Aviva Mimouni-Bloch

Infantile Cerebral and Cerebellar Atrophy Is Associated with a Mutation in the MED17 Subunit of the Transcription Preinitiation Mediator Complex

Primary microcephaly of postnatal onset is a feature of many neurological disorders, mostly associated with mental retardation, seizures, and spasticity, and it typically carries a grave prognosis. Five infants from four unrelated families of Caucasus Jewish origin presented soon after birth with spasticity, epilepsy, and profound psychomotor retardation. Head circumference percentiles declined, and brain MRI disclosed marked cereberal and cerebellar atrophy with severe myelination defect. A search for a common homozygous region revealed a 2.28 Mb genomic segment on chromosome 11 that encompassed 16 protein-coding genes. A missense mutation in one of them, MED17, segregated with the disease state in the families and was carried by four of 79 anonymous Caucasus Jews. A corresponding mutation in the homologous S.cerevisiae gene SRB4 inactivated the protein, according to complementation assays. Screening of MED17 in additional patients with similar clinical and radiologic findings revealed four more patients, all homozygous for the p.L371P mutation and all originating from Caucasus Jewish families. We conclude that the p. L371P mutation in MED17 is a founder mutation in the Caucasus Jewish community and that homozygosity for this mutation is associated with infantile cerebral and cerebellar atrophy with poor myelination.

Breastfeeding May Protect from Developing Attention-Deficit/Hyperactivity Disorder

INTRODUCTION Breastfeeding has a positive influence on physical and mental development. Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder with major social, familial, and academic influences. The present study aimed to evaluate whether ADHD is associated with a shorter duration of breastfeeding. SUBJECTS AND METHODS In this retrospective matched study, children 6-12 years old diagnosed at Schneiders Children Medical Center (Petach Tikva, Israel) with ADHD between 2008 and 2009 were compared with two control groups. The first one consisted of healthy (no ADHD) siblings of ADHD children; the second control group consisted of children without ADHD who consulted at the otolaryngology clinic. A constructed questionnaire about demographic, medical, and perinatal findings, feeding history during the first year of life, and a validated adult ADHD screening questionnaire were given to both parents of every child in each group. RESULTS In children later diagnosed as having ADHD, 43% were breastfed at 3 months of age compared with 69% in the siblings group and 73% in the control non-related group (p=0.002). By 6 months of age 29% of ADHD children were breastfed compared with 50% in the siblings group and 57% in the control non-related group (p=0.011). A stepwise logistic regression that included the variables found to be significant in univariate analysis demonstrated a significant association between ADHD and lack of breastfeeding at 3 months of age, maternal age at birth, male gender, and parental divorce. CONCLUSIONS Children with ADHD were less likely to breastfeed at 3 months and 6 months of age than children in the two control groups. We speculate that breastfeeding may have a protective effect from developing ADHD later in childhood.

eIF2γ mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation.

Together with GTP and initiator methionyl-tRNA, translation initiation factor eIF2 forms a ternary complex that binds the 40S ribosome and then scans an mRNA to select the AUG start codon for protein synthesis. Here, we show that a human X-chromosomal neurological disorder characterized by intellectual disability and microcephaly is caused by a missense mutation in eIF2γ (encoded by EIF2S3), the core subunit of the heterotrimeric eIF2 complex. Biochemical studies of human cells overexpressing the eIF2γ mutant and of yeast eIF2γ with the analogous mutation revealed a defect in binding the eIF2β subunit to eIF2γ. Consistent with this loss of eIF2 integrity, the yeast eIF2γ mutation impaired translation start codon selection and eIF2 function in vivo in a manner that was suppressed by overexpressing eIF2β. These findings directly link intellectual disability to impaired translation initiation, and provide a mechanistic basis for the human disease due to partial loss of eIF2 function.

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.

Familial Vasovagal Syncope Associated With Migraine

Syncope affects all age groups and is characterized by a brief sudden loss of consciousness followed by fast recovery. Vasovagal syncope, the most common type, is generally assumed to be due to venous pooling and an abnormal sympathetic response. In approximately 20% of cases, more than one family member is affected. Vasovagal syncope has been documented in a high proportion of patients with migraine. Three generations of a family with comorbid vasovagal syncope and migraine are described. Data were collected from the medical files (index patient and eight siblings) and interviews with the patients mother. Information was available for 21 family members. Eleven of the 14 family members with a diagnosis of migraine (78%) also had vasovagal syncope, and 11 of the 12 family members with vasovagal syncope (92%) also had migraine. Age at first episode of syncope ranged from 2 to 7 years; age at first migraine headache was less than 10 years in most cases. The high incidence rates combined with the lack of gender predominance may point to a possible common pathophysiology of the two disorders and, perhaps, an autosomal dominant mode of inheritance. Further investigations are needed to corroborate a genetic link.

An Emerging 1q21.1 Deletion-Associated Neurodevelopmental Phenotype

In this study, we describe the neurodevelopmental and epileptic phenotypes in a family with an inherited 1q21.1 deletion. During the pregnancy with the proband, increased nuchal translucency and oligohydramnion were detected. The proband showed mild global developmental delay and ataxic gait. Seizures started in the proband at the age of 2 years and manifested as generalized tonic—clonic seizures, atypical absence seizures, head drops, and drop attacks with no abnormal findings on interictal electroencephalogram. We performed an Agilent Human Genome CGH (comparative genomic hybridization) Microarray 105A, and a microdeletion on chromosome 1q21.1 was identified in both the patient and his asymptomatic father. This deletion encompasses 1.65 Mb and is larger than the reported recurrent class I deletions in this region. Cryptic cytogenetic abnormalities should be considered in patients with neurodevelopmental problems and atypical presentation of epilepsy with a normal electroencephalography (EEG).

Congenital myasthenic syndrome in Israel: Genetic and clinical characterization

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND, CHAT, GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ, RAPSN, and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected.

Neuropsychiatric manifestations in Langerhans' cell histiocytosis disease: a case report and review of the literature.

The spectrum of the possible manifestations of Langerhans’ cell histiocytosis in children is very wide, ranging from a simple rash to major multiorgan disease. There may be hypothalamic and pituitary dysfunction or more global neurological and neuropsychiatric manifestations when the central nervous system is affected. The cerebellum is preferentially affected for yet undetermined reasons. The clinical presentation includes motor dysfunction as well as cognitive, behavioral, and psychiatric expression of the ongoing neurodegeneration. We report a young patient with Langerhans’ cell histiocytosis who underwent an unusual course of psychiatric deterioration.

Trends in Physical Medicine and Rehabilitation Publications Over the Past 16 Years

OBJECTIVES To test the hypothesis that the number of publications in the field of physical medicine and rehabilitation (PMR) has increased over the last 16 years in a linear fashion, and to compare the trends in publication between the pediatric and adult literature. DESIGN We evaluated all MEDLINE articles from January 1, 1998, to December 31, 2013, using Medical Subject Headings categories of rehabilitation. An age filter separated adult and pediatric articles. We divided articles into those with a low level of scientific evidence such as letters and editorials, and those with a high level of evidence such as controlled trials and meta-analyses. We used regression analysis to evaluate the effect of the year of publication on the number of publications of each type. SETTING Not applicable. PARTICIPANTS Not applicable. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Not applicable. RESULTS MEDLINE reported a total of 98,501 adult publications and 30,895 pediatric publications during the evaluated period. There was a significant linear increase in the total number of publications in adult and pediatric rehabilitation publications with multiplication factors of 3.3 and 2.9, respectively. Importantly, publications with a high level of evidence showed larger multiplication factors compared with those with a low level of evidence (5.5 and 5.1 vs 2.1 and 2.0) for the adult and pediatric literature. CONCLUSIONS The number of publications in the PMR field, especially those with a high level of scientific evidence, has increased linearly over the years, reflecting the rapid evolution of both adult and pediatric PMR.

Lesions of the corpus callosum in children with neurofibromatosis 1.

Our aim was to determine the rate of focal lesions of the corpus callosum in children with neurofibromatosis type 1, and to characterize their natural history. Magnetic resonance imaging scans of the brain in 79 children with neurofibromatosis type 1 who were followed at the Neurology Clinic of Schneider Childrens Medical Center (Petah Tiqwa, Israel) from 1990-2005 were reviewed. Focal lesions of the corpus callosum were identified in 11 (14%). These included unidentified bright objects in 7 patients (9%), and a neoplastic process in 4 (5%). Follow-up ranged from 1-16 years. Two of 4 tumors had enlarged during follow-up, and one was excised. Neurofibromatosis type 1 may be associated with a 14% prevalence of corpus callosum lesions. Owing to the apparently high frequency of callosal neoplasms in this population (5% in our series), and their tendency to enlarge, careful evaluation and prolonged follow-up are warranted.