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.

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.

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.

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.

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.

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.

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.

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.

Post-adoption depression among adoptive mothers.

OBJECTIVE: To evaluate the rate of depressive symptomatology and possible underlying factors in adoptive mothers during the transition to motherhood. DESIGN: Cohort survey. SETTING: General Community. PARTICIPANTS: Thirty-nine adoptive mothers of reproductive age registered with international adoption agencies. INTERVENTIONS: All women completed the Edinburgh Postnatal Depression Scale (EPDS), the Beck Depression Inventory (BDI), and the Brief Symptom Inventory (BSI) before and 6 weeks after the adoption. MAIN OUTCOME MEASURES: Responses were compared between the study group and published findings for biological mothers in the general population, and within the study group, before and after adoption. RESULTS: Symptoms of depression were found in 15.4% of the study group. This rate was similar to that for postpartum depression in the general population, and lower than the rate recorded in the study group before adoption (25.6%). All women with symptoms of depression after the adoption had also shown evidence of depressive features before the adoption. Similar findings were noted for other psychopathologies as well. CONCLUSION: Adopting a child does not cause new-onset, reactive depression among adoptive mothers. It may even lead to a decrease in depressive features, perhaps in response to relief from other adjustment difficulties.

The effect of calcium intake and physical activity on bone quantitative ultrasound measurements in children: a pilot study.

Environmental factors, such as nutritional status, physical activity, and drug therapy, can affect bone mineralization. Our objective was to evaluate the relationship between nutritional status, physical activity, and bone mineralization as assessed by multisite quantitative ultrasound technology in children. The study group comprised 67 children, aged 6-17 years (mean, 9.4), attending a primary care clinic. Data on calcium intake and physical activity were collected using a detailed questionnaire. Speed of sound measurements were performed at the distal 1/3 radius and the midshaft tibia using Sunlight Omnisense apparatus. The reported mean calcium intake was 1105 mg/day. There was a significant difference in Z-scores at the radius and tibia between the low-and high-calcium-intake groups (P = 0.004, P = 0.035, respectively). A similar difference was found between the low-and normal-physical-activity groups (P = 0.015, P = 0.036, respectively). In this pilot study, a positive association was found between calcium intake, physical activity, and bone status, as assessed by the quantitative ultrasound technique.

Association between a common haplotype in the COMT gene region and psychiatric disorders in individuals with 22q11.2DS.

The 22q11.2 deletion syndrome (22q11.2DS) is the most common hemizygous deletion syndrome in humans. In addition to a wide range of physical abnormalities 22q11.2DS subjects show high prevalence of several psychiatric disorders. In our previous study we showed that the low-activity allele (158Met) of the COMT gene is a risk factor for attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) in 22q11.2DS individuals. In the present study we have genotyped fifty-five 22q11.2DS individuals and 95 of their parents for eight SNPs in and around the COMT gene. A haplotype composed of three SNPs [rs2097603; rs4680 (158Val/Met); rs165599] representing the major linkage disequilibrium blocks in COMT and previously implicated in functional variation, was found to be associated with ADHD and OCD in 22q11.2DS individuals. A common risk haplotype (G-A-A) was significantly associated with both ADHD (OR 3.13, chi2=4.38, p=0.036) and OCD (OR 4.00, chi2=6.41, p=0.011) in 22q11.2DS individuals. Interestingly, the same haplotype was recently found to be associated with efficient prefrontal performance in the general population. The risk haplotype was not found to be associated with IQ scores in our 22q11.2DS sample. Parental origin of the deletion did not affect the susceptibility to ADHD and OCD in the 22q11.2DS subjects. This study demonstrated the association of a particular COMT haplotype with susceptibility to both ADHD and OCD in 22q11.2DS and supports the hypothesis that COMT gene variations contribute to genetic predisposition to psychiatric disorders in the general population.

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.

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).

Pediatricians' satisfaction with their abilities to care for children with developmental, behavioral and psychosocial problems.

BACKGROUND: Developmental and behavioral pediatrics has emerged as an area of special interest and new responsibility for pediatricians. The aim of this study was to evaluate the impact of training, experience, and other factors on pediatricians' satisfaction with their abilities to care for children with developmental, behavioral and psychosocial problems. METHODS: A questionnaire was sent to 211 pediatricians working in primary care clinics in the community in Israel. Items included personal characteristics and experience, practice and satisfaction with the care of children with developmental, behavioral and psychosocial problems. Overall, pediatrician satisfaction with their personal abilities in this domain was defined as the dependent variable on multivariate analysis. RESULTS: The response rate was 76.3% (n = 161). Pediatricians' satisfaction with their overall professional ability to care for children with developmental, behavioral and psychosocial problems was significantly and positively associated with the following independent variables: (i) satisfaction with training received in the child development field; (ii) satisfaction with psychiatric updates; (iii) general satisfaction with the available child development services; (iv) prescription of methylphenidate to children with attention deficit/hyperactivity disorder; and (v) having completed their medical studies in a country in which the issue is emphasized. CONCLUSIONS: Imparting more knowledge and skills in child development and behavioral pediatrics in pediatric residency and continuing education programs will help improve the attitudes of primary care pediatricians towards developmental and behavioral problems, encourage them to treat these patients and their families, and better the quality of care.

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.

Motor and non-motor sequence learning in children and adolescents with cerebellar damage.

Cerebellar involvement in motor and non-motor sequence learning was examined with serial reaction time tasks (SRT). Our sample consisted of 8 children and adolescents who had undergone surgical removal of a benign posterior fossa tumor (PFT) during childhood. None of them had undergone chemotherapy or cranial radiation therapy (CRT). Ages ranged from 1-11 years at surgery and 9-17 years at testing. The children were tested not earlier than 2.5 years after surgery (M = 5.9 years), enabling brain plasticity and recovery of functions. Their performance was compared with a matched control sample. The PFT group was not impaired in the implicit learning of sequences, as reflected in their performance in blocks with a repeated sequence, both before and after a random block. However, in the perceptual task, their performance deteriorated more than that of the control group when a random block was introduced, suggesting that it was more difficult for the patients to respond flexibly or change their response set when encountering changing task demands. These results are in line with another study by our group on task switching with the same patients.

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.

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.