The online version of this article (doi:10.1186/2040-2392-5-54) contains supplementary material, which is available to authorized users.
An erratum to this article is available at http://dx.doi.org/10.1186/s13229-015-0025-0.
The Icahn School of Medicine at Mount Sinai and Dr. Joseph Buxbaum hold a shared patent for insulin-like growth factor-1 in the treatment of Phelan-McDermid syndrome. No non-financial conflicts of interest exist for any of the authors.
AK, LB, and ATW participated in study design, data collection, data analysis, and manuscript preparation. TT participated in data collection, data analysis, and manuscript preparation. DH, YF and DG participated in data collection and manuscript preparation. RR participated in study design, data analysis, and manuscript preparation. WC participated in data analysis. LS and JDB participated in study design and manuscript preparation. All authors read and approved the manuscript.
Autism spectrum disorder (ASD) is now understood to have multiple genetic risk genes and one example is SHANK3. SHANK3 deletions and mutations disrupt synaptic function and result in Phelan-McDermid syndrome (PMS), which causes a monogenic form of ASD with a frequency of at least 0.5% of ASD cases. Recent evidence from preclinical studies with mouse and human neuronal models of SHANK3 deficiency suggest that insulin-like growth factor-1 (IGF-1) can reverse synaptic plasticity and motor learning deficits. The objective of this study was to pilot IGF-1 treatment in children with PMS to evaluate safety, tolerability, and efficacy for core deficits of ASD, including social impairment and restricted and repetitive behaviors.
Nine children with PMS aged 5 to 15 were enrolled in a placebo-controlled, double-blind, crossover design study, with 3 months of treatment with IGF-1 and 3 months of placebo in random order, separated by a 4-week wash-out period.
Compared to the placebo phase, the IGF-1 phase was associated with significant improvement in both social impairment and restrictive behaviors, as measured by the Aberrant Behavior Checklist and the Repetitive Behavior Scale, respectively. IGF-1 was found to be well tolerated and there were no serious adverse events in any participants.
This study establishes the feasibility of IGF-1 treatment in PMS and contributes pilot data from the first controlled treatment trial in the syndrome. Results also provide proof of concept to advance knowledge about developing targeted treatments for additional causes of ASD associated with impaired synaptic development and function.
Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Roge B, Heron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T: Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007, 39 (1): 25-27. 10.1038/ng1933. PubMedCentralCrossRefPubMed
Gauthier J, Spiegelman D, Piton A, Lafreniere RG, Laurent S, St-Onge J, Lapointe L, Hamdan FF, Cossette P, Mottron L, Fombonne E, Joober R, Marineau C, Drapeau P, Rouleau GA: Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2009, 150B (3): 421-424. 10.1002/ajmg.b.30822. CrossRefPubMed
Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R: Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008, 82 (2): 477-488. 10.1016/j.ajhg.2007.12.009. PubMedCentralCrossRefPubMed
Bonaglia MC, Giorda R, Beri S, De Agostini C, Novara F, Fichera M, Grillo L, Galesi O, Vetro A, Ciccone R, Bonati MT, Giglio S, Guerrini R, Osimani S, Marelli S, Zucca C, Grasso R, Borgatti R, Mani E, Motta C, Molteni M, Romano C, Greco D, Reitano S, Baroncini A, Lapi E, Cecconi A, Arrigo G, Patricelli MG, Pantaleoni C: Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome. PLoS Genet. 2011, 7 (7): e1002173-10.1371/journal.pgen.1002173. PubMedCentralCrossRefPubMed
Denayer A, Van Esch H, de Ravel T, Frijns JP, Van Buggenhout G, Vogels A, Devriendt K, Geutjens J, Thiry P, Swillen A: Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: presence of bipolar disorder and progressive loss of skills. Mol Syndromol. 2012, 3 (1): 14-20. PubMedCentralPubMed
Dhar SU, del Gaudio D, German JR, Peters SU, Ou Z, Bader PI, Berg JS, Blazo M, Brown CW, Graham BH, Grebe TA, Lalani S, Irons M, Sparagana S, Williams M, Phillips JA, Beaudet AL, Stankiewicz P, Patel A, Cheung SW, Sahoo T: 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH. Am J Med Genet A. 2010, 152A (3): 573-581. 10.1002/ajmg.a.33253. PubMedCentralCrossRefPubMed
Koolen DA, Reardon W, Rosser EM, Lacombe D, Hurst JA, Law CJ, Bongers EM, van Ravenswaaij-Arts CM, Leisink MA, van Kessel AG, Veltman JA, de Vries BB: Molecular characterisation of patients with subtelomeric 22q abnormalities using chromosome specific array-based comparative genomic hybridisation. Eur J Hum Genet. 2005, 13 (9): 1019-1024. 10.1038/sj.ejhg.5201456. CrossRefPubMed
Luciani JJ, de Mas P, Depetris D, Mignon-Ravix C, Bottani A, Prieur M, Jonveaux P, Philippe A, Bourrouillou G, de Martinville B, Delobel B, Vallee L, Croquette MF, Mattei MG: Telomeric 22q13 deletions resulting from rings, simple deletions, and translocations: cytogenetic, molecular, and clinical analyses of 32 new observations. J Med Genet. 2003, 40 (9): 690-696. 10.1136/jmg.40.9.690. PubMedCentralCrossRefPubMed
Philippe A, Boddaert N, Vaivre-Douret L, Robel L, Danon-Boileau L, Malan V, de Blois MC, Heron D, Colleaux L, Golse B, Zilbovicius M, Munnich A: Neurobehavioral profile and brain imaging study of the 22q13.3 deletion syndrome in childhood. Pediatrics. 2008, 122 (2): e376-e382. 10.1542/peds.2007-2584. CrossRefPubMed
Soorya L, Kolevzon A, Zweifach J, Lim T, Dobry Y, Schwartz L, Frank Y, Wang AT, Cai G, Parkhomenko E, Halpern D, Grodberg D, Angarita B, Willner JP, Yang A, Canitano R, Chaplin W, Betancur C, Buxbaum JD: Prospective investigation of autism and genotype-phenotype correlations in 22q13 deletion syndrome and SHANK3 deficiency. Molecular Autism. 2013, 4 (1): 18-10.1186/2040-2392-4-18. PubMedCentralCrossRefPubMed
Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML, Harris MJ, Saxena R, Silverman JL, Crawley JN, Zhou Q, Hof PR, Buxbaum JD: Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Molecular Autism. 2010, 1 (1): 15-10.1186/2040-2392-1-15. PubMedCentralCrossRefPubMed
Bakhtiari R, Zurcher NR, Rogier O, Russo B, Hippolyte L, Granziera C, Araabi BN, Nili Ahmadabadi M, Hadjikhani N: Differences in white matter reflect atypical developmental trajectory in autism: A Tract-based Spatial Statistics study. NeuroImage Clinical. 2012, 1 (1): 48-56. 10.1016/j.nicl.2012.09.001. PubMedCentralCrossRefPubMed
Ederberg S, Westerlind A, Houltz E, Svensson SE, Elam M, Ricksten SE: The effects of propofol on cerebral blood flow velocity and cerebral oxygen extraction during cardiopulmonary bypass. Anesth Analg. 1998, 86 (6): 1201-1206. PubMed
Aman MG, Singh NN, Stewart AW, Field CJ: The aberrant behavior checklist: a behavior rating scale for the assessment of treatment effects. Am J Ment Defic. 1985, 89 (5): 485-491. PubMed
Mullen EM: Mullen Scales of Early Learning. 1995, Circle Pines, MN: American Guidance Service
Roid GH, Miller LJ: Leiter International Performance Scale-Revised. 1997, Wood Dale, IL: Stoelting Co.
Sparrow SS, Cicchetti DV, Balla DA: Vineland-II Survey Forms Manual (Vineland Adaptive Behavior Scales). 2005, Minneapolis, MN: AGS Publishing, 2
Lord C, Risi S, Lambrecht L, Cook EH, Leventhal BL, DiLavore PC, Pickles A, Rutter M: The Autism Diagnostic Observation Schedule-Generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000, 30 (3): 205-223. 10.1023/A:1005592401947. CrossRefPubMed
American Psychiatric Association: Diagnostic and statistical manual of mental disorders. 2013, Arlington, VA: American Psychiatric Publishing, 5
Guy W: Assessment manual for psychopharmacology-revised. U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs. 1976, Rockville, MD: DHEW Publication Number ADM 76338, 218-222.
- A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome
A Ting Wang
Joseph D Buxbaum
- BioMed Central
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