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Milano, Italy

Marom D.,Tel Aviv University | Albin A.,Felsenstein Medical Research Center | Schwartz C.,J C Self Research Institute | Har-Zahav A.,Tel Aviv University | And 7 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

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 16.4Mb 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. © 2011 Wiley-Liss, Inc. Source

Grossman E.S.,Bar - Ilan University | Hoffman Y.S.G.,Bar - Ilan University | Berger I.,Neuropediatrics Unit | Zivotofsky A.Z.,Bar - Ilan University
Neuropsychology | Year: 2015

Objective: Adults diagnosed with attentional deficit disorder (ADHD) are easily distracted in many tasks. Yet ADHD performance on inattentional blindness (IB) tasks has not been examined. Such investigation may aid in discriminating between 3 ADHD models: the neurological model, the perceptual load theory, and the "hunter versus farmer" hypothesis. Method: Distractibility was assessed in ADHD and non- ADHD college students using the MOXO task that involves detection of a single attended stimulus that repeatedly appears in the same place and in the well-known IB "gorilla" video which involves tracking of a stimulus moving at a fast pace in a dynamic, complex manner. Results: ADHD college students showed increased distractibility in the MOXO task. By contrast, they performed better than controls in the attended channel of the IB task, while they were also better at noticing the unattended stimuli and thus exhibiting little-to-no inattentional blindness. Conclusions: As no attentional tradeoffs were evident in the IB task, it appears that the results are most consistent with the "hunter versus farmer" hypothesis, which postulates that ADHD individuals have an alternative cognitive style which is less equipped to deal with detection of repeated stimuli while comprising advantages in the tracking of stimuli moving in a fast dynamic manner. Source

Mencacci N.E.,University College London | Rubio-Agusti I.,Hospital Universitario La Paz | Zdebik A.,University College London | Asmus F.,German Center for Neurodegenerative Diseases | And 29 more authors.
American journal of human genetics | Year: 2015

Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. Source

Mencacci N.E.,University College London | R'bibo L.,University College London | Bandres-Ciga S.,University College London | Bandres-Ciga S.,University of Granada | And 14 more authors.
Human Molecular Genetics | Year: 2015

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ~30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p. R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p. R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p. R1389H) variant and M-D. © The Author 2015. Published by Oxford University Press. Source

Hirsch H.J.,Neuropediatrics Unit | Eldar-Geva T.,Hebrew University of Jerusalem | Gross-Tsur V.,Neuropediatrics Unit | Benarroch F.,Hadassah Mount Scopus Hospital | And 2 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Background: Cryptorchidism, incomplete pubertal development, and low testosterone are manifestations of hypogonadism in Prader-Willi syndrome (PWS). Insulin-like peptide-3 (INSL3) facilitates testicular descent in the fetus and reflects Leydig cell number in adults. INSL3 levels in PWS have not been previously reported. Objectives: The objectives of the study were to characterize the age-related changes in INSL3 in PWS males and correlate INSL3 with unilateral vs. bilateral cryptorchidism, body mass index, gonadotropins, testosterone, anti-Mullerian hormone (AMH), and inhibin B. Study Design and Participants: We measured INSL3, LH, FSH, testosterone, AMH, and inhibin B in 40 PWS males (23 deletion, 17 uniparental disomy) aged 2 months to 36 yr. Control samples for INSL3 were obtained from 365 normal males, aged 1 d to 36 yr. Results: INSL3 levels (mean and range) for PWS age groups younger than 6 months, 0.5-10.0 yr, 10.1- 19.0 yr, and older than 19.0 yr were 217 (68-380), 42 (16-112), 390 (16-1028), and 642 (290-964) pg/ml, respectively, and did not differ significantly from values for normal males. In seven of 14 boys aged 10.1-19 yr, INSL3, testosterone, and LH were low (37.4 ± 19.4 pg/ml, 1.44 ± 0.46 nmol/liter, 0.3 ± 0.6 IU/liter). The other seven with higher INSL3, testosterone, and LH (693.1 ± 305.8 pg/ml, 5.91 ± 2.77 nmol/liter, 2.7 ±1.9 IU/liter) had more advanced pubertal development. INSL3 was normal in seven of nine males aged older than 19 yr, despite low testosterone in six. After controlling for age, INSL3 correlated with LH (P = 0.005) and testosterone (P < 0.001) but not with FSH, AMH, or inhibin B. Conclusions: Most PWS males have normal INSL3 levels. By contrast, testosterone levels after infancy are low. These findings suggest a specific defect in Leydig cell function. Copyright © 2013 by The Endocrine Society. Source

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