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Phelan-McDermid Syndrome

Catherine A Ziats, Luke P Grosvenor, Sara M Sarasua, Audrey E Thurm, Susan E Swedo, Ahmed Mahfouz, Owen M Rennert, Mark N Ziats
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS. However, it is still unclear to what extent SHANK3 deletions contribute to the PMS phenotype, and what other genes nearby are causal to the neurologic disease...
2019: PloS One
David M James, Robert A Kozol, Yuji Kajiwara, Adam L Wahl, Emily C Storrs, Joseph D Buxbaum, Mason Klein, Baharak Moshiree, Julia E Dallman
Background and aims: Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods: To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues ( shank3abΔC )...
2019: Molecular Autism
Lijuan Zhao, Bo Wan
OBJECTIVE: To explore the value of single nucleotide polymorphism (SNP) array for molecular diagnosis. METHODS: A Chinese girl suspected for Phelan-McDermid syndrome was subjected to routine G-banding chromosomal analysis, SNP array, and fluorescence in situ hybridization (FISH) assaying. RESULTS: G-banding karyotype analysis has found no abnormality in the girl and her parents. SNP array detected a heterozygous 2.1 Mb deletion at 22q13.33 in the girl, which was confirmed by FISH...
February 10, 2019: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Li Wang, Carolyn J Adamski, Vitaliy V Bondar, Evelyn Craigen, John R Collette, Kaifang Pang, Kihoon Han, Antrix Jain, Sung Y Jung, Zhandong Liu, Richard N Sifers, J Lloyd Holder, Huda Y Zoghbi
Neurons are sensitive to changes in the dosage of many genes, especially those regulating synaptic functions. Haploinsufficiency of SHANK3 causes Phelan-McDermid syndrome and autism, whereas duplication of the same gene leads to SHANK3 duplication syndrome, a disorder characterized by neuropsychiatric phenotypes including hyperactivity and bipolar disorder as well as epilepsy. We recently demonstrated the functional modularity of Shank3, which suggests that normalizing levels of Shank3 itself might be more fruitful than correcting pathways that function downstream of it for treatment of disorders caused by alterations in SHANK3 dosage...
January 29, 2019: Molecular Psychiatry
Teresa Soda, Lisa Mapelli, Francesca Locatelli, Laura Botta, Mitchell Goldfarb, Francesca Prestori, Egidio D'Angelo
Autism spectrum disorders (ASD) are pervasive neurodevelopmental conditions that often involve mutations affecting synaptic mechanisms. Recently, the involvement of cerebellum in ASD has been suggested but the underlying functional alterations remained obscure. We investigated single-neuron and microcircuit properties in IB2 KO mice of either sex. The IB2 gene (chr22q13.3 terminal region) deletion occurs in virtually all cases of Phelan-McDermid syndrome, causing autistic symptoms and a severe delay in motor skill acquisition...
January 29, 2019: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Maya A Rhine, Jennifer M Parrott, Maria N Schultz, Tatiana M Kazdoba, Jacqueline N Crawley
Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA-approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well-replicated autism-relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model...
January 17, 2019: Autism Research: Official Journal of the International Society for Autism Research
Reinhard Roessler, Johanna Goldmann, Chikdu Shivalila, Rudolf Jaenisch
Phelan-McDermid syndrome (also known as 22q13.3 deletion syndrome) is a syndromic form of autism spectrum disorder and currently thought to be caused by heterozygous loss of SHANK3 . However, patients most frequently present with large chromosomal deletions affecting several additional genes. We used human pluripotent stem cell technology and genome editing to further dissect molecular and cellular mechanisms. We found that loss of JIP2 ( MAPK8IP2 ) may contribute to a distinct neurodevelopmental phenotype in neural progenitor cells (NPCs) affecting neuronal maturation...
August 2018: Life Science Alliance
Chantelle Fourie, Yukti Vyas, Kevin Lee, Yewon Jung, Craig C Garner, Johanna M Montgomery
The SHANK family of synaptic proteins (SHANK1-3) are master regulators of the organizational structure of excitatory synapses in the brain. Mutations in SHANK1-3 are prevalent in patients with autism spectrum disorders (ASD), and loss of one copy of SHANK3 causes Phelan-McDermid Syndrome, a syndrome in which Autism occurs in >80% of cases. The synaptic stability of SHANK3 is highly regulated by zinc, driving the formation of postsynaptic protein complexes and increases in excitatory synaptic strength. As ASD-associated SHANK3 mutations retain responsiveness to zinc, here we investigated how increasing levels of dietary zinc could alter behavioral and synaptic deficits that occur with ASD...
2018: Frontiers in Cellular Neuroscience
Siddharth Srivastava, Benoit Scherrer, Anna K Prohl, Rajna Filip-Dhima, Kush Kapur, Alexander Kolevzon, Joseph D Buxbaum, Elizabeth Berry-Kravis, Latha Soorya, Audrey Thurm, Craig M Powell, Jonathan A Bernstein, Simon K Warfield, Mustafa Sahin
OBJECTIVE: Phelan-McDermid syndrome is caused by haploinsufficiency of SHANK3 on terminal chromosome 22. Knowledge about altered neuroanatomic circuitry in Phelan-McDermid syndrome comes from mouse models showing striatal hypertrophy in the basal ganglia, and from humans with evidence of cerebellar atrophy. To date, no studies have performed volumetric analysis on Phelan-McDermid syndrome patients. METHODS: We performed volumetric analysis on baseline brain MRIs of Phelan-McDermid syndrome patients (ages three to 21 years) enrolled in a prospective natural history study (ClinicalTrials...
September 21, 2018: Pediatric Neurology
Petra Jungová, Andrea Čumová, Veronika Kramarová, Jana Lisyová, Pavol Ďurina, Ján Chandoga, Daniel Bӧhmer
Phelan-McDermid syndrome (PMD) is a rare genetic condition with only a few cases describing patients diagnosed as adults. We describe a long diagnostic odyssey of a 30-year-old woman who was diagnosed with Phelan-McDermid syndrom. Array comparative genomic hybridization analysis confirmed a 22q13.33 deletion, encompassing exon 9-23 of the SHANK3 gene and exon 1 of the ACR gene. We provide an uncommon feature of the disease, where psychotic alteration is repeatedly triggered by the same physical factor in our patient - mild fever episodes...
August 2018: Neurocase
Dawn Adams, Richard P Hastings, Clair Alston-Knox, Rina Cianfaglione, Kate Eden, David Felce, Gemma Griffith, Jo Moss, Chris Stinton, Chris Oliver
BACKGROUND: It is well documented that mothers of children with intellectual disabilities or autism experience elevated stress, with mental health compromised. However, comparatively little is known about mothers of children with rare genetic syndromes. This study describes mental health and well-being in mothers of children with 13 rare genetic syndromes and contrasts the results with mothers of children with autism. METHODS: Mothers of children with 13 genetic syndromes (n = 646; Angelman, Cornelia de Lange, Down, Fragile-X, Phelan McDermid, Prader-Willi, Rett, Rubenstein Taybi, Smith Magenis, Soto, Tuberous Sclerosis Complex, 1p36 deletion and 8p23 deletion syndromes) and mothers of children with autism (n = 66) completed measures of positive mental health, stress and depression...
October 25, 2018: Orphanet Journal of Rare Diseases
Taesun Yoo, Heejin Cho, Jiseok Lee, Haram Park, Ye-Eun Yoo, Esther Yang, Jin Yong Kim, Hyun Kim, Eunjoon Kim
Shank3 is an excitatory postsynaptic scaffolding protein implicated in multiple brain disorders, including autism spectrum disorders (ASD) and Phelan-McDermid syndrome (PMS). Although previous neurobiological studies on Shank3 and Shank3 -mutant mice have revealed diverse roles of Shank3 in the regulation of synaptic, neuronal and brain functions, whether Shank3 expression in specific cell types distinctly contributes to mouse phenotypes remains largely unclear. In the present study, we generated two Shank3 -mutant mouse lines (exons 14-16) carrying global and GABA neuron-specific deletions and characterized their electrophysiological and behavioral phenotypes...
2018: Frontiers in Cellular Neuroscience
Elodie Drapeau, Mohammed Riad, Yuji Kajiwara, Joseph D Buxbaum
Phelan-McDermid syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability (ID), and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms...
May 2018: ENeuro
Jariya Upadia, Patrick R Gonzales, T Prescott Atkinson, Harry W Schroeder, Nathaniel H Robin, Natasha L Rudy, Fady M Mikhail
Phelan-McDermid syndrome (PMS, OMIM 606232) is a heterozygous contiguous gene microdeletion syndrome occurring at the distal region of chromosome 22q13. This deletion encompasses the SHANK3 gene at 22q13.33, which is thought to be the critical gene for the neurodevelopmental features seen in this syndrome. PMS is typically characterized by intellectual disability, autism spectrum disorder, absent to severely delayed speech, neonatal hypotonia, and dysmorphic features. Two patients presenting with classic clinical features of PMS have been reported to have interstitial microdeletions in the 22q13...
September 14, 2018: American Journal of Medical Genetics. Part A
Nhan Thi Ho, Barbara Kroner, Zachary Grinspan, Brandy Fureman, Kathleen Farrell, Jingzhou Zhang, Janice Buelow, Dale C Hesdorffer
OBJECTIVE: To describe the prevalence and characteristics of comorbidities in persons with rare epilepsies. STUDY DESIGN: Persons with rare epilepsies and caregivers of those affected were recruited through the Epilepsy Foundation and more than 30 rare epilepsy advocacy organizations affiliated with the Rare Epilepsy Network (REN). A web-based survey was conducted using a questionnaire consisting of core sections to collect data from affected persons on various aspects, including comorbidities...
September 5, 2018: Journal of Pediatrics
Tommy Hu, Paul Kruszka, Ariel F Martinez, Jeffrey E Ming, Emily K Shabason, Manu S Raam, Tamim H Shaikh, Daniel E Pineda-Alvarez, Maximilian Muenke
Holoprosencephaly (HPE), a common developmental forebrain malformation, is characterized by failure of the cerebrum to completely divide into left and right hemispheres. The etiology of HPE is heterogeneous and a number of environmental and genetic factors have been identified. Cytogenetically visible alterations occur in 25% to 45% of HPE patients and cytogenetic techniques have long been used to study copy number variants (CNVs) in this disorder. The karyotype approach initially demonstrated several recurrent chromosomal anomalies, which led to the identification of HPE-specific loci and, eventually, several major HPE genes...
June 2018: American Journal of Medical Genetics. Part C, Seminars in Medical Genetics
Jana Braesel, Camila M Crnkovic, Kevin J Kunstman, Stefan J Green, Mark Maienschein-Cline, Jimmy Orjala, Brian T Murphy, Alessandra S Eustáquio
Actinomycete bacteria isolated from freshwater environments are an unexplored source of natural products. Here we report the complete genome of the Great Lakes-derived Micromonospora sp. strain B006, revealing its potential for natural product biosynthesis. The 7-megabase pair chromosome of strain B006 was sequenced using Illumina and Oxford Nanopore technologies followed by Sanger sequencing to close remaining gaps. All identified biosynthetic gene clusters (BGCs) were manually curated. Five known BGCs were identified encoding desferrioxamine, alkyl- O-dihydrogeranylmethoxyhydroquinone, a spore pigment, sioxanthin, and diazepinomicin, which is currently in phase II clinical trials to treat Phelan-McDermid syndrome and co-morbid epilepsy...
September 28, 2018: Journal of Natural Products
Ponson Laura, Gomot Marie, Blanc Romuald, Barthelemy Catherine, Roux Sylvie, Munnich Arnold, Romana Serge, Aguillon-Hernandez Nadia, Malan Valérie, Bonnet-Brilhault Frédérique
Phelan-McDermid syndrome is related to terminal 22q13 deletions of various sizes affecting the SHANK3 gene. In this neurodevelopmental disorder, behavioural symptoms of autism spectrum disorder (ASD) are reported in half of cases. Extensive clinical and neurophysiological characterization is lacking to understand the genotype-phenotype correlation. Eighteen patients (8 males, mean age 12.7 years, SD = 9.2) with known 22q13 deletions were fully explored with determination of deletion size, along with behavioural, language and cognitive standardized assessments...
August 8, 2018: Translational Psychiatry
Samuel E Taylor, Ruth D Taylor, Jack Price, Laura C Andreae
BACKGROUND: Deletions and mutations in the SHANK3 gene are strongly associated with autism spectrum disorder and underlie the autism-associated disorder Phelan-McDermid syndrome. SHANK3 is a scaffolding protein found at the post-synaptic membrane of excitatory neurons. METHODS: Single-molecule fluorescence in-situ hybridization (smFISH) allows the visualization of single mRNA transcripts in vitro. Here we perform and quantify smFISH in human inducible pluripotent stem cell (hiPSC)-derived cortical neurons, targeting the SHANK3 transcript...
July 31, 2018: Stem Cell Research & Therapy
Haitham Amal, Boaz Barak, Vadiraja Bhat, Guanyu Gong, Brian A Joughin, John S Wishnok, Guoping Feng, Steven R Tannenbaum
Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan-McDermid syndrome. Shank3 disruption in mice leads to dysfunction of synaptic transmission, behavior, and development. Protein S-nitrosylation, the nitric oxide (NO• )-mediated posttranslational modification (PTM) of cysteine thiols (SNO), modulates the activity of proteins that regulate key signaling pathways. We tested the hypothesis that Shank3 mutation would generate downstream effects on PTM of critical proteins that lead to modification of synaptic functions...
July 9, 2018: Molecular Psychiatry
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