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Intellectual deficiency

Marijn Bart Martens, Monica Frega, Jessica Classen, Lisa Epping, Elske Bijvank, Marco Benevento, Hans van Bokhoven, Paul Tiesinga, Dirk Schubert, Nael Nadif Kasri
Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks...
October 21, 2016: Scientific Reports
Ahmad Alodaib, Nara Sobreira, Wendy A Gold, Lisa G Riley, Nicole J Van Bergen, Meredith J Wilson, Bruce Bennetts, David R Thorburn, Corinne Boehm, John Christodoulou
Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.[760C>A];[1528G>C];p.[(Gln254Lys);(Ala510Pro)] in the polyribonucleotide nucleotidyltransferase 1 (PNPT1) gene in both affected individuals...
October 19, 2016: European Journal of Human Genetics: EJHG
Takahiro Yamamoto, Wakaba Endo, Hidenori Ohnishi, Kazuo Kubota, Norio Kawamoto, Takehiko Inui, Atsushi Imamura, Jun-Ichi Takanashi, Masaaki Shiina, Hirotomo Saitsu, Kazuhiro Ogata, Naomichi Matsumoto, Kazuhiro Haginoya, Toshiyuki Fukao
BACKGROUND: Asparagine synthetase (ASNS) deficiency was recently discovered as a metabolic disorder of non-essential amino acids, and presents as severe progressive microcephaly, intellectual disorder, dyskinetic quadriplegia, and intractable seizures. METHODS: Two Japanese children with progressive microcephaly born to unrelated patients were analyzed by whole exome sequencing and novel ASNS mutations were identified. The effects of the ASNS mutations were analyzed by structural evaluation and in silico predictions...
October 12, 2016: Brain & Development
Marie Hully, Juliette Ropars, Laurence Hubert, Nathalie Boddaert, Marlene Rio, Mathieu Bernardelli, Isabelle Desguerre, Valerie Cormier-Daire, Arnold Munnich, Pascale de Lonlay, Louise Reilly, Claude Besmond, Nadia Bahi-Buisson
Mutations in ATP1A3 are involved in a large spectrum of neurological disorders, including rapid onset dystonia parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), with recent descriptions of overlapping phenotypes. In AHC, a few familial cases of autosomal dominant inheritance have been reported, along with cases of de novo sporadic mutations. In contrast, autosomal dominant inheritance has frequently been associated with RDP and CAPOS...
October 10, 2016: Neurogenetics
Marina Diomedi, Ziv Gan-Or, Fabio Placidi, Patrick A Dion, Anna Szuto, Mario Bengala, Guy A Rouleau, Gian Luigi Gigli
Glucose transporter 1 (GLUT1) deficiency syndrome (GLUT1DS) was initially described in the early 90s as a sporadic clinical condition, characterized by seizures, motor and intellectual impairment with variable clinical presentation, and without a known genetic cause. Although causative mutations in SLC2A1 were later identified and much more is known about the disease, it still remains largely underdiagnosed. In the current study, a previously described Italian family was re-analyzed using whole exome sequencing and clinically re-evaluated...
October 7, 2016: European Journal of Medical Genetics
Simon Früh, Jennifer Romanos, Patrizia Panzanelli, Daniela Bürgisser, Shiva K Tyagarajan, Kevin P Campbell, Mirko Santello, Jean-Marc Fritschy
: Distinct types of GABAergic interneurons target different subcellular domains of pyramidal cells, thereby shaping pyramidal cell activity patterns. Whether the presynaptic heterogeneity of GABAergic innervation is mirrored by specific postsynaptic factors is largely unexplored. Here we show that dystroglycan, a protein responsible for the majority of congenital muscular dystrophies when dysfunctional, has a function at postsynaptic sites restricted to a subset of GABAergic interneurons...
October 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Cecilia Magnusson, Michael Lundberg, Brian K Lee, Dheeraj Rai, Håkan Karlsson, Renee Gardner, Kyriaki Kosidou, Stefan Arver, Christina Dalman
BACKGROUND: Maternal vitamin D deficiency may increase risk of autism spectrum disorder (ASD), but direct evidence is lacking. AIMS: To clarify the relationship between maternal vitamin D deficiency and offspring risk of ASD with and without intellectual disability. METHOD: Using a register-based total population study (N=509 639), we calculated adjusted odds ratios (aORs) and 95% confidence intervals (CIs) of ASD with and without intellectual disability in relation to lifetime diagnoses of maternal vitamin D deficiency...
March 2016: BJPsych Open
Isabelle Peretz
The past decade of research has provided compelling evidence that musical engagement is a fundamental human trait, and its biological basis is increasingly scrutinized. In this endeavor, the detailed study of individuals who have musical deficiencies is instructive because of likely neurogenetic underpinnings. Such individuals have 'congenital amusia', an umbrella term for lifelong musical disabilities that cannot be attributed to intellectual disability, lack of exposure, or brain damage after birth. Key points are reviewed here that have emerged during recent years regarding the neurobiology of the disorder, focusing on the importance of recurrent processing between the right inferior frontal cortex and the auditory cortex for conscious monitoring of musical pitch, and how this relates to developmental cognitive disorders in general...
September 29, 2016: Trends in Cognitive Sciences
May Loong Tan, Jacqueline J Ho, Keng Hwang Teh
BACKGROUND: About 5% of school children have a specific learning disorder, defined as unexpected failure to acquire adequate abilities in reading, writing or mathematics that is not a result of reduced intellectual ability, inadequate teaching or social deprivation. Of these events, 80% are reading disorders. Polyunsaturated fatty acids (PUFAs), in particular, omega-3 and omega-6 fatty acids, which normally are abundant in the brain and in the retina, are important for learning. Some children with specific learning disorders have been found to be deficient in these PUFAs, and it is argued that supplementation of PUFAs may help these children improve their learning abilities...
September 28, 2016: Cochrane Database of Systematic Reviews
Muhammad Ummear Raza, Waheed Ullah, Sajid Malik
Congenital constriction ring (CCR) and symbrachydactyly are two distinct, rare, and heterogeneous limb deficiency conditions which affect the digits. Here, we report on two different individuals with an unusual presentation of limb deficiency accompanying intellectual disability (ID) and certain other malformations. In the first index female, CCR occurred with mild ID, squint eyes, obesity, and metatarsus adductus. The second index male was presented with symbrachydactyly, profound ID, and speech/hearing impairments...
September 2016: Journal of the College of Physicians and Surgeons—Pakistan: JCPSP
David Zada, Adi Tovin, Tali Lerer-Goldshtein, Lior Appelbaum
Hypomyelination is a key symptom of the Allan-Herndon-Dudley syndrome (AHDS), a psychomotor retardation associated with mutations in the thyroid-hormone (TH) transporter MCT8. AHDS is characterized by severe intellectual deficiency, neuromuscular impairment, and brain hypothyroidism. In order to understand the mechanism for TH-dependent hypomyelination, we developed an mct8 mutant (mct8-/-) zebrafish model. The quantification of genetic markers for oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes revealed reduced differentiation of OPCs into oligodendrocytes in mct8-/- larvae and adults...
September 23, 2016: Disease Models & Mechanisms
Giselli Scaini, Tássia Tonon, Carolina F Moura de Souza, Patricia F Schuk, Gustavo C Ferreira, Joao Seda Neto, Tatiana Amorin, Ida Vanessa D Schwartz, Emilio L Streck
Maple syrup urine disease (MSUD) is an inherited disorder caused by deficient activity of the branched-chain α-keto acid dehydrogenase complex involved in the degradation pathway of branched-chain amino acids (BCAAs) and their respective α-keto-acids. Patients affected by MSUD present severe neurological symptoms and brain abnormalities, whose pathophysiology is poorly known. However, preclinical studies have suggested alterations in markers involved with neurodegeneration. Because there are no studies in the literature that report the neurodegenerative markers in MSUD patients, the present study evaluated neurodegenerative markers (brain-derived neurotrophic factor (BDNF), cathepsin D, neural cell adhesion molecule (NCAM), plasminogen activator inhibitor-1 total (PAI-1 (total)), platelet-derived growth factor AA (PDGF-AA), PDGF-AB/BB) in plasma from 10 MSUD patients during dietary treatment...
September 22, 2016: Molecular Neurobiology
E K Hreich, C Messarra, S Roux, C Barthélémy, S Richa
: The Behavioral Summarized Evaluation is a rating scale specifically related to the assessment of autistic behaviors in children and young teenagers with Autism Spectrum Disorder, such as communication, social interaction and interests. It also facilitates progressive recording of the evolution of children with ASD involved in short-term therapeutical studies. In the absence of standardized tools to assess autistic behaviors and effects of therapeutics in Lebanon, the BSE-R validation is an urgent need...
September 13, 2016: L'Encéphale
Merve Kasap, Kendra Bonnett, Eric J Aamodt, Donard S Dwyer
The Na(+) leak-current channel (NALCN) regulates locomotion, respiration and intellectual development. Previous work highlighted striking similarities between characteristic movement phenotypes of NALCN-deficient animals (Drosophila and C. elegans) and the major symptoms of Parkinson's disease and primary progressive freezing gait. We have discovered novel physiological connections between the NALCN, K(+) channels and gap junctions that mediate regulation of locomotion in C. elegans. Drugs that block K(+) channels and gap junctions or that activate Ca(++) channels significantly improve movement of NALCN-deficient animals...
September 16, 2016: Journal of Comparative Neurology
Pamela S Lagali, Chantal F Medina, Brandon Y H Zhao, Keqin Yan, Adam N Baker, Stuart G Coupland, Catherine Tsilfidis, Valerie A Wallace, David J Picketts
ATRX is a chromatin remodeling protein that is mutated in several intellectual disability disorders including alpha-thalassemia/mental retardation, X-linked (ATR-X) syndrome. We previously reported the prevalence of ophthalmological defects in ATR-X syndrome patients, and accordingly we find morphological and functional visual abnormalities in a mouse model harbouring a mutation occurring in ATR-X patients. The visual system abnormalities observed in these mice parallels the Atrx-null retinal phenotype characterized by interneuron defects and selective loss of amacrine and horizontal cells...
September 4, 2016: Human Molecular Genetics
Namik Kaya, Maysoon Alsagob, Maria Cristina D'Adamo, Albandary Al-Bakheet, Sonia Hasan, Maria Muccioli, Faten B Almutairi, Rawan Almass, Mazhor Aldosary, Dorota Monies, Osama M Mustafa, Banan Alyounes, Rosan Kenana, Jawaher Al-Zahrani, Eva Naim, Faisal S Binhumaid, Alya Qari, Fatema Almutairi, Brian Meyer, Timothy F Plageman, Mauro Pessia, Dilek Colak, Mohammed Al-Owain
BACKGROUND: Voltage-gated potassium channels are highly diverse proteins representing the most complex class of voltage-gated ion channels from structural and functional perspectives. Deficiency of these channels usually results in various human disorders. OBJECTIVES: To describe a novel autosomal recessive syndrome associated with KCNA4 deficiency leading to congenital cataract, abnormal striatum, intellectual disability and attention deficit hyperactivity disorder...
August 31, 2016: Journal of Medical Genetics
M A Shahrour, O Staretz-Chacham, D Dayan, J Stephen, A Weech, N Damseh, H Pri Chen, S Edvardson, S Mazaheri, A Saada, E Hershkovitz, A Shaag, M Huizing, B Abu-Libdeh, W A Gahl, A Azem, Y Anikster, T Vilboux, O Elpeleg, M C Malicdan
Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V...
August 30, 2016: Clinical Genetics
Daryl A Scott, Andres Hernandez-Garcia, Mahshid S Azamian, Valerie K Jordan, Bum Jun Kim, Molly Starkovich, Jinglan Zhang, Lee-Jun Wong, Sandra A Darilek, Amy M Breman, Yaping Yang, James R Lupski, Amyn K Jiwani, Bibhuti Das, Seema R Lalani, Alejandro D Iglesias, Jill A Rosenfeld, Fan Xia
BACKGROUND: The non-POU domain containing octamer-binding gene (NONO) is located on chromosome Xq13.1 and encodes a member of a small family of RNA-binding and DNA-binding proteins that perform a variety of tasks involved in RNA synthesis, transcriptional regulation and DNA repair. Loss-of-function variants in NONO have been described as a cause of intellectual disability in males but have not been described in association with congenital heart defects or cardiomyopathy. In this article, we seek to further define the phenotypic consequences of NONO depletion in human subjects...
August 22, 2016: Journal of Medical Genetics
William B Rizzo
INTRODUCTION: Sjögren-Larsson syndrome (SLS) is a rare neurocutaneous disease characterized by ichthyosis, spasticity, intellectual disability and a distinctive retinopathy. It is caused by inactivating mutations in ALDH3A2, which codes for fatty aldehyde dehydrogenase (FALDH) and results in abnormal metabolism of long-chain aliphatic aldehydes and alcohols. The potential disease mechanisms leading to symptoms include 1) accumulation of toxic fatty aldehydes that form covalent adducts with lipids and membrane proteins; 2) physical disruption of multi-lamellar membranes in skin and brain; 3) abnormal activation of the JNK cell signaling pathway; and 4) defective farnesol metabolism resulting in abnormal PPAR-α dependent gene expression...
April 2016: Expert Opinion on Orphan Drugs
Estelle Colin, Jens Daniel, Alban Ziegler, Jamal Wakim, Aurora Scrivo, Tobias B Haack, Salim Khiati, Anne-Sophie Denommé, Patrizia Amati-Bonneau, Majida Charif, Vincent Procaccio, Pascal Reynier, Kyrieckos A Aleck, Lorenzo D Botto, Claudia Lena Herper, Charlotte Sophia Kaiser, Rima Nabbout, Sylvie N'Guyen, José Antonio Mora-Lorca, Birgit Assmann, Stine Christ, Thomas Meitinger, Tim M Strom, Holger Prokisch, Antonio Miranda-Vizuete, Georg F Hoffmann, Guy Lenaers, Pascale Bomont, Eva Liebau, Dominique Bonneau
Via whole-exome sequencing, we identified rare autosomal-recessive variants in UBA5 in five children from four unrelated families affected with a similar pattern of severe intellectual deficiency, microcephaly, movement disorders, and/or early-onset intractable epilepsy. UBA5 encodes the E1-activating enzyme of ubiquitin-fold modifier 1 (UFM1), a recently identified ubiquitin-like protein. Biochemical studies of mutant UBA5 proteins and studies in fibroblasts from affected individuals revealed that UBA5 mutations impair the process of ufmylation, resulting in an abnormal endoplasmic reticulum structure...
September 1, 2016: American Journal of Human Genetics
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