Guideline 22q13 deletion syndrome (Phelan-McDermid syndrome)

What does this guideline cover?
This guideline is for22q13 deletion syndrome(Phelan-McDermid syndrome, PMS), which we have shortened to 22q13DS in this guideline. For this guideline 22q13DS is defined as a deletion of 22q13.3including theSHANK3gene, regardless of the cause of the deletion (seeGeneral, Definition5Module).

The following subjects are covered in this guideline
1.General: definition, incidence, prevalence, clinical features and the relationship between genetic anomaliesand clinical features.
2.(Genetic) counselling: reference to clinical geneticist and chance of recurrence.
3.Prevalence, mechanismand the treatment/guidance for specific symptoms in individuals with 22q13DS: language and speech problems; chewing, swallowing and gastrointestinal problems; sensory dysfunction;epilepsy;sleep disorders; lymphedemaand mental disorders.
4.Drug treatment for development and behaviour.
5.Organization of care.

Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency

Latha Soorya 1,2,12 / Alexander Kolevzon 1,2,3 / Jessica Zweifach 1 / Teresa Lim 2 / Yuriy Dobry 2 / Lily Schwartz 1 / Yitzchak Frank 1,2,3,4 / A Ting Wang 1,2,6 / Guiqing Cai 1,2,5 / Elena Parkhomenko 1,2 / Danielle Halpern 1,2 / David Grodberg 1,2 / Benjamin Angarita 2 / Judith P Willner 3,5 / Amy Yang3,5 / Roberto Canitano 1,13 / William Chaplin 8 / Catalina Betancur 9,10,11 / Joseph D Buxbaum 1,2,5,6,7,14

Abstract

Background
22q13 deletion syndrome, also known as Phelan-McDermid syndrome, is a neurodevelopmental disorder characterized by intellectual disability, hypotonia, delayed or absent speech, and autistic features. SHANK3 has been identified as the critical gene in the neurological and behavioral aspects of this syndrome. The phenotype ofSHANK3 deficiency has been described primarily from case studies, with limited evaluation of behavioral and cognitive deficits. The present study used a prospective design and inter-disciplinary clinical evaluations to assess patients with SHANK3 deficiency, with the goal to provide a comprehensive picture of the medical and behavioral profile of the syndrome.

Methods
A serially ascertained sample of patients with SHANK3 deficiency (n = 32) was evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule-G.

Results
Thirty participants with 22q13.3 deletions ranging in size from 101 kb to 8.45 Mb and two participants with de novo SHANK3 mutations were included. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability and only five (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux and seizures were also common. Analysis of genotype-phenotype correlations indicated that larger deletions were associated with increased levels of dysmorphic features, medical comorbidities and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features.

Conclusions
This study supports findings from previous research on the severity of intellectual, motor, and speech impairments seen in SHANK3 deficiency, and highlights the predominance of autism spectrum disorder in the syndrome. Limitations of existing evaluation tools are discussed, along with the need for natural history studies to inform clinical monitoring and treatment development in SHANK3 deficiency.

Severe white matter damage in SHANK3 deficiency:
a human and translational study

Sarah Jesse 1 , Hans-Peter Müller 1 , Michael Schoen 2 , Harun Asoglu 2 , Juergen Bockmann 2 ,
Hans-Juergen Huppertz 3 , Volker Rasche 4 , Albert C. Ludolph 1,5 , Tobias M. Boeckers 2,5 &
Jan Kassubek 1

Abstract

Objective:
Heterozygous SHANK3 mutations or partial deletions of the longarm of chromosome 22, also known as Phelan–McDermid syndrome, result ina syndromic form of the autism spectrum as well as in global developmentaldelay, intellectual disability, and several neuropsychiatric comorbidities. Theexact pathophysiological mechanisms underlying the disease are still far frombeing deciphered but studies ofSHANK3models have contributed to theunderstanding of how the loss of the synaptic proteinSHANK3affects neuronalfunction.

Methods and results:
Diffusion tensor imaging-based and automaticvolumetric brain mapping were performed in 12 SHANK3-deficient participants(mean age 19
15 years) versus 14 age- and gender-matched controls (meanage 29
5 years). Using whole brain–based spatial statistics, we observed ahighly significant pattern of white matter alterations in participants withSHANK3mutations with focus on the long association fiber tracts, particularlythe uncinate tract and the inferior fronto-occipital fasciculus. In contrast, onlysubtle gray matter volumetric abnormalities were detectable. In a back-transla-tional approach, we observed similar white matter alterations in heterozygousisoform–specific Shank3 knockout (KO) mice. Here, in the baseline data sets,the comparison of Shank3 heterozygous KO vs wildtype showed significantfractional anisotropy reduction of the long fiber tract systems in the KO model.The multiparametric Magnetic Resonance Imaging (MRI) analysis by DTI andvolumetry demonstrated a pathology pattern with severe white matter alter-ations and only subtle gray matter changes in the animal model.

Interpretation:
In summary, these translational data provide strong evidence that theSHANK3-deficiency–associated pathomechanism presents predominantly with awhite matter disease. Further studies should concentrate on the role ofSHANK3during early axonal pathfinding/wiring and in myelin formation.

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Claire S. Leblond 1,2,3, CarolineNava 4,5,6, Anne Polge 7, Julie Gauthier 8, Guillaume Huguet 1,2,3,SergeLumbroso 7,Fabienne Giuliano 9, Coline Stordeur 1,2,3,10, Christel Depienne 4,5,6,KevinMouzat 7, Dalila Pinto 11,Jennifer Howe 12, Nathalie Lemie`re 1,2,3, Christelle M. Durand 1,2,3, Jessica Guibert 1,2,3,ElodieEy 1,2,3,Roberto Toro 1,2,3, Hugo Peyre 13, Alexandre Mathieu 1,2,3,Fre ́de ́rique Amsellem 1,10,14,MariaRastam 15,I. Carina Gillberg 16,GudrunA.Rappold 17, Richard Holt 18, Anthony P. Monaco 18, Elena Maestrini 19, Pilar Galan 20,Delphine Heron 21,22,23,Aure ́lia Jacquette 21,22, Alexandra Afenjar 21,22,23,Agne`s Rastetter 4,5,6, Alexis Brice 4,5,6,Franc ̧oise Devillard 24, Brigitte Assouline 25, Fanny Laffargue 26, James Lespinasse 27, Jean Chiesa 28,Franc ̧ois Rivier 29,30, Dominique Bonneau 31,32, Beatrice Regnault 33, Diana Zelenika 34, Marc Delepine 34,Mark Lathrop 34, Damien Sanlaville 35, Caroline Schluth-Bolard 35, Patrick Edery 35, Laurence Perrin 36,Anne Claude Tabet 36, Michael J. Schmeisser 37,TobiasM.Boeckers 37, Mary Coleman 38,DaisukeSato 12,Peter Szatmari 12, Stephen W. Scherer 12, Guy A. Rouleau 39, Catalina Betancur 5,40,41, Marion Leboyer 14,42,43,44,Christopher Gillberg 16,45, Richard Delorme 1,2,3,10,14., Thomas Bourgeron 1,2,3,14,.*

Abstract
SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces theenlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), buttheir prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (dependingon the gene), and, individuals carryingde novoor truncating SHANK mutations underwent an extensive clinicalinvestigation. Copy-number variants and truncating mutations in SHANK genes were present in,1% of patients with ASD:mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were presentin 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rarefrequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. Incontrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability—morethan 1 in 50—warrant its consideration for mutation screening in clinical practice.

Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies

Andreas M.Grabrucker 1,2*, Michael J.Schmeisser 1*, MichaelSchoen 1* and TobiasM.Boeckers 1

Abstract

Intact synaptic homeostasis is a fundamental prerequisite for a healthy brain. Thus, it is not surprising that altered synaptic morphology and function are involved in the molecular pathogenesis of so-called synaptopathies including autism, schizophrenia (SCZ) and Alzheimer’s disease (AD). Intriguingly, various recent studies revealed a crucial role of postsynaptic ProSAP/Shank scaffold proteins in all of the aforementioned disorders. Considering these findings, we follow the hypothesis that ProSAP/Shank proteins are key regulators of synaptic development and plasticity with clear-cut isoform-specific roles. We thus propose a model where ProSAP/Shank proteins are in the center of a postsynaptic signaling pathway that is disrupted in several neuropsychiatric disorders.

Autism-associated SHANK3 mutations impair maturation of neuromuscular junctions and striated muscles

Anne-KathrinLutz 1*, StefaniePfaender 1*, BerraIncearap 1, ValentinIoannidis 1, IlariaOttonelli 1, Karl J.Föhr 2, JudithCammerer 1, MarvinZoller 1, JuliaHigelin 1, FedericaGiona 3,4, MaximilianStetter 1, NicoleStoecker 1, Najwa OualiAlami 5, MichaelSchön 1, MichaelOrth 5, StefanLiebau 6, GottholdBarbi 7, Andreas M.Grabrucker 8,9,10, RichardDelorme 11, MichaelFauler 12, BenjaminMayer 13, SarahJesse 5, FrancescoRoselli 5, Albert C.Ludolph 5, ThomasBourgeron 14, ChiaraVerpelli 3,4, MariaDemestre 1†, Tobias M.Boeckers 1,5†

Abstract

Heterozygous mutations of the gene encoding the postsynaptic protein SHANK3 are associated with syndromic forms of autism spectrum disorders (ASDs). One of the earliest clinical symptoms in SHANK3-associated ASD is neonatal skeletal muscle hypotonia. This symptom can be critical for the early diagnosis of affected children; however, the mechanism mediating hypotonia in ASD is not completely understood. Here, we used a combination of patient-derived human induced pluripotent stem cells (hiPSCs), Shank3 Δ 11(−/−) mice, and Phelan-McDermid syndrome (PMDS) muscle biopsies from patients of different ages to analyze the role of SHANK3 on motor unit development. Our results suggest that the hypotonia in SHANK3 deficiency might be caused by dysfunctions in all elements of the voluntary motor system: motoneurons, neuromuscular junctions (NMJs), and striated muscles. We found that SHANK3 localizes in Z-discs in the skeletal muscle sarcomere and co-immunoprecipitates with α-ACTININ. SHANK3 deficiency lead to shortened Z-discs and severe impairment of acetylcholine receptor clustering in hiPSC-derived myotubes and in muscle from Shank3 Δ 11(−/−) mice and patients with PMDS, indicating a crucial role for SHANK3 in the maturation of NMJs and striated muscle. Functional motor defects in Shank3 Δ 11(−/−) mice could be rescued with the troponin activator Tirasemtiv that sensitizes muscle fibers to calcium. Our observations give insight into the function of SHANK3 besides the central nervous system and imply potential treatment strategies for SHANK3-associated ASD.

Shank3 Transgenic and Prenatal Zinc-Deficient Autism Mouse Models Show Convergent and Individual Alterations of Brain Structures in MRI

Michael Schoen 1, Harun Asoglu 1, Helen F. Bauer 1, Hans-Peter Müller 2, Alireza Abaei 3, Ann Katrin Sauer 4, Rong Zhang 5,6,7, Tian-jia Song 5,6,7, Juergen Bockmann 1, Jan Kassubek 2, Volker Rasche 3, Andreas M. Grabrucker 4,8,9 and Tobias M. Boeckers 1

Abstract

Autism spectrum disorders (ASDs) comprise a range of disorders that share a core of neurobehavioural deficits characterizedby widespread abnormalities in social interactions, deficits in communication as well as restricted interests and repetitivebehaviours. The neurological basis and circuitry mechanisms underlying these abnormal behaviours are poorly understood. SHANK3 is a postsynaptic protein, whose disruption at the genetic level is thought to be responsible for the development of 22q13 deletion syndrome (Phelan–McDermid syndrome) and other non-syndromic ASDs. Here we show that mice with Shank3 gene deletions exhibit self-injurious repetitive grooming and deficits in social interaction. Cellular,electrophysiological and biochemical analyses uncovered defects at striatal synapses and cortico-striatal circuits in Shank3 mutant mice. Our findings demonstrate a critical role for SHANK3 in the normal development of neuronal connectivity andestablish causality between a disruption in theShank3gene and the genesis of autistic-like behaviours in mice.