both professionals and the general public.