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Duan J, Zeng D, Wu T, Luo Z, Jingwen G, Tan W, Zeng Y. Neural connections and molecular mechanisms underlying motor skill deficits in genetic models of autism spectrum disorders. Prog Neurobiol 2025; 249:102759. [PMID: 40254176 DOI: 10.1016/j.pneurobio.2025.102759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 02/14/2025] [Accepted: 04/08/2025] [Indexed: 04/22/2025]
Abstract
Autism spectrum disorders (ASDs) comprise a broad category of neurodevelopmental disorders that include repetitive behaviors and difficulties in social interactions. Notably, individuals with ASDs exhibit significant impairments in motor skills even prior to the manifestation of other core symptoms. These skills are crucial for daily activities, such as communication, imitation, and exploration, and hold significant importance for individuals with ASDs. This review seeks to offer new insights into the understanding of motor skill impairments by delineating the pathological mechanisms underlying motor skill learning impairments associated with gene mutations in Fmr1, Chd8, Shank3, BTBR, 16p11.2, and Mecp2, predominantly drawing from well-characterized genetic mouse model studies and proposing potential targets for future therapeutic interventions. We further discuss the underlying pathogenic abnormalities associated with the development of specific brain regions within the cerebellum and cerebrum, as well as disruptions in the structure and function of critical neuronal connectivity pathways. Additional research utilizing epidemiological data, clinical observations, and animal research methodologies is warranted to enhance our understanding of the effect of motor skill learning on the growth, development, and social integration of children. Ultimately, our review suggests potential targets for future therapeutic interventions.
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Affiliation(s)
- Jingwen Duan
- Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Alzheimer's Disease, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan University of Science and Technology, Wuhan, China; Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China
| | - Deyang Zeng
- Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Alzheimer's Disease, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan University of Science and Technology, Wuhan, China; Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China
| | - Tong Wu
- Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Alzheimer's Disease, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan University of Science and Technology, Wuhan, China; Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China
| | - Zhenzhao Luo
- Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Alzheimer's Disease, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan University of Science and Technology, Wuhan, China; Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China
| | - Geng Jingwen
- Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Alzheimer's Disease, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan University of Science and Technology, Wuhan, China
| | - Wei Tan
- Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China.
| | - Yan Zeng
- Geriatric Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China; Hubei Provincial Clinical Research Center for Alzheimer's Disease, Tianyou Hospital Affiliated to Wuhan University of Science and Technology, Wuhan University of Science and Technology, Wuhan, China; Brain Science and Advanced Technology Institute, Wuhan University of Science and Technology, Wuhan, China.
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Pallarès-Sastre M, Amayra I, Pulido R, Nunes-Xavier CE, Bañuelos S, Cavaliere F, García M. Novel CTNNB1 Gene Variants in Spanish CTNNB1 Syndrome Patients: Clinical and Psychological Manifestations. J Autism Dev Disord 2025:10.1007/s10803-025-06829-5. [PMID: 40240530 DOI: 10.1007/s10803-025-06829-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 04/18/2025]
Abstract
CTNNB1 Syndrome is a neurodevelopmental disorder caused by de novo pathogenic variants characterized by global cognitive impairment, microcephaly, speech and motor delay, abnormal muscle tone, ophthalmologic impairments, behaviour problems and autistic spectrum disorder (ASD) symptoms. The aim of this study is to carry out a thorough clinical and psychological characterization of Spanish CTNNB1 syndrome patients. We used standard clinical assessment instruments and an ad hoc questionnaire to measure motor functioning, neurodevelopmental milestones, sleep problems, daily life activities, behavioural problems, communication and speech impairments, eating disorders and autistic features in 25 participants with CTNNB1 syndrome (15 females, 10 males; mean age 7.1 ± 4.1). Main clinical manifestations reported were microcephaly, motor impairment, sight problems, sleep disturbances and sensorial problems. Attainment of developmental milestones indicated motoric, language and daily living skills to be generally delayed. All participants had adaptative skills below their chronological age, even though verbal individuals had better functioning compared to nonverbal. Regarding behaviour impairments, CTNNB1 syndrome patients scored significantly high at internalizing and externalizing behavioural problems. Additionally, about 60% presented symptoms of ASD. Our findings have important implications for the psychotherapeutic and clinical approaches of CTNNB1 syndrome patients. We show the importance of early stimulation, given that an early attainment of developmental milestones is related to a current better function of many clinical variables. Moreover, previous underrated symptoms such as sleep problems, impaired adaptative skills and high rates of behavioural symptoms should be taken into consideration due to the harmful impact that have on every day life.
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Affiliation(s)
- Mercè Pallarès-Sastre
- Neuro-e-Motion Research Team, Department of Psychology, Faculty of Health Sciences, University of Deusto, Avenida de las Universidades 24, Deusto, 48007, Bilbao, Spain.
| | - Imanol Amayra
- Neuro-e-Motion Research Team, Department of Psychology, Faculty of Health Sciences, University of Deusto, Avenida de las Universidades 24, Deusto, 48007, Bilbao, Spain
| | - Rafael Pulido
- Biobizkaia Health Research Institute, Barakaldo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, CIBERER, Madrid, Spain
- Ikerbasque, The Basque Foundation for Science, Bilbao, Spain
| | - Caroline E Nunes-Xavier
- Biobizkaia Health Research Institute, Barakaldo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, CIBERER, Madrid, Spain
- Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Sonia Bañuelos
- Biofisika Institute (UPV/EHU, CSIC), University of the Basque Country (UPV/EHU), Leioa, Spain
- Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Fabio Cavaliere
- Biofisika Institute (UPV/EHU, CSIC), University of the Basque Country (UPV/EHU), Leioa, Spain
- Achucarro Basque Center for Neuroscience, The Basque Biomodels Platform for Human Research (BBioH), Leioa, Spain
| | - Maitane García
- Neuro-e-Motion Research Team, Department of Psychology, Faculty of Health Sciences, University of Deusto, Avenida de las Universidades 24, Deusto, 48007, Bilbao, Spain
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Nevado J, Ciceri F, Bel-Fenellós C, Tenorio-Castaño JA, Maes T, Xaus J, Buesa C, Lapunzina P. Phenotype and psychometric characterization of Phelan-McDermid syndrome patients: pioneering towards personalized medicine. Front Psychiatry 2025; 16:1511962. [PMID: 40104333 PMCID: PMC11913864 DOI: 10.3389/fpsyt.2025.1511962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/29/2025] [Indexed: 03/20/2025] Open
Abstract
Introduction Phelan-McDermid syndrome (PMS) is a genetic disorder caused by the loss of the terminal region of chromosome 22 or by pathogenic or likely-pathogenic variants in SHANK3 gene. Individuals with PMS are affected by a variable degree of intellectual disability, delay or absence of speech, low muscle tone, motor delay epilepsy, and autistic features. We have performed an observational trial aimed to psychometrically characterize individuals carrying deletions or pathogenic variants in SHANK3, to eventually build a foundation for a subsequent precision psychiatry clinical trial with vafidemstat, a LSD1 inhibitor in Phase II clinical development. Methods We have conducted a pilot study to clinically characterize the profile of 30 subjects, all diagnosed of molecularly confirmed PMS. Subjects were phenotypically characterized by applying different psychometric scales, including Repetitive Behavior Questionnaire (RBQ), Vineland Adaptive Behavior Scales, ADOS-2, the Battelle developmental inventory screening test and the Behavior Problems Inventory (BPI). Nineteen patients were included in the pilot study, followed by additional 11 individuals in the validation set. Results Unsupervised hierarchical clustering of the collected psychometric data identifies three groups of patients, with different cognitive and behavioral profile scores. Statistically significant differences in deletion sizes were detected comparing the three clusters (corrected by gender), and the size of the deletion appears to be positively correlated with ADOS and negatively correlated with Vineland-A and -C scores. No correlation was detected between deletion size and the BPI and RBQ scores. Discussion This analysis presents new data on the best potential endpoints, for a future clinical study exploring vafidemstat actionability for SHANK3-associated psychiatric disorders, constituting a good example of how Precision Medicine may open new avenues to understand and treat Central Nervous System (CNS) disorders, pioneering individual management in PMS.
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Affiliation(s)
- Julián Nevado
- Instituto de Genética Médica y Molecular (INGEMM)-Instituto de Investigación del Hospital Universitario La Paz (IdiPaz), Hospital Universitario La Paz, Madrid, Spain
- Centro de Investigación Biomédica en RED de Enfermedades Raras (CIBERER), Madrid, Spain
- ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Hospital La Paz, Madrid, Spain
| | - Filippo Ciceri
- Oryzon Genomics SA. Cornellà de Llobregat, Barcelona, Spain
| | - Cristina Bel-Fenellós
- Dpto. Investigación y Psicología en Educación, Facultad de Educación, Universidad Complutense, Madrid, Spain
| | - Jair A Tenorio-Castaño
- Instituto de Genética Médica y Molecular (INGEMM)-Instituto de Investigación del Hospital Universitario La Paz (IdiPaz), Hospital Universitario La Paz, Madrid, Spain
- Centro de Investigación Biomédica en RED de Enfermedades Raras (CIBERER), Madrid, Spain
- ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Hospital La Paz, Madrid, Spain
| | - Tamara Maes
- Oryzon Genomics SA. Cornellà de Llobregat, Barcelona, Spain
| | - Jordi Xaus
- Oryzon Genomics SA. Cornellà de Llobregat, Barcelona, Spain
| | - Carlos Buesa
- Oryzon Genomics SA. Cornellà de Llobregat, Barcelona, Spain
| | - Pablo Lapunzina
- Instituto de Genética Médica y Molecular (INGEMM)-Instituto de Investigación del Hospital Universitario La Paz (IdiPaz), Hospital Universitario La Paz, Madrid, Spain
- Centro de Investigación Biomédica en RED de Enfermedades Raras (CIBERER), Madrid, Spain
- ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, Hospital La Paz, Madrid, Spain
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Macke EL, Miller AR, Colwell CM, Gonzalez MH, Hunter J, Venkata LPR, Walker L, Wheeler G, Wilson RK, Mardis ER, Miller KE, Mathew MT, Chaudhari BP, Akkari Y. Optical Genome Mapping (OGM) Identifies Multiple Structural Variants in a Case With Atypical Phelan-McDermid Syndrome. Am J Med Genet A 2025; 197:e63929. [PMID: 39535355 DOI: 10.1002/ajmg.a.63929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 09/11/2024] [Accepted: 10/25/2024] [Indexed: 11/16/2024]
Abstract
Here we describe a neonate exhibiting hypotonia, macrocephaly, renal cysts, and respiratory failure requiring tracheostomy and ventilator support. Genetic analysis via rapid genome sequencing (rGS) identified a loss on chromosome 4 encompassing polycystin-2 (PKD2) and a loss on chromosome 22 encompassing SH3 and Multiple Ankyrin Repeat Domains 3 (SHANK3), indicative of Phelan-McDermid syndrome. Further analysis via traditional karyotyping, Optical Genome Mapping (OGM), and PacBio long-read sequencing revealed a more complex landscape of chromosomal rearrangements in this individual, including a balanced 3;12 translocation, and an unbalanced 17;22 translocation. The proband's phenotypic presentation is thought to be the result of Phelan-McDermid syndrome and represents an expansion of the described phenotypes to include significant respiratory failure. This study underscores the challenges and importance of comprehensive genetic testing in elucidating complex presentations and highlights the need for complementary testing methods to overcome limitations in resolution.
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Affiliation(s)
- Erica L Macke
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Anthony R Miller
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Caitlyn M Colwell
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Maria Hernandez Gonzalez
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Jesse Hunter
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Lakshmi Prakruthi Rao Venkata
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Lauren Walker
- Division of Genetics and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Gregory Wheeler
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Richard K Wilson
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Elaine R Mardis
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Katherine E Miller
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
| | - Mariam T Mathew
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
| | - Bimal P Chaudhari
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio, USA
- Division of Neonatology, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Yassmine Akkari
- The Steve and Cindy Rasmussen Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
- Department of Pathology, The Ohio State University, Columbus, Ohio, USA
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Sun YY, Xia Y, Zhi QN, Liu XY. Diagnosis and treatment of bipolar disorder in Phelan-McDermid syndrome: A case report and review of literature. World J Psychiatry 2025; 15:101948. [PMID: 39974483 PMCID: PMC11758057 DOI: 10.5498/wjp.v15.i2.101948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 11/23/2024] [Accepted: 12/25/2024] [Indexed: 01/14/2025] Open
Abstract
BACKGROUND Phelan-McDermid syndrome (PMS) is a rare genetic disorder characterized by intellectual disability, delayed language development, autism spectrum disorders, motor tone abnormalities, and a high risk of psychiatric symptoms, including bipolar disorder. CASE SUMMARY This report presented an 18-year clinical history of a 36-year-old woman with PMS, marked by intellectual disabilities, social withdrawal, and stereotyped behaviors. Diagnosed with bipolar disorder at the age of 18 years old, she encountered significant treatment challenges, including severe adverse reactions to antipsychotic medications in 2022, which led to speech and functional regression. Through rehabilitation and comprehensive therapy, her condition gradually improved. In 2024, after further treatment, her symptoms stabilized, highlighting the complexities and successes of long-term management. CONCLUSION Effective management of PMS requires a thorough clinical history, genetic testing, and long-term supportive care.
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Affiliation(s)
- Yu-Yong Sun
- Department of Psychiatry, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Yong Xia
- Department of Psychiatry, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Qian-Na Zhi
- Department of Psychiatry, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
| | - Xiao-Yan Liu
- Department of Psychiatry, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310000, Zhejiang Province, China
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Wu X, Xu Q, Chen G, Huang J, Zhong Y, Tian L, Wu Q, Chen J. Identification of a cryptic unbalanced translocation Der(22)t(12;22)(q24.33;q13.33) in a large Chinese family with Phelan-McDermid syndrome by nanopore sequencing. Sci Rep 2025; 15:2656. [PMID: 39838038 PMCID: PMC11750972 DOI: 10.1038/s41598-025-87083-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 01/15/2025] [Indexed: 01/23/2025] Open
Abstract
To explore the genetic cause of a four-generation severe intellectual disability in a Chinese family using nanopore sequencing and to provide genetic counseling and reproductive guidance for family members. Multiple genetic analyses of the proband and family members were performed, including chromosome karyotype analysis, whole exome sequencing, nanopore sequencing, PCR amplification, and Sanger sequencing. The results of G-binding karyotyping, CGG repeats for FMR1, GGC repeats for NOTCH2NCL, and trio-whole-exome sequencing were negative for the proband and his parents. Nanopore sequencing showed that the proband carried 12q24.33 microduplication (3.26 Mb) and 22q13.33 microdeletion (1.5 Mb). According to the guidelines of the American Society for Medical Genetics and Genomics (ACMG), the 22q13.33 microdeletion was classified as pathogenic, whereas the 12q24.33 microduplication was classified as a variant of uncertain significance (VUS). The precise karyotype and location of chromosomal breakpoints in the patient and family members were determined through PCR. According to the results of Sanger sequencing, a cryptic balanced translocation was detected in the proband's father. Additionally, informative SNPs were identified near the breakpoints for preimplantation genetic testing for structure rearrangement (PGT-SR) treatment by nanopore sequencing. We identified a cryptic unbalanced translocation in a large Chinese family with Phelan-McDermid syndrome (22q13.33 deletion syndrome) by nanopore sequencing. Nanopore sequencing can be a powerful tool for the genetic diagnosis of unexplained intellectual disability and the detection of precise breakpoints of chromosomal rearrangement in PGT-SR treatment.
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Affiliation(s)
- Xingwu Wu
- Reproductive Medicine Center, Jiangxi Maternal and Child Health Hospital, 318 Bayi Avenue, Nanchang, 330006, China
- Jiangxi Key Laboratory of Reproductive Health, Jiangxi Maternal and Child Health Hospital, Nanchang, China
| | - Qiang Xu
- Reproductive Medicine Center, Jiangxi Maternal and Child Health Hospital, 318 Bayi Avenue, Nanchang, 330006, China
| | - Ge Chen
- Jiangxi Key Laboratory of Reproductive Health, Jiangxi Maternal and Child Health Hospital, Nanchang, China
| | - Jialyv Huang
- Reproductive Medicine Center, Jiangxi Maternal and Child Health Hospital, 318 Bayi Avenue, Nanchang, 330006, China
- Jiangxi Key Laboratory of Reproductive Health, Jiangxi Maternal and Child Health Hospital, Nanchang, China
| | - Yanying Zhong
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lifeng Tian
- Reproductive Medicine Center, Jiangxi Maternal and Child Health Hospital, 318 Bayi Avenue, Nanchang, 330006, China
| | - Qiongfang Wu
- Reproductive Medicine Center, Jiangxi Maternal and Child Health Hospital, 318 Bayi Avenue, Nanchang, 330006, China
| | - Jia Chen
- Reproductive Medicine Center, Jiangxi Maternal and Child Health Hospital, 318 Bayi Avenue, Nanchang, 330006, China.
- Jiangxi Key Laboratory of Reproductive Health, Jiangxi Maternal and Child Health Hospital, Nanchang, China.
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Asta L, Ricciardello A, Cucinotta F, Turriziani L, Boncoddo M, Bellomo F, Angelini J, Gnazzo M, Scandolo G, Pisanò G, Pelagatti F, Chehbani F, Camia M, Persico AM. Clinical, developmental and serotonemia phenotyping of a sample of 70 Italian patients with Phelan-McDermid Syndrome. J Neurodev Disord 2024; 16:57. [PMID: 39363263 PMCID: PMC11451156 DOI: 10.1186/s11689-024-09572-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 09/18/2024] [Indexed: 10/05/2024] Open
Abstract
BACKGROUND Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD). OBJECTIVES To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels. METHODS 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC. RESULTS Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001). CONCLUSIONS We replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way.
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Affiliation(s)
- Lisa Asta
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Arianna Ricciardello
- Cantonal Psychiatric Clinic, Cantonal Socio-Psychiatric Organization (O.S.C.), Repubblica e Cantone Ticino, Mendrisio, Switzerland
| | | | - Laura Turriziani
- Center for Autism "Dopo Di Noi", Barcellona Pozzo Di Gotto (Messina), Italy
| | - Maria Boncoddo
- Institute for Biomedical Research and Innovation (I.R.I.B.), National Research Council of Italy (C.N.R.), Messina, Italy
| | - Fabiana Bellomo
- Child Neuropsychiatry Unit, "G. Martino" University Hospital, Messina, Italy
| | - Jessica Angelini
- Residency Program in Child & Adolescent Neuropsychiatry, University of Modena and Reggio Emilia, Modena, Italy
| | - Martina Gnazzo
- Residency Program in Child & Adolescent Neuropsychiatry, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Scandolo
- Residency Program in Child & Adolescent Neuropsychiatry, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Pisanò
- Residency Program in Child & Adolescent Neuropsychiatry, University of Modena and Reggio Emilia, Modena, Italy
| | - Francesco Pelagatti
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Fethia Chehbani
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Michela Camia
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonio M Persico
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
- Child & Adolescent Neuropsychiatry Program, Modena University Hospital, Modena, Italy.
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Thibaudeau A, Schmitt K, François L, Chatrousse L, Hoffmann D, Cousin L, Weiss A, Vuidel A, Jacob CB, Sommer P, Benchoua A, Wilbertz JH. Pharmacological modulation of developmental and synaptic phenotypes in human SHANK3 deficient stem cell-derived neuronal models. Transl Psychiatry 2024; 14:249. [PMID: 38858349 PMCID: PMC11165012 DOI: 10.1038/s41398-024-02947-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 05/14/2024] [Accepted: 05/17/2024] [Indexed: 06/12/2024] Open
Abstract
Phelan-McDermid syndrome (PMDS) arises from mutations in the terminal region of chromosome 22q13, impacting the SHANK3 gene. The resulting deficiency of the postsynaptic density scaffolding protein SHANK3 is associated with autism spectrum disorder (ASD). We examined 12 different PMDS patient and CRISPR-engineered stem cell-derived neuronal models and controls and found that reduced expression of SHANK3 leads to neuronal hyperdifferentiation, increased synapse formation, and decreased neuronal activity. We performed automated imaging-based screening of 7,120 target-annotated small molecules and identified three compounds that rescued SHANK3-dependent neuronal hyperdifferentiation. One compound, Benproperine, rescued the decreased colocalization of Actin Related Protein 2/3 Complex Subunit 2 (ARPC2) with ß-actin and rescued increased synapse formation in SHANK3 deficient neurons when administered early during differentiation. Neuronal activity was only mildly affected, highlighting Benproperine's effects as a neurodevelopmental modulator. This study demonstrates that small molecular compounds that reverse developmental phenotypes can be identified in human neuronal PMDS models.
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Mitz AR, Boccuto L, Thurm A. Evidence for common mechanisms of pathology between SHANK3 and other genes of Phelan-McDermid syndrome. Clin Genet 2024; 105:459-469. [PMID: 38414139 PMCID: PMC11025605 DOI: 10.1111/cge.14503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/18/2024] [Accepted: 02/02/2024] [Indexed: 02/29/2024]
Abstract
Chromosome 22q13.3 deletion (Phelan-McDermid) syndrome (PMS, OMIM 606232) is a rare genetic condition that impacts neurodevelopment. PMS most commonly results from heterozygous contiguous gene deletions that include the SHANK3 gene or likely pathogenic variants of SHANK3 (PMS-SHANK3 related). Rarely, chromosomal rearrangements that spare SHANK3 share the same general phenotype (PMS-SHANK3 unrelated). Very recent human and model system studies of genes that likely contribute to the PMS phenotype point to overlap in gene functions associated with neurodevelopment, synaptic formation, stress/inflammation and regulation of gene expression. In this review of recent findings, we describe the functional overlaps between SHANK3 and six partner genes of 22q13.3 (PLXNB2, BRD1, CELSR1, PHF21B, SULT4A1, and TCF20), which suggest a model that explains the commonality between PMS-SHANK3 related and PMS-SHANK3 unrelated classes of PMS. These genes are likely not the only contributors to neurodevelopmental impairments in the region, but they are the best documented to date. The review provides evidence for the overlapping and likely synergistic contributions of these genes to the PMS phenotype.
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Affiliation(s)
- Andrew R. Mitz
- Laboratory of Neuropsychology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
| | - Luigi Boccuto
- Healthcare Genetics and Genomics Interdisciplinary Doctoral Program, School of Nursing, College of Behavioral, Social and Health Sciences, Clemson University, Clemson, SC, USA
| | - Audrey Thurm
- Neurodevelopmental and Behavioral Phenotyping Service, Office of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
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10
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Genovese AC, Butler MG. Behavioral and Psychiatric Disorders in Syndromic Autism. Brain Sci 2024; 14:343. [PMID: 38671997 PMCID: PMC11048128 DOI: 10.3390/brainsci14040343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 03/25/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Syndromic autism refers to autism spectrum disorder diagnosed in the context of a known genetic syndrome. The specific manifestations of any one of these syndromic autisms are related to a clinically defined genetic syndrome that can be traced to certain genes and variants, genetic deletions, or duplications at the chromosome level. The genetic mutations or defects in single genes associated with these genetic disorders result in a significant elevation of risk for developing autism relative to the general population and are related to recurrence with inheritance patterns. Additionally, these syndromes are associated with typical behavioral characteristics or phenotypes as well as an increased risk for specific behavioral or psychiatric disorders and clinical findings. Knowledge of these associations helps guide clinicians in identifying potentially treatable conditions that can help to improve the lives of affected patients and their families.
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Affiliation(s)
- Ann C. Genovese
- Department of Psychiatry and Behavioral Sciences, University of Kansas Medical Center, Kansas City, KS 66160, USA;
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11
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Smith MS, Sarasua SM, Rogers C, Phelan K, Boccuto L. Lymphedema is associated with CELSR1 in Phelan-McDermid syndrome. Clin Genet 2023; 104:472-478. [PMID: 37232218 DOI: 10.1111/cge.14364] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/11/2023] [Accepted: 05/12/2023] [Indexed: 05/27/2023]
Abstract
Lymphedema is a troubling condition present in many disorders including the rare genetic disorder known as Phelan-McDermid syndrome (PMS). The neurobehavioral features of PMS, also known as 22q13.3 deletion syndrome, have been investigated, but little research exists on lymphedema in PMS. In this investigation, clinical and genetic data from 404 people with PMS were reviewed from the PMS-International Registry revealing a prevalence of 5% with lymphedema. Lymphedema was reported in 1 out of 47 people (2.1%) with PMS due to a SHANK3 variant and 19 out of 357 people (5.3%) with PMS due to 22q13.3 deletions. Lymphedema was more common among those in their teens or adulthood (p = 0.0011) and those with deletions >4 Mb. People with lymphedema had significantly larger deletions (mean 5.375 Mb) than those without lymphedema (mean 3.464 Mb, p = 0.00496). Association analysis identified a deletion of the CELSR1 gene to be the biggest risk factor (OR = 12.9 95% CI [2.9-56.2]). Detailed assessment of 5 subjects identified all had deletions of CELSR1, developed symptoms of lymphedema starting at age 8 or older, and typically responded well to standard therapy. In conclusion, this is the largest assessment of lymphedema in PMS to date and our results suggest that individuals with deletions >4 Mb or those with CELSR1 deletions should be assessed for lymphedema.
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Affiliation(s)
- Marie S Smith
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, South Carolina, USA
| | - Sara M Sarasua
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, South Carolina, USA
| | - Curtis Rogers
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Katy Phelan
- Genetics Laboratory, Florida Cancer Specialists & Research Institute, Fort Myers, Florida, USA
| | - Luigi Boccuto
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, South Carolina, USA
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12
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Dhossche D, de Billy C, Laurent-Levinson C, Le Normand MT, Recasens C, Robel L, Philippe A. Early-onset catatonia associated with SHANK3 mutations: looking at the autism spectrum through the prism of psychomotor phenomena. Front Psychiatry 2023; 14:1186555. [PMID: 37810596 PMCID: PMC10557257 DOI: 10.3389/fpsyt.2023.1186555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 08/04/2023] [Indexed: 10/10/2023] Open
Abstract
Background Individuals with Phelan-McDermid syndrome (PMS) present with a wide range of diagnoses: autism spectrum disorder, intellectual disability, or schizophrenia. Differences in the genetic background could explain these different neurodevelopmental trajectories. However, a more parsimonious hypothesis is to consider that they may be the same phenotypic entity. Catatonic disturbances occasionally reported from adolescence onwards in PMS prompts exploration of the hypothesis that this clinical entity may be an early-onset form of catatonia. The largest cohort of children with childhood catatonia was studied by the Wernicke-Kleist-Leonhard school (WKL school), which regards catatonia as a collection of qualitative abnormalities of psychomotricity that predominantly affecting involuntary motricity (reactive and expressive). The aim of this study was to investigate the presence of psychomotor signs in three young adults carrying a mutation or intragenic deletion of the SHANK3 gene through the prism of the WKL school conception of catatonia. Methods This study was designed as an exploratory case study. Current and childhood psychomotor phenomena were investigated through semi-structured interviews with the parents, direct interaction with the participants, and the study of documents reporting observations of the participants at school or by other healthcare professionals. Results The findings show catatonic manifestations from childhood that evolved into a chronic form, with possible phases of sub-acute exacerbations starting from adolescence. Conclusion The presence of catatonic symptoms from childhood associated with autistic traits leads us to consider that this singular entity fundamentally related to SHANK3 mutations could be a form of early-onset catatonia. Further case studies are needed to confirm our observations.
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Affiliation(s)
- Dirk Dhossche
- Department of Adolescent Psychiatry, Inland Northwest Behavioral Health, Spokane, WA, United States
| | - Clément de Billy
- CEMNIS – Noninvasive Neuromodulation Center, University Hospital Strasbourg, Strasbourg, France
| | - Claudine Laurent-Levinson
- Faculté de Médecine Sorbonne Université, Groupe de Recherche Clinique no. 15 – Troubles Psychiatriques et Développement (PSYDEV), Paris, France
- Centre de Référence des Maladies Rares à Expression Psychiatrique, Département de Psychiatrie de l’enfant et l’adolescent, Hôpital Pitié-Salpétrière, Paris, France
| | - Marie T. Le Normand
- Institut de l’Audition, Institut Pasteur, Paris, France
- Laboratoire de Psychopathologie et Processus de Santé, Université de Paris Cité, Paris, France
| | - Christophe Recasens
- Service universitaire de Psychiatrie de l’Enfant et de l’Adolescent, Centre hospitalier Intercommunal de Créteil, Créteil, France
| | - Laurence Robel
- Unité de Psychopathologie de l’Enfant et de l’Adolescent, GHU Paris, Psychiatrie et Neurosciences, Hôpital Sainte Anne, Paris, France
| | - Anne Philippe
- Université Paris Cité, Paris, France
- INSERM U1163 Institut Imagine, Paris, France
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Srivastava S, Sahin M, Buxbaum JD, Berry-Kravis E, Soorya LV, Thurm A, Bernstein JA, Asante-Otoo A, Bennett WE, Betancur C, Brickhouse TH, Passos Bueno MR, Chopra M, Christensen CK, Cully JL, Dies K, Friedman K, Gummere B, Holder JL, Jimenez-Gomez A, Kerins CA, Khan O, Kohlenberg T, Lacro RV, Levy LA, Levy T, Linnehan D, Loth E, Moshiree B, Neumeyer A, Paul SM, Phelan K, Persico A, Rapaport R, Rogers C, Saland J, Sethuram S, Shapiro J, Tarr PI, White KM, Wickstrom J, Williams KM, Winrow D, Wishart B, Kolevzon A. Updated consensus guidelines on the management of Phelan-McDermid syndrome. Am J Med Genet A 2023; 191:2015-2044. [PMID: 37392087 PMCID: PMC10524678 DOI: 10.1002/ajmg.a.63312] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 05/04/2023] [Accepted: 05/18/2023] [Indexed: 07/02/2023]
Abstract
Phelan-McDermid syndrome (PMS) is a genetic condition caused by SHANK3 haploinsufficiency and characterized by a wide range of neurodevelopmental and systemic manifestations. The first practice parameters for assessment and monitoring in individuals with PMS were published in 2014; recently, knowledge about PMS has grown significantly based on data from longitudinal phenotyping studies and large-scale genotype-phenotype investigations. The objective of these updated clinical management guidelines was to: (1) reflect the latest in knowledge in PMS and (2) provide guidance for clinicians, researchers, and the general community. A taskforce was established with clinical experts in PMS and representatives from the parent community. Experts joined subgroups based on their areas of specialty, including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry. Taskforce members convened regularly between 2021 and 2022 and produced specialty-specific guidelines based on iterative feedback and discussion. Taskforce leaders then established consensus within their respective specialty group and harmonized the guidelines. The knowledge gained over the past decade allows for improved guidelines to assess and monitor individuals with PMS. Since there is limited evidence specific to PMS, intervention mostly follows general guidelines for treating individuals with developmental disorders. Significant evidence has been amassed to guide the management of comorbid neuropsychiatric conditions in PMS, albeit mainly from caregiver report and the experience of clinical experts. These updated consensus guidelines on the management of PMS represent an advance for the field and will improve care in the community. Several areas for future research are also highlighted and will contribute to subsequent updates with more refined and specific recommendations as new knowledge accumulates.
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Affiliation(s)
- Siddharth Srivastava
- Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
- Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Mustafa Sahin
- Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
- Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Joseph D. Buxbaum
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Elizabeth Berry-Kravis
- Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
- Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA
| | | | - Audrey Thurm
- Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
| | | | - Afua Asante-Otoo
- Rehabilitation Medicine Department, NIH Clinical Center, Bethesda, MD, USA
| | - William E. Bennett
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Catalina Betancur
- Sorbonne Université, INSERM, CNRS, Neuroscience Paris Seine, Institut de Biologie Paris Seine, Paris, France
| | - Tegwyn H. Brickhouse
- Department of Dental Public Health & Policy, School of Dentistry, Virginia Commonwealth University, Richmond, VA, USA
| | - Maria Rita Passos Bueno
- Departamento de Genética e Biologia Evolutiva, Centro de Estudos do Genoma Humano e Células-tronco, Instituto de Biociências, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Maya Chopra
- Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
- Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Celanie K. Christensen
- Division of Developmental Medicine, Department of Pediatrics, Riley Children’s Health, Indianapolis, IN, USA
- Division of Child Neurology, Department of Neurology, Riley Children’s Health, Indianapolis, IN, USA
| | - Jennifer L. Cully
- Department of Pediatrics, College of Medicine and Division of Dentistry and Orthodontics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
| | - Kira Dies
- Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
- Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Kate Friedman
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - J. Lloyd Holder
- Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA
| | | | - Carolyn A. Kerins
- Department of Pediatric Dentistry, School of Dentistry, Texas A&M University, Dallas, TX, USA
| | - Omar Khan
- National Institute of Neurological Disease and Stroke, Bethesda, MD, USA
| | | | - Ronald V. Lacro
- Department of Cardiology, Boston Children’s Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | | | - Tess Levy
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Eva Loth
- Kings College London, London, UK
| | - Baharak Moshiree
- Department of Medicine, Wake Forest/Atrium Health, Charlotte, NC, USA
| | - Ann Neumeyer
- Lurie Center for Autism, Massachusetts General Hospital, Lexington MA, USA, Harvard Medical School, Boston, MA USA
| | - Scott M. Paul
- Rehabilitation Medicine Department, NIH Clinical Center, Bethesda, MD, USA
| | - Katy Phelan
- Genetics Laboratory, Florida Cancer Specialists and Research Institute, Fort Myers, FL, USA
| | - Antonio Persico
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Robert Rapaport
- Department of Pediatrics, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Jeffrey Saland
- Department of Pediatrics, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Swathi Sethuram
- Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA
| | | | - Phillip I. Tarr
- Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Kerry M. White
- Division of Developmental Medicine, Department of Pediatrics, Riley Children’s Health, Indianapolis, IN, USA
- Department of Medical and Molecular Genetics, Riley Children’s Health, Indianapolis, IN, USA
| | - Jordan Wickstrom
- Sinai Rehabilitation Center, Lifebridge Health, Baltimore, MD, USA
| | - Kent M. Williams
- Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH, USA
| | | | | | - Alexander Kolevzon
- Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pediatrics, Kravis Children’s Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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14
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van Balkom ID, Burdeus-Olavarrieta M, Cooke J, de Cuba AG, Turner A. Consensus recommendations on mental health issues in Phelan-McDermid syndrome. Eur J Med Genet 2023; 66:104770. [PMID: 37085014 DOI: 10.1016/j.ejmg.2023.104770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 04/23/2023]
Abstract
Phelan-McDermid syndrome is a rare genetic condition caused by a deletion encompassing the 22q13.3 region or a pathogenic variant of the gene SHANK3. The clinical presentation is variable, but main characteristics include global developmental delay/intellectual disability (ID), marked speech impairment or delay, along with other features like hypotonia and somatic or psychiatric comorbidities. This publication delineates mental health, developmental and behavioural themes across the lifetime of individuals with PMS as informed by parents/caregivers, experts, and other key professionals involved in PMS care. We put forward several recommendations based on the available literature concerning mental health and behaviour in PMS. Additionally, this article aims to improve our awareness of the importance of considering developmental level of the individual with PMS when assessing mental health and behavioural issues. Understanding how the discrepancy between developmental level and chronological age may impact concerning behaviours offers insight into the meaning of those behaviours and informs care for individuals with PMS, enabling clinicians to address unmet (mental health) care needs and improve quality of life.
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Affiliation(s)
- Ingrid Dc van Balkom
- Jonx, Department of (Youth) Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands; Rob Giel Research Centre, Department of Psychiatry, University Medical Center Groningen, Groningen, the Netherlands.
| | - Monica Burdeus-Olavarrieta
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; School of Psychology, Universidad Autónoma, Madrid, Spain
| | - Jennifer Cooke
- Forensic and Neurodevelopmental Sciences Department, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, United Kingdom
| | - A Graciela de Cuba
- Jonx, Department of (Youth) Mental Health and Autism, Lentis Psychiatric Institute, Groningen, the Netherlands
| | - Alison Turner
- Phelan-McDermid Syndrome Foundation UK, 99 Highgate W Hill, London, N6 6NR, United Kingdom
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15
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Burdeus-Olavarrieta M, Nevado J, van Weering-Scholten S, Parker S, Swillen A. Consensus recommendations on communication, language and speech in Phelan-McDermid syndrome. Eur J Med Genet 2023; 66:104745. [PMID: 36871884 DOI: 10.1016/j.ejmg.2023.104745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/22/2023] [Accepted: 03/02/2023] [Indexed: 03/07/2023]
Abstract
Phelan-McDermid syndrome is a genetic condition primarily caused by a deletion on the 22q13.3 region or a likely pathogenic/pathogenic variant of SHANK3. The main features comprise global developmental delay, marked impairment or absence of speech, and other clinical characteristics to a variable degree, such as hypotonia or psychiatric comorbidities. A set of clinical guidelines for health professionals covering relevant aspects of clinical management have been written by the European PMS Consortium, and consensus has been reached regarding final recommendations. In this work, attention is given to communication, language and speech impairments in PMS, and the findings from available literature are presented. Findings from the literature review reveal marked speech impairment in up to 88% of deletions and 70% of SHANK3 variants. Absence of speech is frequent and affects 50%-80% of the individuals with PMS. Communicative skills in the expressive domain other than spoken language remain understudied, but some studies offer data on non-verbal language or the use of alternative/augmentative communication support. Loss of language and other developmental skills is reported in around 40% of individuals, with variable course. Deletion size and possibly other clinical variables (e.g., conductive hearing problems, neurological issues, intellectual disability, etc.) are related to communicative and linguistic abilities. Recommendations include regular medical check-ups of hearing and the assessment of other factors influencing communication, thorough evaluation of preverbal and verbal communicative skills, early intervention, and support via alternative/augmentative communication systems.
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Affiliation(s)
- Monica Burdeus-Olavarrieta
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, IiSGM, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain; School of Psychology, Universidad Autónoma, Madrid, Spain.
| | - Julián Nevado
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain; CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain; ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | | | - Susanne Parker
- Phelan-McDermid-Gesellschaft e.V. Geschäftsstelle Universitätsklinikum Ulm, Sekretariat Neurologie, Oberer Eselsberg 45, 89081, Ulm, Germany
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- Coordinated by C.M.A. van Ravenswaaij-Arts, University of Groningen, University Medical Centre Groningen, Dept. Genetics, Groningen, the Netherlands
| | - Ann Swillen
- Center for Human Genetics, University Hospital Leuven, Belgium; Department of Human Genetics, KU Leuven, Herestraat 49, 3000, Leuven, Belgium
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16
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Huang M, Qi Q, Xu T. Targeting Shank3 deficiency and paresthesia in autism spectrum disorder: A brief review. Front Mol Neurosci 2023; 16:1128974. [PMID: 36846568 PMCID: PMC9948097 DOI: 10.3389/fnmol.2023.1128974] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 01/18/2023] [Indexed: 02/11/2023] Open
Abstract
Autism spectrum disorder (ASD) includes a group of multifactorial neurodevelopmental disorders characterized by impaired social communication, social interaction, and repetitive behaviors. Several studies have shown an association between cases of ASD and mutations in the genes of SH3 and multiple ankyrin repeat domain protein 3 (SHANK3). These genes encode many cell adhesion molecules, scaffold proteins, and proteins involved in synaptic transcription, protein synthesis, and degradation. They have a profound impact on all aspects of synaptic transmission and plasticity, including synapse formation and degeneration, suggesting that the pathogenesis of ASD may be partially attributable to synaptic dysfunction. In this review, we summarize the mechanism of synapses related to Shank3 in ASD. We also discuss the molecular, cellular, and functional studies of experimental models of ASD and current autism treatment methods targeting related proteins.
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Affiliation(s)
- Min Huang
- Department of Anesthesiology, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Department of Anesthesiology, Suzhou Hospital of Anhui Medical University, Suzhou, China
| | - Qi Qi
- Department of Anesthesiology, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Department of Anesthesiology, Suzhou Hospital of Anhui Medical University, Suzhou, China
| | - Tao Xu
- Department of Anesthesiology, Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Department of Anesthesiology, Suzhou Hospital of Anhui Medical University, Suzhou, China,*Correspondence: Tao Xu,
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Serrada-Tejeda S, Cuadrado ML, Martínez-Piédrola RM, Máximo-Bocanegra N, Sánchez-Herrera-Baeza P, Camacho-Montaño LR, Pérez-de-Heredia-Torres M. Sensory processing and adaptive behavior in Phelan-McDermid syndrome: a cross-sectional study. Eur J Pediatr 2022; 181:3141-3152. [PMID: 35840778 PMCID: PMC9352617 DOI: 10.1007/s00431-022-04564-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/05/2022] [Accepted: 07/10/2022] [Indexed: 12/29/2022]
Abstract
Phelan-McDermid syndrome (PMS) is a genetic disorder caused by a mutation or deletion of the SHANK3 gene (chromosome 22q13.3), characterized by different sensory processing anomalies. The objective of this study is to expand and provide a detailed definition of the sensory profile of patients with PMS. The secondary objective was to examine the relationship between sensory patterns and adaptive behavior. A cross-sectional study was carried out among 51 Spanish patients with a confirmed genetic diagnosis of PMS. All the participants' parents completed the Short Sensory Profile-Spanish (SSP-S) and the Adaptive Behavior Assessment System II (ABAS-II). Correlational, multiple regression and hierarchical cluster analyses were performed. An atypical sensory profile was identified in almost 75% of PMS patients. Definite differences were found among scores; nonetheless, sub-threshold values were observed in tactile sensitivity, underresponsive/seeks sensation, auditory filtering, and low energy/weak sensory categories. Conceptual, social, and practical domains, as well as the General Adaptive Composite (GAC) of the ABAS-II showed extremely low scores (i.e., <70). Significant correlations were found (p<0.005) between SSP-S scores and the conceptual, social, practical, and GAC index of the ABAS-II, whereby higher SSP-S scores were associated with better skills and higher adaptive performance. The cluster analysis indicated that the group with the largest mutation size (7.23 Mb) showed the greatest sensory processing difficulties and very low adaptive skills. CONCLUSIONS Patients with PMS show an atypical sensory profile, which correlates with limitations in general adaptive behaviors. WHAT IS KNOWN • PMS sensory processing difficulties were associated with a pattern of underresponsive/seeks sensation, low energy/weak, and tactile hyporeactivity. • Sensory processing difficulties have been associated with limitations in the development of appropriate adaptive communication and interaction behaviors. WHAT IS NEW • Sensory definite differences associated with tactile hyperreactivity, as well as significant effects of underresponsiveness/seeks sensation and auditory filtering categories on the adaptive abilities were found in SHANK3deletion patients. • Cluster analysis suggests that smaller mutation sizes were related to better sensory processing and higher adaptive skills, while patients with larger deletion sizes have greater adaptive difficulties and worse sensory processing skills.
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Affiliation(s)
- Sergio Serrada-Tejeda
- Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Avenida de Atenas s/n. CP.28922, Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | - María-Luz Cuadrado
- Department of Neurology, Hospital Clínico San Carlos, Madrid, Spain
- Department of Medicine, School of Medicine, Universidad Complutense, Madrid, Spain
| | - Rosa Mª Martínez-Piédrola
- Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Avenida de Atenas s/n. CP.28922, Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | - Nuria Máximo-Bocanegra
- Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Avenida de Atenas s/n. CP.28922, Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | - Patricia Sánchez-Herrera-Baeza
- Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Avenida de Atenas s/n. CP.28922, Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | - Lucía Rocío Camacho-Montaño
- Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Avenida de Atenas s/n. CP.28922, Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | - Marta Pérez-de-Heredia-Torres
- Department of Physical Therapy, Occupational Therapy, Rehabilitation and Physical Medicine, Avenida de Atenas s/n. CP.28922, Rey Juan Carlos University, Alcorcón, Madrid, Spain
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18
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Zheng S, Kaat A, Farmer C, Thurm A, Burrows CA, Kanne S, Georgiades S, Esler A, Lord C, Takahashi N, Nowell KP, Will E, Roberts J, Bishop SL. Bias in measurement of autism symptoms by spoken language level and non-verbal mental age in minimally verbal children with neurodevelopmental disorders. Front Psychol 2022; 13:927847. [PMID: 35967726 PMCID: PMC9372407 DOI: 10.3389/fpsyg.2022.927847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Increasing numbers of children with known genetic conditions and/or intellectual disability are referred for evaluation of autism spectrum disorder (ASD), highlighting the need to refine autism symptom measures to facilitate differential diagnoses in children with cognitive and language impairments. Previous studies have reported decreased specificity of ASD screening and diagnostic measures in children with intellectual disability. However, little is known about how cognitive and language abilities impact the measurement of specific ASD symptoms in this group. We aggregated a large sample of young children (N = 1196; aged 31-119 months) to examine measurement invariance of ASD symptoms among minimally verbal children within the context of the Autism Diagnostic Observation Schedule (ADOS) Module 1. Using confirmatory factor analysis (CFA) and moderated non-linear factor analysis (MNLFA), we examined how discrete behaviors were differentially associated with the latent symptom domains of social communication impairments (SCI) and restricted and repetitive behaviors (RRB) across spoken language levels and non-verbal mental age groupings. While the two-factor structure of SCI and RRB held consistently across language and cognitive levels, only partial invariance was observed for both ASD symptom domains of SCI and RRB. Specifically, four out of the 15 SCI items and one out of the three RRB items examined showed differential item functioning between children with "Few to No Words" and those with "Some Words"; and one SCI item and one RRB item showed differential item functioning across non-verbal mental age groups. Moreover, even after adjusting for the differential item functioning to reduce measurement bias across groups, there were still differences in ASD symptom domain scores across spoken language levels. These findings further underscore the influence of spoken language level on measurement of ASD symptoms and the importance of measuring ASD symptoms within refined spoken language levels, even among those with minimal verbal abilities.
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Affiliation(s)
- Shuting Zheng
- Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
| | - Aaron Kaat
- Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Cristan Farmer
- Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, Bethesda, MD, United States
| | - Audrey Thurm
- Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, Bethesda, MD, United States
| | - Catherine A. Burrows
- Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
- Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN, United States
| | - Stephen Kanne
- Center for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, NY, United States
| | - Stelios Georgiades
- Offord Centre for Child Studies, McMaster University, Hamilton, ON, Canada
| | - Amy Esler
- Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN, United States
| | - Catherine Lord
- UCLA Semel Institute for Neuroscience & Human Behavior, Center for Autism Research and Treatment, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Nicole Takahashi
- Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri, Columbia, MO, United States
| | - Kerri P. Nowell
- Thompson Center for Autism and Neurodevelopmental Disorders, University of Missouri, Columbia, MO, United States
- Department of Health Psychology, University of Missouri, Columbia, MO, United States
| | - Elizabeth Will
- Department of Psychology, University of South Carolina, Columbia, SC, United States
| | - Jane Roberts
- Department of Psychology, University of South Carolina, Columbia, SC, United States
| | - Somer L. Bishop
- Department of Psychiatry and Behavioral Sciences, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
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19
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Reyes-Martín J, Simó-Pinatella D, Font-Roura J. Assessment of Challenging Behavior Exhibited by People with Intellectual and Developmental Disabilities: A Systematic Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:8701. [PMID: 35886552 PMCID: PMC9324269 DOI: 10.3390/ijerph19148701] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/11/2022] [Accepted: 07/12/2022] [Indexed: 11/16/2022]
Abstract
The assessment of challenging behavior exhibited by people with intellectual and developmental disabilities is essential for the planning of prevention and intervention programs. This review aimed to identify and analyze the standardized instruments that exclusively focus on the assessment of challenging behavior. We identified and organized 141 articles into four categories: original instrument studies, validation studies, relational studies, and intervention studies. The results identified 24 instruments that generally show high-quality psychometric properties and other utilities beyond the observation of the presence of challenging behavior and diagnostic categorization. Age, level of adaptive behavior, disability, presence of autism spectrum disorder, and medication are some of the variables that were found to be possibly related to the occurrence of challenging behavior. Additionally, the results suggest that interventions focused on supporting positive behavior or providing training on behavior to professionals and caregivers significantly reduced the occurrence of these behaviors. Instruments that help us to understand and measure the challenging behavior exhibited by people with intellectual and developmental disabilities are essential for the design of effective evaluation and intervention protocols.
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Affiliation(s)
- Juliana Reyes-Martín
- Facultat de Psicologia, Ciències de l’Educació i de l’Esport, Blanquerna, Ramon Llull University, 08022 Barcelona, Spain;
- Fundació Vallparadís, Mutua Terrassa, 08221 Barcelona, Spain
| | - David Simó-Pinatella
- Facultat de Psicologia, Ciències de l’Educació i de l’Esport, Blanquerna, Ramon Llull University, 08022 Barcelona, Spain;
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20
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Serrada-Tejeda S, Martínez-Piédrola RM, Máximo-Bocanegra N, Sánchez-Herrera-Baeza P, Pérez-de-Heredia-Torres M. Descriptive Analysis of Adaptive Behavior in Phelan–McDermid Syndrome and Autism Spectrum Disorder. Front Neurosci 2022; 16:893003. [PMID: 35864987 PMCID: PMC9295709 DOI: 10.3389/fnins.2022.893003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/07/2022] [Indexed: 12/02/2022] Open
Abstract
Introduction The variety in symptomatology and clinical presentation of individuals diagnosed with Phelan-McDermid Syndrome (PMS) can delay medical diagnosis, so identifying specific neurobehavioral variables and facilitating differential diagnosis with patients with idiopathic Autism Spectrum Disorder (ASD) can guide early detection. Methods A descriptive analysis of the level of adaptive behavior in 50 patients diagnosed with PMS was performed (SHANK3deletion: N = 44; SHANKmutation: N = 6). Subsequently, a comparative analysis was performed with 28 children aged between 4 years and 6 years and 11 months (SHANK3deletion = 14; ASD = 14). Differences between the two groups were evaluated and Bonferroni correction was applied for multiple comparisons. Results Differences were identified in the variables of communication (z = −2.715, p = 0.007), Self-Direction (z = −2.199, p = 0.028) and social participation (z = −3.190, p = 0.001), with better adaptive behavior skills being observed in participants with a SHANK3mutation. Better adaptive skills in the sample of participants with ASD, were found and statistically significant differences were identified in the variables of academic skills (z = −3.084, p = 0.002), use of community resources (z = −1.889, p = 0.050) and health and safety (z = −2.90, p = 0.004). Conclusion Participants with SHANK3mutation show better communication and social participation skills than those with a diagnosis of SHANK3deletion. The observed differences between ASD and individuals with PMS reflect deficits in practical and conceptual adaptive skills that may limit and hinder daily adaptive functioning.
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21
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Two Genetic Mechanisms in Two Siblings with Intellectual Disability, Autism Spectrum Disorder, and Psychosis. J Pers Med 2022; 12:jpm12061013. [PMID: 35743796 PMCID: PMC9224546 DOI: 10.3390/jpm12061013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 06/08/2022] [Accepted: 06/17/2022] [Indexed: 12/04/2022] Open
Abstract
Intellectual disability (ID) and autism spectrum disorder (ASD) are complex neurodevelopmental disorders with high heritability. To search for the genetic deficits in two siblings affected with ID and ASD in a family, we first performed a genome-wide copy number variation (CNV) analysis using chromosomal microarray analysis (CMA). We found a 3.7 Mb microdeletion at 22q13.3 in the younger sister. This de novo microdeletion resulted in the haploinsufficiency of SHANK3 and several nearby genes involved in neurodevelopment disorders. Hence, she was diagnosed with Phelan–McDermid syndrome (PMS, OMIM#606232). We further performed whole-genome sequencing (WGS) analysis in this family. We did not detect pathogenic mutations with significant impacts on the phenotypes of the elder brother. Instead, we identified several rare, likely pathogenic variants in seven genes implicated in neurodevelopmental disorders: KLHL17, TDO2, TRRAP, EIF3F, ATP10A, DICER1, and CDH15. These variants were transmitted from his unaffected parents, indicating these variants have only moderate clinical effects. We propose that these variants worked together and led to the clinical phenotypes in the elder brother. We also suggest that the combination of multiple genes with moderate effects is part of the genetic mechanism of neurodevelopmental disorders.
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22
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Nevado J, García-Miñaúr S, Palomares-Bralo M, Vallespín E, Guillén-Navarro E, Rosell J, Bel-Fenellós C, Mori MÁ, Milá M, del Campo M, Barrúz P, Santos-Simarro F, Obregón G, Orellana C, Pachajoa H, Tenorio JA, Galán E, Cigudosa JC, Moresco A, Saleme C, Castillo S, Gabau E, Pérez-Jurado L, Barcia A, Martín MS, Mansilla E, Vallcorba I, García-Murillo P, Cammarata-Scalisi F, Gonçalves Pereira N, Blanco-Lago R, Serrano M, Ortigoza-Escobar JD, Gener B, Seidel VA, Tirado P, Lapunzina P. Variability in Phelan-McDermid Syndrome in a Cohort of 210 Individuals. Front Genet 2022; 13:652454. [PMID: 35495150 PMCID: PMC9044489 DOI: 10.3389/fgene.2022.652454] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/16/2022] [Indexed: 12/18/2022] Open
Abstract
Phelan-McDermid syndrome (PMS, OMIM# 606232) results from either different rearrangements at the distal region of the long arm of chromosome 22 (22q13.3) or pathogenic sequence variants in the SHANK3 gene. SHANK3 codes for a structural protein that plays a central role in the formation of the postsynaptic terminals and the maintenance of synaptic structures. Clinically, patients with PMS often present with global developmental delay, absent or severely delayed speech, neonatal hypotonia, minor dysmorphic features, and autism spectrum disorders (ASD), among other findings. Here, we describe a cohort of 210 patients with genetically confirmed PMS. We observed multiple variant types, including a significant number of small deletions (<0.5 Mb, 64/189) and SHANK3 sequence variants (21 cases). We also detected multiple types of rearrangements among microdeletion cases, including a significant number with post-zygotic mosaicism (9.0%, 17/189), ring chromosome 22 (10.6%, 20/189), unbalanced translocations (de novo or inherited, 6.4%), and additional rearrangements at 22q13 (6.3%, 12/189) as well as other copy number variations in other chromosomes, unrelated to 22q deletions (14.8%, 28/189). We compared the clinical and genetic characteristics among patients with different sizes of deletions and with SHANK3 variants. Our findings suggest that SHANK3 plays an important role in this syndrome but is probably not uniquely responsible for all the spectrum features in PMS. We emphasize that only an adequate combination of different molecular and cytogenetic approaches allows an accurate genetic diagnosis in PMS patients. Thus, a diagnostic algorithm is proposed.
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Affiliation(s)
- Julián Nevado
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | - Sixto García-Miñaúr
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | - María Palomares-Bralo
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | - Elena Vallespín
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | | | | | - Cristina Bel-Fenellós
- Departamento de Investigación y Psicología en Educación, Facultad de Educación, UCM, Madrid, Spain
- CEE Estudio-3, Afanias, Madrid, Spain
| | - María Ángeles Mori
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | | | | | - Pilar Barrúz
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
| | - Fernando Santos-Simarro
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | | | | | | | - Jair Antonio Tenorio
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | - Enrique Galán
- Hospital Materno-Infantil Infanta Cristina, Badajoz, Spain
| | | | | | - César Saleme
- Maternity Nuestra Señora de la Merced, Tucumán, Argentina
| | - Silvia Castillo
- Sección Genética, Hospital Clínico Universidad de Chile, Santiago, Chile
- Clínica Alemana, Santiago, Chile
| | | | - Luis Pérez-Jurado
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- Servicio de Genética, Instituto de Investigaciones Médicas Hospital del Mar (IMIM)/Universitat Pompeu Fabra, Barcelona, Spain
| | - Ana Barcia
- Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Maria Soledad Martín
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
| | - Elena Mansilla
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | - Isabel Vallcorba
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
| | | | | | | | - Raquel Blanco-Lago
- Servicio de Neuropediatría, Hospital Universitario Central de Asturias, Oviedo (Asturias), Spain
| | - Mercedes Serrano
- Unidad de Neuropediatría, Hospital San Joan de Deu, Barcelona, Spain
| | | | | | | | - Pilar Tirado
- Servicio de Neuropediatría, Hospital Universitario La Paz, Madrid, Spain
| | - Pablo Lapunzina
- Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain
- CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain
- ITHACA-European Reference Network, Hospital La Paz, Madrid, Spain
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23
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Isenstein EL, Grosman HE, Guillory SB, Zhang Y, Barkley S, McLaughlin CS, Levy T, Halpern D, Siper PM, Buxbaum JD, Kolevzon A, Foss-Feig JH. Neural Markers of Auditory Response and Habituation in Phelan-McDermid Syndrome. Front Neurosci 2022; 16:815933. [PMID: 35592263 PMCID: PMC9110667 DOI: 10.3389/fnins.2022.815933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
Phelan-McDermid Syndrome (PMS) is a rare genetic disorder caused by deletion or sequence variation in the SHANK3 gene at terminal chromosome 22 that confers high likelihood of comorbid autism spectrum disorder (ASD). Whereas individuals with idiopathic ASD (iASD) can demonstrate diverse patterns of sensory differences, PMS is mainly characterized by sensory hyporesponsiveness. This study used electrophysiology and a passive auditory habituation paradigm to test for neural markers of hyporesponsiveness. EEG was recorded from 15 individuals with PMS, 15 with iASD, and 16 with neurotypical development (NT) while a series of four consecutive 1,000 Hz tones was repeatedly presented. We found intact N1, P2, and N2 event-related potentials (ERPs) and habituation to simple auditory stimuli, both in individuals with iASD and in those with PMS. Both iASD and PMS groups showed robust responses to the initial tone and decaying responses to each subsequent tone, at levels comparable to the NT control group. However, in PMS greater initial N1 amplitude and habituation were associated with auditory hypersensitivity, and P2 habituation correlated with ASD symptomatology. Additionally, further classification of the PMS cohort into genetic groupings revealed dissociation of initial P2 amplitude and habituation of N1 based on whether the deletions included additional genes beyond solely SHANK3 and those not thought to contribute to phenotype. These results provide preliminary insight into early auditory processing in PMS and suggest that while neural response and habituation is generally preserved in PMS, genotypic and phenotypic characteristics may drive some variability. These initial findings provide early evidence that the robust pattern of behavioral hyporesponsiveness in PMS may be due, at least in audition, to higher order factors.
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Affiliation(s)
- Emily L Isenstein
- Department of Brain and Cognitive Sciences, University of Rochester, Rochester, NY, United States
| | - Hannah E Grosman
- Department of Psychological and Brain Sciences, Drexel University, Philadelphia, PA, United States
| | - Sylvia B Guillory
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Yian Zhang
- Center for Neural Science, New York University, New York, NY, United States
| | - Sarah Barkley
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Christopher S McLaughlin
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Tess Levy
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Danielle Halpern
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Paige M Siper
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Joseph D Buxbaum
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Alexander Kolevzon
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jennifer H Foss-Feig
- Seaver Autism Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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24
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Jain L, Oberman LM, Beamer L, Cascio L, May M, Srikanth S, Skinner C, Jones K, Allen B, Rogers C, Phelan K, Kaufmann WE, DuPont B, Sarasua SM, Boccuto L. Genetic and metabolic profiling of individuals with Phelan-McDermid syndrome presenting with seizures. Clin Genet 2021; 101:87-100. [PMID: 34664257 DOI: 10.1111/cge.14074] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 09/23/2021] [Accepted: 10/13/2021] [Indexed: 12/25/2022]
Abstract
Phelan-McDermid syndrome (PMS) (OMIM*606232) is a rare genetic disorder characterized by intellectual disability, autistic features, speech delay, minor dysmorphia, and seizures. This study was conducted to investigate the prevalence of seizures and the association with genetic and metabolic features since there has been little research related to seizures in PMS. For 57 individuals, seizure data was collected from caregiver interviews, genetic data from existing cytogenetic records and Sanger sequencing for nine 22q13 genes, and metabolic profiling from the Phenotype Mammalian MicroArray (PM-M) developed by Biolog. Results showed that 46% of individuals had seizures with the most common type being absence and grand-mal seizures. Seizures were most prevalent in individuals with pathogenic SHANK3 mutations (70%), those with deletion sizes >4 Mb (16%), and those with deletion sizes <4 Mb (71%) suggesting involvement of genes in addition to SHANK3. Additionally, a 3 Mb genomic region on 22q13.31 containing the gene TBC1D22A, was found to be significantly associated with seizure prevalence. A distinct metabolic profile was identified for individuals with PMS with seizures and suggested among other features a disrupted utilization of main energy sources using Biolog plates. The results of this study will be helpful for clinicians and families in anticipating seizures in these children and for researchers to identify candidate genes for the seizure phenotype.
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Affiliation(s)
- Lavanya Jain
- Greenwood Genetic Center, Greenwood, South Carolina, USA.,School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, South Carolina, USA
| | - Lindsay M Oberman
- Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA.,Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland, USA
| | - Laura Beamer
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Lauren Cascio
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Melanie May
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | | | - Cindy Skinner
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Kelly Jones
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Bridgette Allen
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, South Carolina, USA
| | - Curtis Rogers
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Katy Phelan
- Genetics Laboratory, Florida Cancer Specialists and Research Institute, Fort Myers, Florida, USA
| | - Walter E Kaufmann
- Greenwood Genetic Center, Greenwood, South Carolina, USA.,Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.,Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.,Anavex Life Sciences Corp, New York, New York, USA
| | - Barbara DuPont
- Greenwood Genetic Center, Greenwood, South Carolina, USA
| | - Sara M Sarasua
- School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, South Carolina, USA
| | - Luigi Boccuto
- Greenwood Genetic Center, Greenwood, South Carolina, USA.,School of Nursing, Healthcare Genetics Program, Clemson University, Clemson, South Carolina, USA.,Clemson University School of Health Research, Clemson, South Carolina, USA
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