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Molecular Autism
Published in: Molecular Autism 1/2019

Open Access 01-12-2019 | Intellectual Disability | Review

Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature

Authors: Alexander Kolevzon, Elsa Delaby, Elizabeth Berry-Kravis, Joseph D. Buxbaum, Catalina Betancur

Published in: Molecular Autism | Issue 1/2019

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Abstract

Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the SHANK3 gene on chromosome 22q13.33 and is characterized by intellectual disability, hypotonia, severe speech impairments, and autism spectrum disorder. Emerging evidence indicates that there are changes over time in the phenotype observed in individuals with PMS, including severe neuropsychiatric symptoms and loss of skills occurring in adolescence and adulthood. To gain further insight into these phenomena and to better understand the long-term course of the disorder, we conducted a systematic literature review and identified 56 PMS cases showing signs of behavioral and neurologic decompensation in adolescence or adulthood (30 females, 25 males, 1 gender unknown). Clinical presentations included features of bipolar disorder, catatonia, psychosis, and loss of skills, occurring at a mean age of 20 years. There were no apparent sex differences in the rates of these disorders except for catatonia, which appeared to be more frequent in females (13 females, 3 males). Reports of individuals with point mutations in SHANK3 exhibiting neuropsychiatric decompensation and loss of skills demonstrate that loss of one copy of SHANK3 is sufficient to cause these manifestations. In the majority of cases, no apparent cause could be identified; in others, symptoms appeared after acute events, such as infections, prolonged or particularly intense seizures, or changes in the individual’s environment. Several individuals had a progressive neurological deterioration, including one with juvenile onset metachromatic leukodystrophy, a severe demyelinating disorder caused by recessive mutations in the ARSA gene in 22q13.33. These reports provide insights into treatment options that have proven helpful in some cases, and are reviewed herein. Our survey highlights how little is currently known about neuropsychiatric presentations and loss of skills in PMS and underscores the importance of studying the natural history in individuals with PMS, including both cross-sectional and long-term longitudinal analyses. Clearer delineation of these neuropsychiatric symptoms will contribute to their recognition and prompt management and will also help uncover the underlying biological mechanisms, potentially leading to improved interventions.
Literature
1.
Kolevzon A, Angarita B, Bush L, Wang AT, Frank Y, Yang A, et al. Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring. J Neurodev Disord. 2014;6:39.PubMedPubMedCentralCrossRef
2.
Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39:25–7.PubMedCrossRef
3.
Bonaglia MC, Giorda R, Beri S, De Agostini C, Novara F, Fichera M, et al. Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. PLoS Genet. 2011;7:e1002173.PubMedPubMedCentralCrossRef
4.
De Rubeis S, Siper PM, Durkin A, Weissman J, Muratet F, Halpern D, et al. Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations. Mol Autism. 2018;9:31.PubMedPubMedCentralCrossRef
5.
Gong X, Jiang YW, Zhang X, An Y, Zhang J, Wu Y, et al. High proportion of 22q13 deletions and SHANK3 mutations in Chinese patients with intellectual disability. PLoS One. 2012;7:e34739.PubMedPubMedCentralCrossRef
6.
Betancur C, Buxbaum JD. SHANK3 haploinsufficiency: a "common" but underdiagnosed highly penetrant monogenic cause of autism spectrum disorders. Mol Autism. 2013;4:17.PubMedPubMedCentralCrossRef
7.
Leblond CS, Nava C, Polge A, Gauthier J, Huguet G, Lumbroso S, et al. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments. PLoS Genet. 2014;10:e1004580.PubMedPubMedCentralCrossRef
8.
Samogy-Costa CI, Varella-Branco E, Monfardini F, Ferraz H, Fock RA, Barbosa RHA, et al. A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case. J Neurodev Disord. 2019;11:13.PubMedPubMedCentralCrossRef
9.
Monteiro P, Feng G. SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci. 2017;18:147–57.PubMedCrossRef
10.
Vucurovic K, Landais E, Delahaigue C, Eutrope J, Schneider A, Leroy C, et al. Bipolar affective disorder and early dementia onset in a male patient with SHANK3 deletion. Eur J Med Genet. 2012;55:625–9.PubMedCrossRef
11.
Denayer A, Van Esch H, de Ravel T, Frijns JP, Van Buggenhout G, Vogels A, et al. Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: presence of bipolar disorder and progressive loss of skills. Mol Syndromol. 2012;3:14–20.PubMedPubMedCentral
12.
Verhoeven WM, Egger JI, Cohen-Snuijf R, Kant SG, de Leeuw N. Phelan-McDermid syndrome: clinical report of a 70-year-old woman. Am J Med Genet A. 2013;161A:158–61.PubMedCrossRef
13.
Anderlid BM, Schoumans J, Anneren G, Tapia-Paez I, Dumanski J, Blennow E, et al. FISH-mapping of a 100-kb terminal 22q13 deletion. Hum Genet. 2002;110:439–43.PubMedCrossRef
14.
Stewart A, Richards BW. A note on a patient with a ring-22 chromosome identified by banding. J Ment Defic Res. 1976;20:95–8.PubMed
15.
Reeve A, Shulman SA, Zimmerman AW, Cassidy SB. Methylphenidate therapy for aggression in a man with ring 22 chromosome. Report and literature review. Arch Neurol. 1985;42:69–72.PubMedCrossRef
16.
Arinami T, Kondo I, Hamaguchi H, Nakajima S. Multifocal meningiomas in a patient with a constitutional ring chromosome 22. J Med Genet. 1986;23:178–80.PubMedPubMedCentralCrossRef
17.
Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, et al. Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Mol Autism. 2013;4:18.PubMedPubMedCentralCrossRef
18.
Macedoni-Luksic M, Krgovic D, Zagradisnik B, Kokalj-Vokac N. Deletion of the last exon of SHANK3 gene produces the full Phelan-McDermid phenotype: a case report. Gene. 2013;524:386–9.PubMedCrossRef
19.
Philippe A, Craus Y, Rio M, Bahi-Buisson N, Boddaert N, Malan V, et al. Case report: an unexpected link between partial deletion of the SHANK3 gene and Heller's dementia infantilis, a rare subtype of autism spectrum disorder. BMC Psychiatry. 2015;15:256.PubMedPubMedCentralCrossRef
20.
Reierson G, Bernstein J, Froehlich-Santino W, Urban A, Purmann C, Berquist S, et al. Characterizing regression in Phelan McDermid Syndrome (22q13 deletion syndrome). J Psychiatr Res. 2017;91:139–44.PubMedPubMedCentralCrossRef
21.
Jeffries AR, Curran S, Elmslie F, Sharma A, Wenger S, Hummel M, et al. Molecular and phenotypic characterization of ring chromosome 22. Am J Med Genet A. 2005;137:139–47.PubMedCrossRef
22.
Millichap JG. Ring 22 syndrome and polyembolokoilomania. Ped Neurol Briefs. 1994;8:10.
23.
Sovner R, Stone A, Fox C. Ring chromosome 22 and mood disorders. J Intellect Disabil Res. 1996;40:82–6.PubMedCrossRef
24.
Kehrer-Sawatzki H, Udart M, Krone W, Baden R, Fahsold R, Thomas G, et al. Mutational analysis and expression studies of the neurofibromatosis type 2 (NF2) gene in a patient with a ring chromosome 22 and NF2. Hum Genet. 1997;100:67–74.PubMedCrossRef
25.
26.
Tsilchorozidou T, Menko FH, Lalloo F, Kidd A, De Silva R, Thomas H, et al. Constitutional rearrangements of chromosome 22 as a cause of neurofibromatosis 2. J Med Genet. 2004;41:529–34.PubMedPubMedCentralCrossRef
27.
Nawab K, Hussain I, Findlay L. Ring chromosome 22, mood disorder and sodium valproate (a case report). Brit J Dev Disabil. 2007;53:153–6.CrossRef
28.
Gauthier J, Champagne N, Lafreniere RG, Xiong L, Spiegelman D, Brustein E, et al. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci USA. 2010;107:7863–8.PubMedCrossRefPubMedCentral
29.
Pasini A, D'Agati E, Casarelli L, Curatolo P. Dose-dependent effect of risperidone treatment in a case of 22q13.3 deletion syndrome. Brain Dev. 2010;32:425–7.PubMedCrossRef
30.
Willemsen MH, Rensen JH, van Schrojenstein-Lantman de Valk HM, Hamel BC, Kleefstra T. Adult phenotypes in Angelman- and Rett-like syndromes. Mol Syndromol. 2011;2:217–34.
31.
Verhoeven WM, Egger JI, Willemsen MH, de Leijer GJ, Kleefstra T. Phelan-McDermid syndrome in two adult brothers: atypical bipolar disorder as its psychopathological phenotype? Neuropsychiatr Dis Treat. 2012;8:175–9.PubMedPubMedCentralCrossRef
32.
Egger JI, Zwanenburg RJ, van Ravenswaaij-Arts CM, Kleefstra T, Verhoeven WM. Neuropsychological phenotype and psychopathology in seven adult patients with Phelan-McDermid syndrome: implications for treatment strategy. Genes Brain Behav. 2016;15:395–404.PubMedCrossRef
33.
Breckpot J, Vercruyssen M, Weyts E, Vandevoort S, D'Haenens G, Van Buggenhout G, et al. Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor. Eur J Med Genet. 2016;59:436–43.PubMedCrossRef
34.
Smith JH, Smith VD, Philbrick KL, Kumar N. Catatonic disorder due to a general medical or psychiatric condition. J Neuropsychiatry Clin Neurosci. 2012;24:198–207.PubMedCrossRef
35.
Messias E, Kaley SN, McKelvey KD. Adult-onset psychosis and clinical genetics: a case of Phelan-McDermid syndrome. J Neuropsychiatry Clin Neurosci. 2013;25:E27.PubMedPubMedCentralCrossRef
36.
McKelvey KD Jr, Trana CJ, Kelsay J, Sawyer J, Clothier J. Phelan-McDermid syndrome and cancer predisposition: The value of a karyotype. Am J Med Genet A. 2018;176:144–5.PubMedCrossRef
37.
Guilherme RS, Soares KC, Simioni M, Vieira TP, Gil-da-Silva-Lopes VL, Kim CA, et al. Clinical, cytogenetic, and molecular characterization of six patients with ring chromosomes 22, including one with concomitant 22q11.2 deletion. Am J Med Genet A. 2014;164A:1659–65.PubMedCrossRef
38.
Serret S, Thummler S, Dor E, Vesperini S, Santos A, Askenazy F. Lithium as a rescue therapy for regression and catatonia features in two SHANK3 patients with autism spectrum disorder: case reports. BMC Psychiatry. 2015;15:107.PubMedPubMedCentralCrossRef
39.
Fokstuen S, Makrythanasis P, Hammar E, Guipponi M, Ranza E, Varvagiannis K, et al. Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders. Hum Genomics. 2016;10:24.PubMedPubMedCentralCrossRef
40.
Egger JIM, Verhoeven WMA, Groenendijk-Reijenga R, Kant SG. Phelan-McDermid syndrome due to SHANK3 mutation in an intellectually disabled adult male: successful treatment with lithium. BMJ Case Rep. 2017;2017:bcr-2017-220778.
41.
Tabet AC, Rolland T, Ducloy M, Levy J, Buratti J, Mathieu A, et al. A framework to identify contributing genes in patients with Phelan-McDermid syndrome. NPJ Genom Med. 2017;2:32.PubMedPubMedCentralCrossRef
42.
Ballesteros A, Rosero ÁS, Inchausti F, Manrique E, Sáiz H, Carlos C, et al. Clinical case: Phelan-McDermid and pharmacological management. Abstract V0081, 25th European Congress of Psychiatry, 2017. Eur Psychiatry:41S–S430.
43.
Lyons-Warren AM, Cheung SW, Holder JL Jr. Clinical reasoning: a common cause for Phelan-McDermid syndrome and neurofibromatosis type 2: One ring to bind them. Neurology. 2017;89:e205–9.PubMedPubMedCentralCrossRef
44.
45.
Jungova P, Cumova A, Kramarova V, Lisyova J, Durina P, Chandoga J, et al. Phelan-McDermid syndrome in adult patient with atypical bipolar psychosis repeatedly triggered by febrility. Neurocase. 2018;24:227–30.PubMedCrossRef
46.
Richards BW, Rundle AT, Hatton WM, Stewart A. G-group ring chromosome in a mentally subnormal girl. J Ment Defic Res. 1971;15:61–72.PubMed
47.
Kondo I, Hamaguchi H, Nakajima S, Haneda T. A cytogenetic survey of 449 patients in a Japanese institution for the mentally retarded. Clin Genet. 1980;17:177–82.PubMedCrossRef
48.
Anderlid BM, Schoumans J, Anneren G, Sahlen S, Kyllerman M, Vujic M, et al. Subtelomeric rearrangements detected in patients with idiopathic mental retardation. Am J Med Genet. 2002;107:275–84.PubMedCrossRef
49.
Darville H, Poulet A, Rodet-Amsellem F, Chatrousse L, Pernelle J, Boissart C, et al. Human pluripotent stem cell-derived cortical neurons for high throughput medication screening in autism: a proof of concept study in SHANK3 haploinsufficiency syndrome. EBioMedicine. 2016;9:293–305.PubMedPubMedCentralCrossRef
50.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th edition, text revision. Washington, DC: American Psychiatric Association; 2013.CrossRef
51.
Barnhill J, Cooper SA, Fletcher RJ, editors. Diagnostic manual–intellectual disability 2 (DM-ID): a textbook of diagnosis of mental disorders in persons with intellectual disability. Second ed.: NADD; 2017.
52.
Gomez-Ospina N. Arylsulfatase A deficiency. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 2006 [updated 2017 Dec 14].
53.
Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes T, Cipriani A, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30:495–553.PubMedPubMedCentralCrossRef
54.
Verhoeven WMA, Egger JIM, de Leeuw N. A longitudinal perspective on the pharmacotherapy of 24 adult patients with Phelan McDermid syndrome. Eur J Med Genet. 2019 (advance online publication).
55.
Dhossche DM, Wachtel LE. Catatonia is hidden in plain sight among different pediatric disorders: a review article. Pediatr Neurol. 2010;43:307–15.PubMedCrossRef
56.
Phelan K, Rogers RC, Boccuto L. Phelan-McDermid Syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 2005 [updated 2018 Jun 7].
57.
Cohen D, Flament M, Dubos PF, Basquin M. Case series: catatonic syndrome in young people. J Am Acad Child Adolesc Psychiatry. 1999;38:1040–6.PubMedCrossRef
58.
Takaoka K, Takata T. Catatonia in childhood and adolescence. Psychiatry Clin Neurosci. 2003;57:129–37.PubMedCrossRef
59.
Fink M, Taylor MA, Ghaziuddin N. Catatonia in autistic spectrum disorders: a medical treatment algorithm. Int Rev Neurobiol. 2006;72:233–44.PubMedCrossRef
60.
Zirn B, Arning L, Bartels I, Shoukier M, Hoffjan S, Neubauer B, et al. Ring chromosome 22 and neurofibromatosis type II: proof of two-hit model for the loss of the NF2 gene in the development of meningioma. Clin Genet. 2012;81:82–7.PubMedCrossRef
61.
Evans DG. Neurofibromatosis 2. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1998 [updated 2018 Mar 15].
62.
Verhoeven WM, Kleefstra T, Egger JI. Behavioral phenotype in the 9q subtelomeric deletion syndrome: a report about two adult patients. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:536–41.PubMedCrossRef
63.
Verhoeven WM, Egger JI, Vermeulen K, van de Warrenburg BP, Kleefstra T. Kleefstra syndrome in three adult patients: further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course. Am J Med Genet A. 2011;155A:2409–15.PubMedCrossRef
64.
Mitra AK, Dodge J, Van Ness J, Sokeye I, Van Ness B. A de novo splice site mutation in EHMT1 resulting in Kleefstra syndrome with pharmacogenomics screening and behavior therapy for regressive behaviors. Mol Genet Genomic Med. 2017;5:130–40.PubMedCrossRef
65.
Vermeulen K, de Boer A, Janzing JGE, Koolen DA, Ockeloen CW, Willemsen MH, et al. Adaptive and maladaptive functioning in Kleefstra syndrome compared to other rare genetic disorders with intellectual disabilities. Am J Med Genet A. 2017;173:1821–30.PubMedCrossRef
66.
Vermeulen K, Staal WG, Janzing JG, van Bokhoven H, Egger JIM, Kleefstra T. Sleep disturbance as a precursor of severe regression in Kleefstra syndrome suggests a need for firm and rapid pharmacological treatment. Clin Neuropharmacol. 2017;40:185–8.PubMedCrossRef
67.
Schneider M, Debbane M, Bassett AS, Chow EW, Fung WL, van den Bree M, et al. Psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome: results from the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome. Am J Psychiatry. 2014;171:627–39.PubMedPubMedCentralCrossRef
68.
Vorstman JA, Breetvelt EJ, Duijff SN, Eliez S, Schneider M, Jalbrzikowski M, et al. Cognitive decline preceding the onset of psychosis in patients with 22q11.2 deletion syndrome. JAMA Psychiatry. 2015;72:377–85.PubMedPubMedCentralCrossRef
69.
Faedda GL, Wachtel LE, Higgins AM, Shprintzen RJ. Catatonia in an adolescent with velo-cardio-facial syndrome. Am J Med Genet A. 2015;167A:2150–3.PubMedCrossRef
70.
Hodge JC, Mitchell E, Pillalamarri V, Toler TL, Bartel F, Kearney HM, et al. Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities. Mol Psychiatry. 2014;19:368–79.PubMedCrossRef
71.
Verhoeven W, Egger J, Kipp J, Verheul-Aan de Wiel J, Ockeloen C, Kleefstra T, et al. A novel MBD5 mutation in an intellectually disabled adult female patient with epilepsy: Suggestive of early onset dementia? Mol Genet Genomic Med. 2019;7:e849.PubMedPubMedCentralCrossRef
72.
Dykens EM, Shah B, Davis B, Baker C, Fife T, Fitzpatrick J. Psychiatric disorders in adolescents and young adults with Down syndrome and other intellectual disabilities. J Neurodev Disord. 2015;7:9.PubMedPubMedCentralCrossRef
73.
74.
Jacobs J, Schwartz A, McDougle CJ, Skotko BG. Rapid clinical deterioration in an individual with Down syndrome. Am J Med Genet A. 2016;170:1899–902.PubMedCrossRef
75.
Jap SN, Ghaziuddin N. Catatonia among adolescents with Down syndrome: a review and 2 case reports. J ECT. 2011;27:334–7.PubMedCrossRef
76.
Tatton-Brown K, Zachariou A, Loveday C, Renwick A, Mahamdallie S, Aksglaede L, et al. The Tatton-Brown-Rahman syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants. Wellcome Open Res. 2018;3:46.PubMedPubMedCentralCrossRef
77.
78.
Wachtel LE. The multiple faces of catatonia in autism spectrum disorders: descriptive clinical experience of 22 patients over 12 years. Eur Child Adolesc Psychiatry. 2019;28:471–80.PubMedCrossRef
79.
Ghaziuddin N, Dhossche D, Marcotte K. Retrospective chart review of catatonia in child and adolescent psychiatric patients. Acta Psychiatr Scand. 2012;125:33–8.PubMedCrossRef
Metadata
Title
Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature
Authors
Alexander Kolevzon
Elsa Delaby
Elizabeth Berry-Kravis
Joseph D. Buxbaum
Catalina Betancur
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2019
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-019-0291-3

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