Research Publications

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Frazier TW, Busch RM, Klaas P, Lachlan K, Jeste S, Kolevzon A, Loth E, Harris J, Pepper T, Anthony K, Graglia JM, Helde K, Delagrammatikas C, Bedrosian-Sermone S, Smith-Hicks C, Sahin M, Youngstrom EA, Eng C, Chetcuti L, Hardan AY, Uljarevic M. Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability. Autism Res. 2024 Dec 6. doi: 10.1002/aur.3290. Epub ahead of print. PMID: 39643599.

Neurodevelopmental genetic syndromes are conditions that affect the development of brain function. Many individuals with these syndromes experience altered social attention that can impact their ability to accurately perceive social information in their world.

In this study, researchers evaluated remote monitoring of social attention in children, adolescents, and adults with a wide range of neurodevelopmental outcomes. Participants included individuals with three genetic syndromes (PTEN hamartoma tumor syndrome, Malan syndrome, and SYNGAP1-related disorder), a mixed group of other neurodevelopmental genetic syndromes, and individuals with a range of idiopathic neurodevelopmental disorders, as well as neurotypical siblings and unrelated controls. Each participant completed a four-minute social attention paradigm via webcam.

Results show that social attention measures had good scale and test-retest reliability, with the exception of measures of non-social preference and face-specific processing. Findings demonstrate that remote monitoring of social attention may be useful for characterizing phenotypic profiles and tracking the natural history of distinct neurodevelopmental genetic syndromes and idiopathic neurodevelopmental disorders, as well as identifying autism spectrum disorder in patients with neurodevelopmental genetic syndromes. Authors note that global social attention and several distinct social attention measures may also be useful outcomes for future clinical trials.

Farach LS, Richard MA, Wulsin AC, Bebin EM, Krueger DA, Sahin M, Porter BE, McPherson TO, Peters JM, O'Kelley S, Taub KS, Rajaraman R, Randle SC, McClintock WM, Koenig MK, Frost MD, Werner K, Nolan DA, Wong M, Cutter G, Northrup H, Au KS; PREVeNT Study Group. Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial. Pediatr Neurol. 2024 Oct;159:62-71. doi: 10.1016/j.pediatrneurol.2024.06.012. Epub 2024 Jul 4.

Srivastava S, Cole JJ, Cohen JS, Chopra M, Smith HS, Deardorff MA, Pedapati E, Corner B, Anixt JS, Jeste S, Sahin M, Gurnett CA, Campbell CA. Survey of the Landscape of Society Practice Guidelines for Genetic Testing of Neurodevelopmental Disorders. Ann Neurol. 2024 Sep 25. doi: 10.1002/ana.27045. Epub ahead of print. PMID: 39319594.

Neurodevelopmental disorders are a spectrum of conditions that affect how the brain functions. These disorders can impact many different areas of childhood development, including motor, problem solving, social-communication, and adaptive skills. Genetic testing of patients with neurodevelopmental disorders is critical for diagnosis, medical management, and access to precision therapies. However, the creation and implementation of professional society practice guidelines for genetic testing can be challenging due to the rapid evolution of approaches.

In this review, authors assessed the current state of United States professional societies' guidelines for genetic testing of neurodevelopmental disorders. The team focused on disorders including unexplained global developmental delay, intellectual disability, autism spectrum disorder, and cerebral palsy. Authors describe several shortcomings of current guidelines and express the need for a unified, frequently updated, and easily accessible cross-specialty society guideline.

Gluckman J, Levy T, Friedman K, Garces F, Filip-Dhima R, Quinlan A, Iannotti I, Pekar M, Hernandez AL, Nava MT, Kravets E, Siegel A, Bernstein JA, Berry-Kravis E, Powell CM, Soorya LV, Thurm A, Srivastava S, Buxbaum JD, Sahin M, Kolevzon A, Gelb BD. Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome. Am J Med Genet A. 2024 Sep 11:e63872. doi: 10.1002/ajmg.a.63872. Epub ahead of print. PMID: 39257296.

Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder that results from the loss of a small piece of chromosome 22. While many features of PMS are well-understood, less is known about cardiovascular abnormalities.

In this study, researchers evaluated the prevalence and risk of aortic root dilation (ARD) in patients with PMS. Among 59 individuals with PMS, the team analyzed echocardiographic and genetic reports for aortic root measurements and genetic variant data.

Results reveal that eight participants had ARD, which was associated with larger chromosome 22 deletions. Participants with ARD also had significantly more genes deleted on chromosome 22 than participants without ARD. Authors note that these results could help identify individuals with PMS who are at higher risk for ARD.

Ahtam B, Yun HJ, Vyas R, Pienaar R, Wilson JH, Goswami CP, Berto LF, Warfield SK, Sahin M, Grant PE, Peters JM, Im K. Morphological Features of Language Regions in Individuals with Tuberous Sclerosis Complex. J Autism Dev Disord. 2024 Aug;54(8):3155-3175. doi: 10.1007/s10803-023-06004-8. Epub 2023 May 24. Erratum in: J Autism Dev Disord. 2024 Mar;54(3):1232. doi: 10.1007/s10803-023-06098-0. PMID: 37222965.

Tuberous sclerosis complex (TSC) is a genetic condition in which typically benign tumors affect multiple organs including the brain, kidneys, heart, lungs, eyes, and skin. Many individuals with TSC also experience delay in several aspects of development, including language.

In this structural brain MRI study, researchers examined the morphological features of cortical language regions in individuals with TSC. Participants included seven individuals with TSC and comorbid autism spectrum disorder (ASD), 13 with TSC but no ASD, 10 with ASD-only, and 29 typically developing controls.

Results suggest that comorbid ASD in TSC as well as tuber load in TSC is associated with changes in the morphometry of language regions. Authors note that future studies with larger sample sizes are needed to confirm these findings.

Brown JA, Faley SL, Judge M, Ward P, Ihrie RA, Carson R, Armstrong L, Sahin M, Wikswo JP, Ess KC, Neely MD. Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit. J Neurodev Disord. 2024 May 23;16(1):27. doi: 10.1186/s11689-024-09543-y. PMID: 38783199; PMCID: PMC11112784.

Tuberous sclerosis complex (TSC) is a genetic condition that affects many organs and can cause benign tumors in the skin, kidney, brain, heart, eyes, lungs, and other organs. The most severe symptoms—including seizures, intellectual disability, autism, and behavioral problems—result from complications in the central nervous system. Although these neurological complications are well-understood, less is known about how the genetic mutations that cause TSC might affect different components of the brain, including the blood-brain barrier.

In this study, researchers examined the function of the blood-brain barrier in TSC. The team created TSC patient-specific brain tissue models to explore how mutations in the TSC2 gene affect the blood-brain barrier.

Results show altered function of a blood-brain barrier generated from TSC2 mutant cells, which can improve with treatment of the drug rapamycin or replacement of mutant cells with astrocytes (glial cells in the brain) that do not carry the mutation. Authors note that these findings demonstrate the importance of their methods in ongoing research for TSC and other neurogenetic disorders.

Levy T, Gluckman J, Siper PM, Halpern D, Zweifach J, Filip-Dhima R, Holder JL Jr, Trelles MP, Johnson K, Bernstein JA, Berry-Kravis E, Powell CM, Soorya LV, Thurm A, Buxbaum JD, Sahin M, Kolevzon A, Srivastava S; Developmental Synaptopathies Consortium. Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome. J Neurodev Disord. 2024 May 10;16(1):25. doi: 10.1186/s11689-024-09541-0.

Dhawan A, Baitamouni S, Liu D, Busch R, Klaas P, Frazier TW, Srivastava S, Parikh S, Hsich GE, Friedman NR, Ritter DM, Hardan AY, Martinez-Agosto JA, Sahin M, Eng C. Exploring the neurological features of individuals with germline PTEN variants: A multicenter study. Ann Clin Transl Neurol. 2024 May;11(5):1301-1309. doi: 10.1002/acn3.52046. Epub 2024 Mar 19.

Richard MA, Lupo PJ, Ehli EA, Sahin M, Krueger DA, Wu JY, Bebin EM, Au KS, Northrup H, Farach LS; TACERN Study Group. Common epilepsy variants from the general population are not associated with epilepsy among individuals with tuberous sclerosis complex. Am J Med Genet A. 2024 Jun;194(6):e63569. doi: 10.1002/ajmg.a.63569. Epub 2024 Feb 17.

Macaluso M, Rothenberg ME, Ferkol T, Kuhnell P, Kaminski HJ, Kimberlin DW, Benatar M, Chehade M; Principal Investigators of the Rare Diseases Clinical Research Network – Cycle 4. Impact of the COVID-19 Pandemic on People Living With Rare Diseases and Their Families: Results of a National Survey. JMIR Public Health Surveill. 2024 Feb 14;10:e48430. doi: 10.2196/48430.

Afshar-Saber W, Teaney NA, Winden KD, Jumo H, Shi X, McGinty G, Hubbs J, Chen C, Tokatly Latzer I, Gasparoli F, Ebrahimi-Fakhari D, Buttermore ED, Roullet JB, Pearl PL, Sahin M. ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations. Neurobiol Dis. 2024 Jan;190:106386. doi: 10.1016/j.nbd.2023.106386. Epub 2023 Dec 16.

Brown JA, Faley SL, Judge M, Ward P, Ihrie RA, Carson R, Armstrong L, Sahin M, Wikswo JP, Ess KC, Neely MD. Rescue of Impaired Blood-Brain Barrier in Tuberous Sclerosis Complex Patient Derived Neurovascular Unit. bioRxiv. 2023 Dec 16:2023.12.15.571738. doi: 10.1101/2023.12.15.571738.

Eng C, Kim A, Yehia L. Genomic diversity in functionally relevant genes modifies neurodevelopmental versus neoplastic risks in individuals with germline PTEN variants. Res Sq. 2023 Dec 14:rs.3.rs-3734368. doi: 10.21203/rs.3.rs-3734368/v1.

Clements CC, Ascunce K, Nelson CA. In Context: A Developmental Model of Reward Processing, With Implications for Autism and Sensitive Periods. J Am Acad Child Adolesc Psychiatry. 2023 Nov;62(11):1200-1216. doi: 10.1016/j.jaac.2022.07.861. Epub 2022 Nov 3.

Heunis TM, Chambers N, Vanclooster S, Bissell S, Byars AW, Capal JK, Cukier S, Davis PE, de Vries MC, De Waele L, Flinn J, Gardner-Lubbe S, Gipson T, Kingswood JC, Krueger DA, Kumm AJ, Sahin M, Schoeters E, Smith C, Srivastava S, Takei M, van Eeghen AM, Waltereit R, Jansen AC, de Vries PJ. Development and Feasibility of the Self-Report Quantified Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders Checklist (TAND-SQ). Pediatr Neurol. 2023 Oct;147:101-123. doi: 10.1016/j.pediatrneurol.2023.07.001. Epub 2023 Jul 7. PMID: 37598571

Tuberous sclerosis complex (TSC) is a genetic condition in which typically benign tumors affect multiple organs including the brain, kidneys, heart, lungs, eyes, and skin. TSC-associated neuropsychiatric disorders (TAND) include difficulties at the behavioral, psychiatric, intellectual, academic, neuropsychologic, and psychosocial levels. Although TAND are often present in individuals with TSC, they are also underidentified and undertreated.

In this study, researchers developed a self-report quantified TAND Checklist (TAND-SQ). The team conducted feasibility and acceptability testing of the TAND-SQ Checklist with 23 technical experts from the TAND consortium and 58 caregivers and individuals with TSC.

The resulting Checklist can be completed by caregivers or individuals with TSC and used to quantify TAND difficulties. Authors state that next steps include further validation of the checklist and development of a smartphone application.

Srivastava S, Sahin M, Buxbaum JD, Berry-Kravis E, Soorya LV, Thurm A, Bernstein JA, Asante-Otoo A, Bennett WE Jr, Betancur C, Brickhouse TH, Passos Bueno MR, Chopra M, Christensen CK, Cully JL, Dies K, Friedman K, Gummere B, Holder JL Jr, Jimenez-Gomez A, Kerins CA, Khan O, Kohlenberg T, Lacro RV, Levi LA, Levy T, Linnehan D, Eva L, 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 Jul 1. doi: 10.1002/ajmg.a.63312. Epub ahead of print. PMID: 37392087

Phelan–McDermid syndrome (PMS) is a genetic condition caused by the deletion of a small portion of chromosome 22 or a mutation in the SHANK3 gene resulting in a wide range of neurodevelopmental and systemic characteristics. The first guidelines for assessment and monitoring in individuals with PMS were published in 2014. Due to recent studies and investigations, knowledge about PMS has since grown significantly.

In this study, researchers aimed to update clinical management guidelines for PMS based on the latest knowledge. A taskforce of clinical experts in PMS and representatives from the parent community collaborated to produce specialty-specific guidelines—including genetics, neurology, neurodevelopment, gastroenterology, primary care, physiatry, nephrology, endocrinology, cardiology, gynecology, and dentistry.

These updated guidelines allow for improved assessment and monitoring of individuals with PMS. Authors highlight several areas for future research with plans to update the guidelines as new knowledge becomes available.

Morgan FC, Yehia L, McDonald C, Martinez-Agosto JA, Hardan AY, Tamburro J, Sahin M, Bayart C, Eng C; Developmental Synaptopathies Consortium. Characterizing dermatologic findings among patients with PTEN hamartoma tumor syndrome: Results of a multicenter cohort study. J Am Acad Dermatol. 2023 Jul;89(1):90-98. doi: 10.1016/j.jaad.2022.01.045. Epub 2022 Feb 7.

Levine A, Davis P, Zhang B, Peters J, Filip-Dhima R, Warfield SK, Prohl A, Capal J, Krueger D, Bebin EM, Northrup H, Wu JY, Sahin M; TACERN Study Group. Epilepsy Severity Is Associated With Head Circumference and Growth Rate in Infants With Tuberous Sclerosis Complex. Pediatr Neurol. 2023 Jul;144:26-32. doi: 10.1016/j.pediatrneurol.2023.03.015. Epub 2023 Mar 29.

Patterson AM, O'Boyle M, VanNoy GE, Dies KA. Emerging roles and opportunities for rare disease patient advocacy groups. Ther Adv Rare Dis. 2023 Apr 24;4:26330040231164425. doi: 10.1177/26330040231164425. eCollection 2023 Jan-Dec.

Yehia L, Plitt G, Tushar AM, Joo J, Burke CA, Campbell SC, Heiden K, Jin J, Macaron C, Michener CM, Pederson HJ, Radhakrishnan K, Shin J, Tamburro J, Patil S, Eng C. Longitudinal Analysis of Cancer Risk in Children and Adults With Germline PTEN Variants. JAMA Netw Open. 2023 Apr 3;6(4):e239705. doi: 10.1001/jamanetworkopen.2023.9705.

Yehia L, Heald B, Eng C. Clinical Spectrum and Science Behind the Hamartomatous Polyposis Syndromes. Gastroenterology. 2023 Apr;164(5):800-811. doi: 10.1053/j.gastro.2023.01.026. Epub 2023 Jan 28.

Applequist J, Burroughs C, Merkel PA, Rothenberg M, Trapnell B, Desnick R, Sahin M, Krischer J. Direct-to-Consumer Recruitment Methods via Traditional and Social Media to Aid in Research Accrual for Clinical Trials for Rare Diseases: Comparative Analysis Study. J Med Internet Res. 2023 Mar 14;25:e39262. doi: 10.2196/39262.

Cohen AL, Kroeck MR, Wall J, McManus P, Ovchinnikova A, Sahin M, Krueger DA, Bebin EM, Northrup H, Wu JY, Warfield SK, Peters JM, Fox MD; Tuberous Sclerosis Complex Autism Center of Excellence Network Study Group. Tubers Affecting the Fusiform Face Area Are Associated with Autism Diagnosis. Ann Neurol. 2023 Mar;93(3):577-590. doi: 10.1002/ana.26551. Epub 2022 Nov 30. PMID: 36394118; PMCID: PMC9974824.

Tuberous sclerosis complex (TSC) is a genetic condition in which typically benign tumors affect multiple organs. TSC is associated with tubers—tumors that form in the brain—and a high incidence of autism spectrum disorder (ASD).

In this study, researchers explored the relationship between location of brain tubers and ASD diagnosis. The team began by determining tuber locations for 115 TSC patients with and without ASD. Next, researchers tested for associations between ASD diagnosis and tuber burden within the whole brain and specific locations relevant to ASD. Finally, they created a map of the data to calculate the risk of ASD.

Results show that tubers involving the right fusiform face area (FFA) were associated with a 3.7-fold increased risk of developing ASD. Authors note that this strong association highlights a potential causal mechanism for developing autism in TSC, which may help guide more general research on ASD symptoms.

Busch RM, Frazier Ii TW, Sonneborn C, Hogue O, Klaas P, Srivastava S, Hardan AY, Martinez-Agosto JA, Sahin M, Eng C. Longitudinal neurobehavioral profiles in children and young adults with PTEN hamartoma tumor syndrome and reliable methods for assessing neurobehavioral change. J Neurodev Disord. 2023 Jan 14;15(1):3. doi: 10.1186/s11689-022-09468-4. PMID: 36641436; PMCID: PMC9840250.

PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by mutations in the PTEN gene, which typically suppresses formation of tumors. In addition to its role in cancer, PTEN plays crucial roles in brain function. Individuals with PHTS show distinct neurobehavioral profiles, suggesting primary disruption of frontal lobe systems. More severe cognitive deficits are seen in individuals with associated autism spectrum disorder (ASD) that also extend to other areas of neurobehavioral function, such as adaptive behavior and sensory deficits. In this study, researchers aimed to characterize longitudinal neurobehavioral profiles in individuals with PHTS. Ninety-two children and young adults with PHTS and/or ASD completed two to three neurobehavioral evaluations over a two-year time period. The team used spaghetti plots and linear mixed effects models to visualize individual patient profiles and group trends, examining differences in cognitive and behavioral test scores over time. Results suggest that neurobehavioral characteristics observed in individuals with PHTS remain relatively stable over time, even in those with ASD. Reliable change indices and standardized regression-based change scores were calculated and provided in an easy-to-use Excel calculator that can be used in future research to examine patient outcomes at the individual level and inform intervention strategies.

Srivastava S, Jo B, Zhang B, Frazier T, Gallagher AS, Peck F, Levin AR, Mondal S, Li Z, Filip-Dhima R, Geisel G, Dies KA, Diplock A, Eng C, Hanna R, Sahin M, Hardan A; Developmental Synaptopathies Consortium. A randomized controlled trial of everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome. Hum Mol Genet. 2022 Oct 10;31(20):3393-3404. doi: 10.1093/hmg/ddac111. PMID: 35594551.

PTEN hamartoma tumor syndrome (PHTS) is a complex neurodevelopmental disorder characterized by overactivity of the mechanistic target of rapamycin (mTOR) pathway, which serves as a major regulator of growth. Limited data suggest that mTOR inhibitors may be therapeutic for patients with PHTS. However, no placebo-controlled studies have explored the effects of mTOR inhibition on cognition and behavior in PHTS patients with or without autism. In this study, researchers conducted a phase II, placebo-controlled trial to examine the safety and efficacy of everolimus, an mTOR inhibitor, in patients with PHTS. The team measured cognitive and behavioral outcomes in addition to biomarkers of electroencephalography (measurement of electrical activity in different parts of the brain). Results show that everolimus was well tolerated in individuals with PHTS. Electroencephalography supported engagement of the drug target in the brain, and some of the secondary (but not primary) outcome measures moved in the direction of improvement. Although this trial provides early evidence that everolimus is safe for use in patients with PHTS, authors note that further study is needed.

Breen MS, Fan X, Levy T, Pollak RM, Collins B, Osman A, Tocheva AS, Sahin M, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Kolevzon A, Buxbaum JD; Developmental Synaptopathies Consortium. Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome. HGG Adv. 2022 Sep 26;4(1):100145. doi: 10.1016/j.xhgg.2022.100145. eCollection 2023 Jan 12.

Chopra M, Modi ME, Dies KA, Chamberlin NL, Buttermore ED, Brewster SJ, Prock L, Sahin M. GENE TARGET: A framework for evaluating Mendelian neurodevelopmental disorders for gene therapy. Mol Ther Methods Clin Dev. 2022 Aug 29;27:32-46. doi: 10.1016/j.omtm.2022.08.007. eCollection 2022 Dec 8.

Siper PM, Rowe MA, Guillory SB, Rouhandeh AA, George-Jones JL, Tavassoli T, Lurie S, Zweifach J, Weissman J, Foss-Feig J, Halpern D, Trelles MP, Mulhern MS, Brittenham C, Gordon J, Zemon V, Buxbaum JD, Kolevzon A. Visual Evoked Potential Abnormalities in Phelan-McDermid Syndrome. J Am Acad Child Adolesc Psychiatry. 2022 Apr;61(4):565-574.e1. doi: 10.1016/j.jaac.2021.07.006. Epub 2021 Jul 22. PMID: 34303785; PMCID: PMC8782912.

Yehia L, Ni Y, Sadler T, Frazier TW, Eng C.. Distinct metabolic profiles associated with autism spectrum disorder versus cancer in individuals with germline PTEN mutations. NPJ Genom Med. 2022 Mar 3;7(1):16. doi: 10.1038/s41525-022-00289-x. PMID: 35241692; PMCID: PMC8894426.

Levy T, Foss-Feig JH, Betancur C, Siper PM, Trelles-Thorne MDP, Halpern D, Frank Y, Lozano R, Layton C, Britvan B, Bernstein JA, Buxbaum JD, Berry-Kravis E, Powell CM, Srivastava S, Sahin M, Soorya L, Thurm A, Kolevzon A; Developmental Synaptopathies Consortium. Strong evidence for genotype-phenotype correlations in Phelan-McDermid syndrome: results from the developmental synaptopathies consortium. Hum Mol Genet. 2022 Feb 21;31(4):625-637. doi: 10.1093/hmg/ddab280. PMID: 34559195; PMCID: PMC8863417.

Guillory SB, Baskett VZ, Grosman HE, McLaughlin CS, Isenstein EL, Wilkinson E, Weissman J, Britvan B, Trelles MP, Halpern DB, Buxbaum JD, Siper PM, Wang AT, Kolevzon A, Foss-Feig JH. Social visual attentional engagement and memory in Phelan-McDermid syndrome and autism spectrum disorder: a pilot eye tracking study. J Neurodev Disord. 2021 Dec 4;13(1):58. doi: 10.1186/s11689-021-09400-2. PMID: 34863106.

Phelan-McDermid Syndrome (PMS) is a rare genetic disorder characterized by intellectual disability and motor delays. It is also one of the most common genetic causes of autism spectrum disorder (ASD). Social deficits are a core feature of ASD. In order to characterize social attention and recognition memory, researchers tested a group of patients with PMS and another group of patients with idiopathic (no cause identified) ASD on a visual paired-comparison task. They analyzed the behavior of test subjects looking at a novel image versus a previously viewed, familiar image. Researchers found differences in attention and memory for social stimuli in the PMS group v. the idiopathic ASD group. Study authors say that these unique patterns could both clarify underlying mechanistic alterations and inform treatment targets for PMS. They could also help stratify individuals with idiopathic ASD and potentially apply knowledge gained in PMS to those individuals.

Cable J, Purcell RH, Robinson E, Vorstman JAS, Chung WK, Constantino JN, Sanders SJ, Sahin M, Dolmetsch RE, Shah BM, Thurm A, Martin CL, Bearden CE, Mulle JG. Harnessing rare variants in neuropsychiatric and neurodevelopment disorders-a Keystone Symposia report. Ann N Y Acad Sci. 2021 Dec;1506(1):5-17. doi: 10.1111/nyas.14658. Epub 2021 Aug 2. PMID: 34342000; PMCID: PMC8688183.

Neurodevelopmental neuropsychiatric disorders—such as autism spectrum disorder and schizophrenia—have strong genetic risk components, but researchers are still deciphering the underlying mechanisms. Rare variants could help us better understand the biological mechanisms for more common idiopathic diseases and reveal new therapeutic targets. This review summarizes insights from the 2021 Keystone eSymposium "Neuropsychiatric and Neurodevelopmental Disorders: Harnessing Rare Variants.” Experts describe progress in genomic discovery and human phenotyping, as well as raise consistent issues.

Capal JK, Williams ME, Pearson DA, Kissinger R, Horn PS, Murray D, Currans K, Kent B, Bebin M, Northrup H, Wu JY, Sahin M, Krueger DA; TACERN Study Group. Profile of Autism Spectrum Disorder in Tuberous Sclerosis Complex: Results from a Longitudinal, Prospective, Multisite Study. Ann Neuro. 2021 Dec;90(6):874-886. doi: 10.1002/ana.26249. Epub 2021 Oct 29. PMID: 34668231; PMCID: PMC8639652.

Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that causes noncancerous tumors to develop in many parts of the body. It is highly associated with autism spectrum disorder (ASD). Researchers seeking to characterize autistic features in young children with TSC evaluated 138 children from ages 3 to 36 months. They used both development and autism-specific assessments. One in four children in the study had been diagnosed with ASD by 36 months. Many individuals with TSC without an autism diagnosis also exhibited a range of autistic behaviors that were below the diagnostic threshold. Study authors report a broader autism phenotype (set of characteristics) that can be identified in young children with TSC, offering an opportunity for early, targeted treatments.

Srivastava S, Condy E, Carmody E, Filip-Dhima R, Kapur K, Bernstein JA, Berry-Kravis E, Powell CM, Soorya L, Thurm A, Buxbaum JD, Sahin M, Kolevzon AL; Developmental Synaptopathies Consortium. Parent-reported measure of repetitive behavior in Phelan-McDermid syndrome. J Neurodev Disord. 2021 Nov 5;13(1):53. doi: 10.1186/s11689-021-09398-7. PMID: 34740315; PMCID: PMC8570010.

Repetitive behaviors are often seen in individuals with autism spectrum disorder as well as intellectual disability. Due to the association of these diagnoses with Phelan-McDermid syndrome (PMS), researchers characterized the severity and profile of repetitive behaviors in PMS relative to previously published scores in other neurodevelopmental disorders. The team used the Repetitive Behavior Scale-Revised (RBS-R) as a parent-report measure of what was collected as part of a natural history study of PMS through the Developmental Synaptopathies Consortium (DSC). Researchers demonstrated that individuals with PMS in this cohort had lower rates of repetitive behaviors compared to previous studies of individuals with autism spectrum disorder and Fragile X syndrome. They also showed that more severe motor repetitive behaviors (e.g., body rocking, finger movements) were associated with lower IQ scores in PMS, but this relationship was not present between IQ and other types of repetitive behaviors. These findings indicate that repetitive behaviors may be milder overall in PMS compared to previous studies characterizing autism spectrum disorder and other genetic conditions. Stereotyped motor behaviors may be related to level of cognitive functioning, and not an autism spectrum disorder diagnosis, in PMS. Authors note the need to better understand these findings by continuing to study repetitive behaviors in PMS using objective measures.

de Vries PJ, Leclezio L, Gardner-Lubbe S, Krueger D, Sahin M, Sparagana S, De Waele L, Jansen A. Multivariate data analysis identifies natural clusters of Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND). Orphanet J Rare Dis. 2021 Oct 24;16(1):447. doi: 10.1186/s13023-021-02076-w. PMID: 34689816; PMCID: PMC8543869.

Uljarević M, Frazier TW, Rached G, Busch RM, Klaas P, Srivastava S, Martinez-Agosto JA, Sahin M, Eng C, Hardan AY; Developmental Synaptopathies Consortium. Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations. Am J Med Genet A. 2021 Aug 23. doi: 10.1002/ajmg.a.62458. Online ahead of print.

Mutations in the PTEN gene are an important genetic risk factor for autism spectrum disorder (ASD). PTEN mutations are identified in 2% of all ASD cases and 17-20% of cases with both ASD and macrocephaly (larger than typical head size). Restricted and repetitive behaviors (RRB) are a core diagnostic symptom of ASD and one of the earlier predictors of a subsequent ASD diagnosis. RRBs include repetitive motor behaviors (RMB), insistence on sameness (IS), and circumscribed interests (CI). Researchers believe these symptom domains, which have a significant negative impact on affected individuals and their families, likely have distinct mechanisms and might therefore require different treatments. Seeking to develop a more nuanced understanding of RRB in individuals with PTEN mutations, researchers compared RMB, IS, and CI symptoms captured by two different measures across three groups: 38 individuals with PTEN mutations with ASD, 23 with PTEN mutations without ASD, and 25 with ASD and macrocephaly but without PTEN mutations. After adjusting for age and full-scale intelligence quotient (FSIQ) scores, the researchers found that differences between the three study groups were not statistically significant. However, all three symptom domains showed distinct association patterns with sex, age, and FSIQ. Study authors conclude that their findings highlight the importance of comprehensively assessing RRB in people with PTEN mutations. Their findings further support the hypothesis that RMB, IS, and CI are indeed distinct RRB domains that might, therefore, require different treatment approaches in this population. They recommend that future studies are needed to further understand mechanisms behind specific RRB subdomains and inform most optimal strategies for individuation of treatment options. This research offers the largest, most comprehensive comparison of distinct RRB domains in individuals with PTEN mutations to date.

Steele M, Uljarević M, Rached G, Frazier TW, Phillips JM, Libove RA, Busch RM, Klaas P, Martinez-Agosto JA, Srivastava S, Eng C, Sahin M, Hardan AY. Psychiatric Characteristics Across Individuals With PTEN Mutations. Front Psychiatry. 2021 Aug 17;12:672070. doi: 10.3389/fpsyt.2021.672070. eCollection 2021.

Ihnen SKZ, Capal JK, Horn PS, Griffith M, Sahin M, Bebin EM, Wu JY, Northrup H, Krueger DA; TACERN study group. Epilepsy Is Heterogeneous in Early-Life Tuberous Sclerosis Complex. Pediatr Neurol. 2021 Oct;123:1-9. doi: 10.1016/j.pediatrneurol.2021.06.012. Epub 2021 Jul 6.

Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors to grow in vital organs including the brain, kidneys, heart, eyes, lungs, and skin. Epilepsy in TSC typically presents with early onset, multiple seizure types, and intractability. However, this varies among individual patients. In this study, researchers aimed to define epilepsy profiles in the TSC population. The team prospectively collected detailed individual data on seizure characteristics in children aged zero to 36 months. Caregivers kept daily seizure diaries, including onset and daily counts, for each seizure type. Researchers then compared developmental outcomes at 36 months between subgroups. Epilepsy was seen in 79 percent of participants. Hierarchical clustering based on six metrics of seizure burden—age of onset, total seizures, ratio of seizure days to nonseizure days, seizures per seizure day, and worst seven- and 30-day stretches—revealed two distinct groups with broadly favorable and unfavorable epilepsy profiles. Within each group, subpopulations showed clinically meaningful differences in seizure burden, and groups with higher burden had worse developmental outcomes at 36 months. These findings indicate that early and aggressive treatments for epilepsy in TSC may be best leveraged by targeting specific subgroups based on phenotype severity.

Anderson NC, Chen PF, Meganathan K, Afshar Saber W, Petersen AJ, Bhattacharyya A, Kroll KL, Sahin M; Cross-IDDRC Human Stem Cell Working Group. Balancing serendipity and reproducibility: Pluripotent stem cells as experimental systems for intellectual and developmental disorders. Stem Cell Reports. 2021 Jun 8;16(6):1446-1457. doi: 10.1016/j.stemcr.2021.03.025. Epub 2021 Apr 15. PMID: 33861989; PMCID: PMC8190574.

Mariscal MG, Berry-Kravis E, Buxbaum JD, Ethridge LE, Filip-Dhima R, Foss-Feig JH, Kolevzon A, Modi ME, Mosconi MW, Nelson CA, Powell CM, Siper PM, Soorya L, Thaliath A, Thurm A, Zhang B, Sahin M, Levin AR; Developmental Synaptopathies Consortium. Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome. Mol Autism. 2021 Apr 28;12(1):29. doi: 10.1186/s13229-020-00411-9.

Cohen AL, Mulder BPF, Prohl AK, Soussand L, Davis P, Kroeck MR, McManus P, Gholipour A, Scherrer B, Bebin EM, Wu JY, Northrup H, Krueger DA, Sahin M, Warfield SK, Fox MD, Peters JM; Tuberous Sclerosis Complex Autism Center of Excellence Network Study Group. Tuber Locations Associated with Infantile Spasms Map to a Common Brain Network. Ann Neurol. 2021 Apr;89(4):726-739. doi: 10.1002/ana.26015. Epub 2021 Jan 21.

Uljarević M, Frazier TW, Rached G, Busch RM, Klaas P, Srivastava S, Martinez-Agosto JA, Sahin M, Eng C, Hardan AY; Developmental Synaptopathies Consortium. Brief Report: Role of Parent-Reported Executive Functioning and Anxiety in Insistence on Sameness in Individuals with Germline PTEN Mutations. J Autism Dev Disord. 2021 Feb 17. doi: 10.1007/s10803-021-04881-5. Online ahead of print.

Jia M, Sangwan N, Tzeng A, Eng C.. Interplay Between Class II HLA Genotypes and the Microbiome and Immune Phenotypes in Individuals With PTEN Hamartoma Tumor Syndrome. JCO Precis Oncol. 2021 Feb 9;5:PO.20.00374. doi: 10.1200/PO.20.00374. PMID: 34250407; PMCID: PMC8232567.

Hardan AY, Jo B, Frazier TW, Klaas P, Busch RM, Dies KA, Filip-Dhima R, Snow AV, Eng C, Hanna R, Zhang B, Sahin M. A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations. Contemp Clin Trials Commun. 2021 Feb 6;21:100733. doi: 10.1016/j.conctc.2021.100733. eCollection 2021 Mar.

Frazier TW, Jaini R, Busch RM, Wolf M, Sadler T, Klaas P, Hardan AY, Martinez-Agosto JA, Sahin M, Eng C; Developmental Synaptopathies Consortium. Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism. Mol Autism. 2021 Jan 28;12(1):5. doi: 10.1186/s13229-020-00406-6.

Although PTEN is a well-established risk gene for autism spectrum disorder (ASD), little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). In this study, researchers evaluated the influence of PTEN mutation and ASD diagnostic status on relevant pathway protein levels in peripheral blood. They also examined the associations between protein levels and neurobehavioral functions. They found that several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. These results show that protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. The team notes that future longitudinal analyses are needed to replicate these findings and evaluate relationships between protein and neurobehavioral measures.

Farach LS, Richard MA, Lupo PJ, Sahin M, Krueger DA, Wu JY, Bebin EM, Au KS, Northrup H; TACERN Study Group. Epilepsy Risk Prediction Model for Patients With Tuberous Sclerosis Complex. Pediatr Neurol. 2020 Dec;113:46-50. doi: 10.1016/j.pediatrneurol.2020.07.015. Epub 2020 Jul 29.

Shao DD, Achkar CM, Lai A, Srivastava S, Doan RN, Rodan LH, Chen AY; Brain Development Study Group, Poduri A, Yang E, Walsh CA. Polymicrogyria is Associated With Pathogenic Variants in PTEN. Ann Neurol. 2020 Dec;88(6):1153-1164. doi: 10.1002/ana.25904. Epub 2020 Oct 8.

Sahin M, Sweeney JA, Jones SR. Editorial: Biomarkers to Enable Therapeutics Development in Neurodevelopmental Disorders. Front Integr Neurosci. 2020 Nov 12;14:616641. doi: 10.3389/fnint.2020.616641. PMID: 33262695; PMCID: PMC7686575.

Nariai H, Hussain SA, Bernardo D, Motoi H, Sonoda M, Kuroda N, Asano E, Nguyen JC, Elashoff D, Sankar R, Bragin A, Staba RJ, Wu JY. Scalp EEG interictal high frequency oscillations as an objective biomarker of infantile spasms. Clin Neurophysiol. 2020 Nov;131(11):2527-2536. doi: 10.1016/j.clinph.2020.08.013. Epub 2020 Sep 3.

Yehia L, Eng C. PTEN hamartoma tumour syndrome: what happens when there is no PTEN germline mutation?. Hum Mol Genet. 2020 Oct 20;29(R2):R150-R157. doi: 10.1093/hmg/ddaa127.

More than 400 hereditary cancer syndromes have been described to date and account for 5-10% of all cancers. PTEN hamartoma tumour syndrome (PHTS) is an umbrella term for subsets of four syndromes associated with germline (inherited) PTEN mutations. However, many patients with phenotypes similar to those in PHTS do not carry germline PTEN mutations. This paper reviews gene discovery efforts over the last decade to identify alterations in cancer-predisposing genes in order to facilitate gene-informed molecular diagnosis, cancer risk assessment, and gene-specific clinical management. Authors conclude that validating these discoveries is critical to bringing these patients specific gene-informed risk assessment and subsequent management.

Gergoudis K, Weinberg A, Templin J, Farmer C, Durkin A, Weissman J, Siper P, Foss-Feig J, Del Pilar Trelles M, Bernstein JA, Buxbaum JD, Berry-Kravis E, Powell CM, Sahin M, Soorya L, Thurm A, Kolevzon A; Developmental Synaptopathies Consortium. Psychometric Study of the Social Responsiveness Scale in Phelan-McDermid Syndrome. Autism Res. 2020 Aug;13(8):1383-1396. doi: 10.1002/aur.2299. Epub 2020 May 14.

Bassell J, Srivastava S, Prohl AK, Scherrer B, Kapur K, Filip-Dhima R, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Buxbaum JD, Kolevzon A, Warfield SK, Sahin M; Developmental Synaptopathies Consortium. Diffusion Tensor Imaging Abnormalities in the Uncinate Fasciculus and Inferior Longitudinal Fasciculus in Phelan-McDermid Syndrome. Pediatr Neurol. 2020 May;106:24-31. doi: 10.1016/j.pediatrneurol.2020.01.006. Epub 2020 Jan 31.

Scherrer B, Prohl AK, Taquet M, Kapur K, Peters JM, Tomas-Fernandez X, Davis PE, M Bebin E, Krueger DA, Northrup H, Y Wu J, Sahin M, Warfield SK. The Connectivity Fingerprint of the Fusiform Gyrus Captures the Risk of Developing Autism in Infants with Tuberous Sclerosis Complex. Cereb Cortex. 2020 Apr 14;30(4):2199-2214. doi: 10.1093/cercor/bhz233.

Karimi D, Peters JM, Ouaalam A, Prabhu SP, Sahin M, Krueger DA, Kolevzon A, Eng C, Warfield SK, Gholipour A. LEARNING TO DETECT BRAIN LESIONS FROM NOISY ANNOTATIONS. Proc IEEE Int Symp Biomed Imaging. 2020 Apr;2020:1910-1914. doi: 10.1109/isbi45749.2020.9098599. Epub 2020 May 22.

Applequist J, Burroughs C, Ramirez A Jr, Merkel PA, Rothenberg ME, Trapnell B, Desnick RJ, Sahin M, Krischer JP. A novel approach to conducting clinical trials in the community setting: utilizing patient-driven platforms and social media to drive web-based patient recruitment. BMC Med Res Methodol. 2020 Mar 13;20(1):58. doi: 10.1186/s12874-020-00926-y.

Afshar Saber W, Sahin M. Recent advances in human stem cell-based modeling of Tuberous Sclerosis Complex. Mol Autism. 2020 Feb 19;11(1):16. doi: 10.1186/s13229-020-0320-2.

Kohlenberg TM, Trelles MP, McLarney B, Betancur C, Thurm A, Kolevzon A. Psychiatric illness and regression in individuals with Phelan-McDermid syndrome. J Neurodev Disord. 2020 Feb 12;12(1):7. doi: 10.1186/s11689-020-9309-6.

Schoenberger A, Capal JK, Ondracek A, Horn PS, Murray D, Byars AW, Pearson DA, Williams ME, Bebin M, Northrup H, Wu JY, Sahin M, Krueger DA. Language predictors of autism spectrum disorder in young children with tuberous sclerosis complex. Epilepsy Behav. 2020 Feb;103(Pt A):106844. doi: 10.1016/j.yebeh.2019.106844. Epub 2019 Dec 18.

Yehia L, Seyfi M, Niestroj LM, Padmanabhan R, Ni Y, Frazier TW, Lal D, Eng C. Copy Number Variation and Clinical Outcomes in Patients With Germline PTEN Mutations. JAMA Netw Open. 2020 Jan 3;3(1):e1920415. doi: 10.1001/jamanetworkopen.2019.20415.

Peters JM, Hyde DE, Chu CJ, Boom M, Scherrer B, Madsen JR, Stone SS, Ouaalam H, Prabhu SP, Sahin M, Warfield SK. Lesion-Constrained Electrical Source Imaging: A Novel Approach in Epilepsy Surgery for Tuberous Sclerosis Complex. J Clin Neurophysiol. 2020 Jan;37(1):79-86. doi: 10.1097/WNP.0000000000000615.

Kolevzon A, Delaby E, Berry-Kravis E, Buxbaum JD, Betancur C. Neuropsychiatric decompensation in adolescents and adults with Phelan-McDermid syndrome: a systematic review of the literature. Mol Autism. 2019 Dec 24;10:50. doi: 10.1186/s13229-019-0291-3. eCollection 2019.

Modi ME, Sahin M. A unified circuit for social behavior. Neurobiol Learn Mem. 2019 Nov;165:106920. doi: 10.1016/j.nlm.2018.08.010. Epub 2018 Aug 24.

Nariai H, Hussain SA, Bernardo D, Fallah A, Murata KK, Nguyen JC, Rajaraman RR, Rao LM, Matsumoto JH, Lerner JT, Salamon N, Elashoff D, Sankar R, Wu JY. Prospective observational study: Fast ripple localization delineates the epileptogenic zone. Clin Neurophysiol. 2019 Nov;130(11):2144-2152. doi: 10.1016/j.clinph.2019.08.026. Epub 2019 Sep 17.

Ahtam B, Dehaes M, Sliva DD, Peters JM, Krueger DA, Bebin EM, Northrup H, Wu JY, Warfield SK, Sahin M, Grant PE; TACERN Study Group. Resting-State fMRI Networks in Children with Tuberous Sclerosis Complex. J Neuroimaging. 2019 Nov;29(6):750-759. doi: 10.1111/jon.12653. Epub 2019 Jul 14.

Busch RM, Srivastava S, Hogue O, Frazier TW, Klaas P, Hardan A, Martinez-Agosto JA, Sahin M, Eng C; Developmental Synaptopathies Consortium. Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Transl Psychiatry. 2019 Oct 8;9(1):253. doi: 10.1038/s41398-019-0588-1.

Yehia L, Ni Y, Feng F, Seyfi M, Sadler T, Frazier TW, Eng C. Distinct Alterations in Tricarboxylic Acid Cycle Metabolites Associate with Cancer and Autism Phenotypes in Cowden Syndrome and Bannayan-Riley-Ruvalcaba Syndrome. Am J Hum Genet. 2019 Oct 3;105(4):813-821. doi: 10.1016/j.ajhg.2019.09.004. Epub 2019 Sep 26.

Witmer C, Mattingly A, DʼSouza P, Thurm A, Hadigan C. Incontinence in Phelan-McDermid Syndrome. J Pediatr Gastroenterol Nutr. 2019 Aug;69(2):e39-e42. doi: 10.1097/MPG.0000000000002342.

Davis PE, Kapur K, Filip-Dhima R, Trowbridge SK, Little E, Wilson A, Leuchter A, Bebin EM, Krueger D, Northrup H, Wu JY, Sahin M, Peters JM; Tuberous Sclerosis Autism Centers of Excellence Research Network. Increased electroencephalography connectivity precedes epileptic spasm onset in infants with tuberous sclerosis complex. Epilepsia. 2019 Aug;60(8):1721-1732. doi: 10.1111/epi.16284. Epub 2019 Jul 12.

Farach LS, Pearson DA, Woodhouse JP, Schraw JM, Sahin M, Krueger DA, Wu JY, Bebin EM, Lupo PJ, Au KS, Northrup H; TACERN Study Group. Tuberous Sclerosis Complex Genotypes and Developmental Phenotype. Pediatr Neurol. 2019 Jul;96:58-63. doi: 10.1016/j.pediatrneurol.2019.03.003. Epub 2019 Mar 13.

Peters JM, Struyven RR, Prohl AK, Vasung L, Stajduhar A, Taquet M, Bushman JJ, Lidov H, Singh JM, Scherrer B, Madsen JR, Prabhu SP, Sahin M, Afacan O, Warfield SK. White matter mean diffusivity correlates with myelination in tuberous sclerosis complex. Ann Clin Transl Neurol. 2019 Jul;6(7):1178-1190. doi: 10.1002/acn3.793. Epub 2019 Jun 23.

Smith IN, Thacker S, Seyfi M, Cheng F, Eng C. Conformational Dynamics and Allosteric Regulation Landscapes of Germline PTEN Mutations Associated with Autism Compared to Those Associated with Cancer. Am J Hum Genet. 2019 May 2;104(5):861-878. doi: 10.1016/j.ajhg.2019.03.009. Epub 2019 Apr 18.

Marami B, Scherrer B, Khan S, Afacan O, Prabhu SP, Sahin M, Warfield SK, Gholipour A. Motion-robust diffusion compartment imaging using simultaneous multi-slice acquisition. Magn Reson Med. 2019 May;81(5):3314-3329. doi: 10.1002/mrm.27613. Epub 2018 Nov 16.

Smith IN, Thacker S, Jaini R, Eng C. Dynamics and structural stability effects of germline PTEN mutations associated with cancer versus autism phenotypes. J Biomol Struct Dyn. 2019 Apr;37(7):1766-1782. doi: 10.1080/07391102.2018.1465854. Epub 2018 May 14.

Yehia L, Ngeow J, Eng C. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019 Feb 1;129(2):452-464. doi: 10.1172/JCI121277. Epub 2019 Jan 7.

The tumor suppressor phosphatase and tensin homolog (PTEN) classically counteracts the PI3K/AKT/mTOR signaling cascade. Germline pathogenic PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), featuring various benign and malignant tumors, as well as neurodevelopmental disorders such as autism spectrum disorder. Germline and somatic mosaic mutations in genes encoding components of the PI3K/AKT/mTOR pathway downstream of PTEN predispose to syndromes with partially overlapping clinical features, termed the "PTEN-opathies." Experimental models of PTEN pathway disruption uncover the molecular and cellular processes influencing clinical phenotypic manifestations. Such insights not only teach us about biological mechanisms in states of health and disease, but also enable more accurate gene-informed cancer risk assessment, medical management, and targeted therapeutics. Hence, the PTEN-opathies serve as a prototype for bedside to bench, and back to the bedside, practice of evidence-based precision medicine.

Peters JM, Prohl A, Kapur K, Nath A, Scherrer B, Clancy S, Prabhu SP, Sahin M, Franz DN, Warfield SK, Krueger DA. Longitudinal Effects of Everolimus on White Matter Diffusion in Tuberous Sclerosis Complex. Pediatr Neurol. 2019 Jan;90:24-30. doi: 10.1016/j.pediatrneurol.2018.10.005. Epub 2018 Oct 18.

Srivastava S, Scherrer B, Prohl AK, Filip-Dhima R, Kapur K, Kolevzon A, Buxbaum JD, Berry-Kravis E, Soorya L, Thurm A, Powell CM, Bernstein JA, Warfield SK, Sahin M; Developmental Synaptopathies Consortium. Volumetric Analysis of the Basal Ganglia and Cerebellar Structures in Patients with Phelan-McDermid Syndrome. Pediatr Neurol. 2019 Jan;90:37-43. doi: 10.1016/j.pediatrneurol.2018.09.008. Epub 2018 Sep 21.

Hussain SA, Schmid E, Peters JM, Goyal M, Bebin EM, Northrup H, Sahin M, Krueger DA, Wu JY; Tuberous Sclerosis Complex Autism Center of Excellence Network. High vigabatrin dosage is associated with lower risk of infantile spasms relapse among children with tuberous sclerosis complex. Epilepsy Res. 2018 Dec;148:1-7. doi: 10.1016/j.eplepsyres.2018.09.016. Epub 2018 Oct 2.

Nariai H, Wu JY, Bernardo D, Fallah A, Sankar R, Hussain SA. Interrater reliability in visual identification of interictal high-frequency oscillations on electrocorticography and scalp EEG. Epilepsia Open. 2018 Nov 2;3(Suppl Suppl 2):127-132. doi: 10.1002/epi4.12266. eCollection 2018 Dec.

Frazier TW, Klingemier EW, Parikh S, Speer L, Strauss MS, Eng C, Hardan AY, Youngstrom EA. Development and Validation of Objective and Quantitative Eye Tracking-Based Measures of Autism Risk and Symptom Levels. J Am Acad Child Adolesc Psychiatry. 2018 Nov;57(11):858-866. doi: 10.1016/j.jaac.2018.06.023. Epub 2018 Sep 13.

Baumer FM, Peters JM, Clancy S, Prohl AK, Prabhu SP, Scherrer B, Jansen FE, Braun KPJ, Sahin M, Stamm A, Warfield SK. Corpus Callosum White Matter Diffusivity Reflects Cumulative Neurological Comorbidity in Tuberous Sclerosis Complex. Cereb Cortex. 2018 Oct 1;28(10):3665-3672. doi: 10.1093/cercor/bhx247.

Modi ME, Sahin M. The Way Forward for Mechanism-Based Therapeutics in Genetically Defined Neurodevelopmental Disorders. Clin Pharmacol Ther. 2018 Oct;104(4):603-606. doi: 10.1002/cpt.1181. Epub 2018 Aug 12.

Jacobs J, Wu JY, Perucca P, Zelmann R, Mader M, Dubeau F, Mathern GW, Schulze-Bonhage A, Gotman J. Removing high-frequency oscillations: A prospective multicenter study on seizure outcome.. Neurology. 2018 Sep 11;91(11):e1040-e1052. doi: 10.1212/WNL.0000000000006158. Epub 2018 Aug 17. PMID: 30120133; PMCID:PMC6140372

de Vries PJ, Wilde L, de Vries MC, Moavero R, Pearson DA, Curatolo P. A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):309-320. doi: 10.1002/ajmg.c.31637. Epub 2018 Aug 16.

Peron A, Au KS, Northrup H. Genetics, genomics, and genotype-phenotype correlations of TSC: Insights for clinical practice. Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):281-290. doi: 10.1002/ajmg.c.31651. Epub 2018 Sep 26.

Peron A, Northrup H. Tuberous sclerosis complex. Am J Med Genet C Semin Med Genet. 2018 Sep;178(3):274-277. doi: 10.1002/ajmg.c.31657. Epub 2018 Oct 16.

Soorya L, Leon J, Trelles MP, Thurm A. Framework for assessing individuals with rare genetic disorders associated with profound intellectual and multiple disabilities (PIMD): the example of Phelan McDermid Syndrome. Clin Neuropsychol. 2018 Aug-Oct;32(7):1226-1255. doi: 10.1080/13854046.2017.1413211. Epub 2017 Dec 21.

van der Poest Clement EA, Sahin M, Peters JM. Vigabatrin for Epileptic Spasms and Tonic Seizures in Tuberous Sclerosis Complex. J Child Neurol. 2018 Jul;33(8):519-524. doi: 10.1177/0883073818768309. Epub 2018 Apr 24.

Bernardo D, Nariai H, Hussain SA, Sankar R, Salamon N, Krueger DA, Sahin M, Northrup H, Bebin EM, Wu JY; UCLA Pediatric Epilepsy Group; TACERN Study Group. Visual and semi-automatic non-invasive detection of interictal fast ripples: A potential biomarker of epilepsy in children with tuberous sclerosis complex. Clin Neurophysiol. 2018 Jul;129(7):1458-1466. doi: 10.1016/j.clinph.2018.03.010. Epub 2018 Apr 3.

Curtin P, Austin C, Curtin A, Gennings C, Arora M; (for the Emergent Dynamical Systems Group), Tammimies K, Willfors C, Berggren S, Siper P, Rai D, Meyering K, Kolevzon A, Mollon J, David AS, Lewis G, Zammit S, Heilbrun L, Palmer RF, Wright RO, Bölte S, Reichenberg A. Dynamical features in fetal and postnatal zinc-copper metabolic cycles predict the emergence of autism spectrum disorder. Sci Adv. 2018 May 30;4(5):eaat1293. doi: 10.1126/sciadv.aat1293. eCollection 2018 May.

De Rubeis S, Siper PM, Durkin A, Weissman J, Muratet F, Halpern D, Trelles MDP, Frank Y, Lozano R, Wang AT, Holder JL Jr, Betancur C, Buxbaum JD, Kolevzon A. Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations. Mol Autism. 2018 Apr 27;9:31. doi: 10.1186/s13229-018-0205-9. eCollection 2018.

Srivastava S, Prohl AK, Scherrer B, Kapur K, Krueger DA, Warfield SK, Sahin M; TACERN Study Group. Cerebellar volume as an imaging marker of development in infants with tuberous sclerosis complex. Neurology. 2018 Apr 24;90(17):e1493-e1500. doi: 10.1212/WNL.0000000000005352. Epub 2018 Mar 23.

Rensonnet G, Scherrer B, Warfield SK, Macq B, Taquet M. Assessing the validity of the approximation of diffusion-weighted-MRI signals from crossing fascicles by sums of signals from single fascicles. Magn Reson Med. 2018 Apr;79(4):2332-2345. doi: 10.1002/mrm.26832. Epub 2017 Jul 16.

Khan OI, Zhou X, Leon J, Kessler R, Gaughan T, D'Souza P, Gropman A, Cohen N, Rennert O, Buckley A, Inati S, Thurm A. Prospective longitudinal overnight video-EEG evaluation in Phelan-McDermid Syndrome. Epilepsy Behav. 2018 Mar;80:312-320. doi: 10.1016/j.yebeh.2017.11.034. Epub 2018 Feb 3.

Byrd V, Getz T, Padmanabhan R, Arora H, Eng C. The microbiome in PTEN hamartoma tumor syndrome. Endocr Relat Cancer. 2018 Mar;25(3):233-243. doi: 10.1530/ERC-17-0442. Epub 2017 Dec 12.

Farach LS, Little ME, Duker AL, Logan CV, Jackson A, Hecht JT, Bober M. The expanding phenotype of RNU4ATAC pathogenic variants to Lowry Wood syndrome. Am J Med Genet A. 2018 Feb;176(2):465-469. doi: 10.1002/ajmg.a.38581. Epub 2017 Dec 19.

Frazier TW, Strauss M, Klingemier EW, Zetzer EE, Hardan AY, Eng C, Youngstrom EA. A Meta-Analysis of Gaze Differences to Social and Nonsocial Information Between Individuals With and Without Autism. J Am Acad Child Adolesc Psychiatry. 2017 Jul;56(7):546-555. doi: 10.1016/j.jaac.2017.05.005. Epub 2017 May 11.

Srivastava S, Sahin M. Autism spectrum disorder and epileptic encephalopathy: common causes, many questions. J Neurodev Disord. 2017 Jun 23;9:23. doi: 10.1186/s11689-017-9202-0. PMID: 28649286; PMCID: PMC5481888.

Martin KR, Zhou W, Bowman MJ, Shih J, Au KS, Dittenhafer-Reed KE, Sisson KA, Koeman J, Weisenberger DJ, Cottingham SL, DeRoos ST, Devinsky O, Winn ME, Cherniack AD, Shen H, Northrup H, Krueger DA, MacKeigan JP. The genomic landscape of tuberous sclerosis complex. Nat Commun. 2017 Jun 15;8:15816. doi: 10.1038/ncomms15816.

Siper PM, Kolevzon A, Wang AT, Buxbaum JD, Tavassoli T. A clinician-administered observation and corresponding caregiver interview capturing DSM-5 sensory reactivity symptoms in children with ASD. Autism Res. 2017 Jun;10(6):1133-1140. doi: 10.1002/aur.1750. Epub 2017 Mar 11.

Rankine J, Li E, Lurie S, Rieger H, Fourie E, Siper PM, Wang AT, Buxbaum JD, Kolevzon A. Language ENvironment Analysis (LENA) in Phelan-McDermid Syndrome: Validity and Suggestions for Use in Minimally Verbal Children with Autism Spectrum Disorder. J Autism Dev Disord. 2017 Jun;47(6):1605-1617. doi: 10.1007/s10803-017-3082-8.

Capal JK, Bernardino-Cuesta B, Horn PS, et al. Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav. 2017;70(Pt A):245-252. PMID: 28457992, PMCID: PMC5497719.

Hussain SA, Mathern GW, Hung P, Weng J, Sankar R, Wu JY. Intraoperative fast ripples independently predict postsurgical epilepsy outcome: Comparison with other electrocorticographic phenomena. Epilepsy Res. 2017;135:79-86. PMID: 28644979, PMCID: PMC5568451.

Davis PE, Filip-Dhima R, Sideridis G, Peters JM, Au KS, Northrup H, Bebin EM, Wu JY, Krueger D, Sahin M; Tuberous Sclerosis Complex Autism Center of Excellence Research Network. Presentation and Diagnosis of Tuberous Sclerosis Complex in Infants. Pediatrics. 2017;140(6). PMID: 29101226, PMCID: PMC5703775.

Capal JK, Horn PS, Murray DS, Byars AW, Bing NM, Kent B, Bucher LA, Williams ME, O'Kelley S, Pearson DA, Sahin M, Krueger DA; TACERN Study Group. Utility of the Autism Observation Scale for Infants in Early Identification of Autism in Tuberous Sclerosis Complex. Pediatr Neurol. 2017;75:80-86. PMID: 28844798, PMCID: PMC5610103.

Krueger DA, Wilfong AA, Mays M, Talley CM, Agricola K, Tudor C, Capal J, Holland-Bouley K, Franz DN. Long-term treatment of epilepsy with everolimus in tuberous sclerosis. Neurology. 2016 Dec 6;87(23):2408-2415. doi: 10.1212/WNL.0000000000003400. Epub 2016 Nov 4. PMID: 27815402; PMCID: PMC5177677.

Markowitz LA, Reyes C, Embacher RA, Speer LL, Roizen N, Frazier TW. Development and psychometric evaluation of a psychosocial quality-of-life questionnaire for individuals with autism and related developmental disorders. Autism. 2016 Oct;20(7):832-44. doi: 10.1177/1362361315611382. Epub 2015 Dec 10.

Scherrer B, Schwartzman A, Taquet M, Sahin M, Prabhu SP, Warfield SK. Characterizing brain tissue by assessment of the distribution of anisotropic microstructural environments in diffusion-compartment imaging (DIAMOND). Magn Reson Med. Sep 12 2015. PMID: 26362832.

Sahin M, Henske EP, Manning BD, Ess KC, Bissler JJ, Klann E, Kwiatkowski DJ, Roberds SL, Silva AJ, Hillaire-Clarke CS, Young LR, Zervas M, Mamounas LA; Tuberous Sclerosis Complex Working Group to Update the Research Plan. Advances and Future Directions for Tuberous Sclerosis Complex Research: Recommendations From the 2015 Strategic Planning Conference. Pediatr Neurol. 2016 Jul;60:1-12. doi: 10.1016/j.pediatrneurol.2016.03.015. Epub 2016 Apr 2. PMID: 27267556; PMCID: PMC4921275.

Im K, Ahtam B, Haehn D, Peters JM, Warfield SK, Sahin M, Ellen Grant P. Altered Structural Brain Networks in Tuberous Sclerosis Complex. Cereb Cortex. 2016 May;26(5):2046-58. doi: 10.1093/cercor/bhv026. Epub 2015 Mar 5. PMID: 25750257; PMCID: PMC4830286.

Dölen G, Sahin M. Editorial: Essential Pathways and Circuits of Autism Pathogenesis. Front Neurosci. 2016 Apr 26;10:182. doi: 10.3389/fnins.2016.00182. eCollection 2016.

Frazier TW, Klingemier EW, Beukemann M, Speer L, Markowitz L, Parikh S, Wexberg S, Giuliano K, Schulte E, Delahunty C, Ahuja V, Eng C, Manos MJ, Hardan AY, Youngstrom EA, Strauss MS. Development of an Objective Autism Risk Index Using Remote Eye Tracking. J Am Acad Child Adolesc Psychiatry. Apr 2016;55(4):301-309. PMID: 27015721, PMCID: PMC4808563.

Ebrahimi-Fakhari D, Saffari A, Wahlster L, Lu J, Byrne S, Hoffmann GF, Jungbluth H, Sahin M. Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism. Brain. 2016 Feb;139(Pt 2):317-37. doi: 10.1093/brain/awv371. Epub 2015 Dec 29. PMID: 26715604; PMCID: PMC5841365.

Marami B, Scherrer B, Afacan O, Erem B, Warfield SK, Gholipour A. Motion-Robust Diffusion-Weighted Brain MRI Reconstruction Through Slice-Level Registration-Based Motion Tracking. IEEE Trans Med Imaging. 2016;35(10):2258-2269. PMID: 27834639, PMCID: PMC5108524.

Siper PM, Zemon V, Gordon J, et al. Siper PM. PLoS ONE. 2016;11(10):e0164422. PMID: 27716799, PMCID: PMC5055293.

Keppler-Noreuil KM, Parker VE, Darling TN, Martinez-Agosto JA. Somatic overgrowth disorders of the PI3K/AKT/mTOR pathway & therapeutic strategies. Am J Med Genet C Semin Med Genet. 2016;172(4):402-421. PMID: 27860216, PMCID: PMC5592089.

The phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway plays an essential role in regulation of normal cell growth, metabolism, and survival. Somatic activating mutations in the PI3K/AKT/mTOR pathway are among the most common mutations identified in cancer, and have been shown to cause a spectrum of overgrowth syndromes including PIK3CA-Related Overgrowth Spectrum, Proteus syndrome, and brain overgrowth conditions. Clinical findings in these disorders may be isolated or multiple, including sporadic or mosaic overgrowth (adipose, skeletal, muscle, brain, vascular, or lymphatic), and skin abnormalities (including epidermal nevi, hyper-, and hypopigmented lesions), and have the potential risk of tumorigenesis. Key negative regulators of the PI3K-AKT signaling pathway include PTEN and TSC1/TSC2 and germline loss-of function mutations of these genes are established to cause PTEN Hamartoma Tumor Syndrome and Tuberous Sclerosis Complex. Mosaic forms of these conditions lead to increased activation of PI3K and mTOR at affected sites and there is phenotypic overlap between these conditions. All are associated with significant morbidity with limited options for treatment other than symptomatic therapies and surgeries. As dysregulation of the PI3K/AKT/mTOR pathway has been implicated in cancer, several small molecule inhibitors targeting different components of the PI3K/AKT/mTOR signaling pathway are under clinical investigation. The development of these therapies brings closer the prospect of targeting treatment for somatic PI3K/AKT/mTOR-related overgrowth syndromes. This review describes the clinical findings, gene function and pathogenesis of these mosaic overgrowth syndromes, and presents existing and future treatment strategies to reduce or prevent associated complications of these disorders. © 2016 Wiley Periodicals, Inc.

Costales J, Kolevzon A. The therapeutic potential of insulin-like growth factor-1 in central nervous system disorders. Neurosci Biobehav Rev. 2016;63:207-222. PMID: 26780584, PMCID: PMC4790729.

Taquet M, Scherrer B, Boumal N, Peters JM, Macq B, Warfield SK. Improved fidelity of brain microstructure mapping from single-shell diffusion MRI. Med Image Anal. Dec 2015;26(1):268- 286. PMID: 26529580, PMCID: PMC4679640.

Sahin M, Sur M. Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science. Nov 20 2015;350(6263). PMID: 26472761, PMCID: PMC4739545.

He X, Thacker S, Romigh T, Yu Q, Frazier TW Jr, Eng C. Cytoplasm-predominant Pten associates with increased region-specific brain tyrosine hydroxylase and dopamine D2 receptors in mouse model with autistic traits. Mol Autism. 2015 Nov 17;6:63. doi: 10.1186/s13229-015-0056-6. eCollection 2015.

Tyburczy ME, Dies KA, Glass J, Camposano S, Chekaluk Y, Thorner AR, Lin L, Krueger D, Franz DN, Thiele EA, Sahin M, Kwiatkowski DJ. Mosaic and Intronic Mutations in TSC1/TSC2 Explain the Majority of TSC Patients with No Mutation Identified by Conventional Testing. PLoS Genet. 2015 Nov 5;11(11):e1005637. doi: 10.1371/journal.pgen.1005637. eCollection 2015 Nov.

Frazier TW, Youngstrom EA, Hardan AY, Georgiades S, Constantino JN, Eng C. Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families. Mol Autism. 2015 Oct 27;6:58. doi: 10.1186/s13229-015-0050-z. eCollection 2015.

Tilot AK, Frazier TW 2nd, Eng C. Balancing Proliferation and Connectivity in PTEN-associated Autism Spectrum Disorder. Neurotherapeutics. 2015 Jul;12(3):609-19. doi: 10.1007/s13311-015-0356-8. PMID: 25916396; PMCID: PMC4489960.

Neul JL, Sahin M. Therapeutic Advances in Autism and Other Neurodevelopmental Disorders. Neurotherapeutics. Jul 2015;12(3):519-520. PMID: 26076992, PMCID: PMC4489958.

Davis PE, Peters JM, Krueger DA, Sahin M. Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism. Neurotherapeutics. Jul 2015;12(3):572-583. PMID: 25986747, PMCID: PMC4489948.

Baumer FM, Song JW, Mitchell PD, Pienaar R, Sahin M, Grant PE, Takahashi E. Longitudinal changes in diffusion properties in white matter pathways of children with tuberous sclerosis complex. Pediatr Neurol. Jun 2015;52(6):615-623. PMID: 25817702, PMCID: PMC4442035.

Ebrahimi-Fakhari D, Sahin M. Autism and the synapse: emerging mechanisms and mechanism-based therapies. Curr Opin Neurol. Apr 2015;28(2):91-102. PMID: 25695134.

Sundberg M, Sahin M. Cerebellar Development and Autism Spectrum Disorder in Tuberous Sclerosis Complex. J Child Neurol. Aug 24 2015. PMID: 26303409, PMCID: PMC4644486.

Hussain SA, Kwong G, Millichap JJ, Mytinger JR, Ryan N, Matsumoto JH, Wu JY, Lerner JT, Sankar R. Hypsarrhythmia assessment exhibits poor interrater reliability: a threat to clinical trial validity. Epilepsia. 2015 Jan;56(1):77-81. doi: 10.1111/epi.12861. Epub 2014 Nov 10.

Lipton JO, Sahin M. The neurology of mTOR. Neuron. Oct 22 2014;84(2):275-291. PMID: 25374355, PMCID: PMC4223653.

The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.