Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening

详细信息    查看全文

• 作者：Maria Marchese (1)
  Valerio Conti (2)
  Giulia Valvo (3)
  Francesca Moro (1)
  Filippo Muratori (4)
  Raffaella Tancredi (4)
  Filippo M Santorelli (1)
  Renzo Guerrini (2) (3)
  Federico Sicca (3)
  
• 关键词：Autism spectrum disorders ; Autism ; epilepsy phenotype ; Macrocephaly ; GLIALCAM ; PTEN
• 刊名：BMC Medical Genetics
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：15
• 期：1
• 全文大小：365 KB
• 参考文献：1. Blake J, Hoyme HE, Crotwell PL: A brief history of autism, the autism/vaccine hypothesis and a review of the genetic basis of autism spectrum disorders. / S D Med 2013, Spec no:58-5.
  2. Tuchman R, Cuccaro M, Alessandri M: Autism and epilepsy: historical perspective. / Brain Dev 2010, 32:709-18. CrossRef
  3. Freitag CM: The genetics of autistic disorders and its clinical relevance: a review of the literature. / Mol Psychiatry 2007, 12:2-2. CrossRef
  4. Abrahams BS, Geschwind DH: Advances in autism genetics: on the threshold of a new neurobiology. / Nat Rev Genet 2008, 9:341-55. CrossRef
  5. Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P: Sibling recurrence and the genetic epidemiology of autism. / Am J Psychiatry 2010, 167:1349-356. CrossRef
  6. Pal DK, Pong AW, Chung WK: Genetic evaluation and counseling for epilepsy. / Nat Rev Neurol 2010, 6:445-53. CrossRef
  7. Steiner CE, Guerreiro MM, Marques-de-Faria AP: On macrocephaly, epilepsy, autism, specific facial features, and mental retardation. / Am J Med Genet 2003, 120A:564-65. CrossRef
  8. Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G, Deutsch CK, Dunn M, Estes A, Tager-Flusberg H, Folstein S, Hepburn S, Hyman S, McMahon W, Minshew N, Munson J, Osann K, Ozonoff S, Rodier P, Rogers S, Sigman M, Spence MA, Stodgell CJ, Volkmaret F: Head circumference and height in autism: a study by the collaborative program of excellence in autism. / Am J Med Genet 2006, 140A:2257-274. CrossRef
  9. Barnard-Brak L, Sulak T, Hatz JK: Macrocephaly in children with autism spectrum disorders. / Pediatr Neurol 2011, 44:97-00. CrossRef
  10. Chawarska K, Campbell D, Chen L, Shic F, Klin A, Chang J: Early generalized overgrowth in boys with autism. / Arch Gen Psychiatry 2011, 68:1021-031. CrossRef
  11. Courchesne E, Carper R, Akshoomoff N: Evidence of brain overgrowth in the first year of life in autism. / JAMA 2003, 290:337-44. CrossRef
  12. Dementieva YA, Vance DD, Donnelly SL, Elston LA, Wolpert CM, Ravan SA, DeLong GR, Abramson RK, Wright HH, Cuccaro ML: Accelerated head growth in early development of individuals with autism. / Pediatr Neurol 2005, 32:102-08. CrossRef
  13. Webb SJ, Nalty T, Munson J, Brock C, Abbott R, Dawson G: Rate of head circumference growth as a function of autism diagnosis and history of autistic regression. / J Child Neurol 2007, 22:1182-190. CrossRef
  14. Muratori F, Calderoni S, Apicella F, Filippi T, Santocchi E, Calugi S, Cosenza A, Tancredi R, Narzisi A: Tracing back to the onset of abnormal head circumference growth in Italian children with autism spectrum disorder. / Res Autism Spectrum Disord 2012, 6:442-49. CrossRef
  15. Shen MD, Nordahl CW, Young GS, Wootton-Gorges SL, Lee A, Liston SE, Harrington KR, Ozonoff S, Amaral DG: Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder. / Brain 2013, 136:2825-835. CrossRef
  16. Valvo G, Baldini S, Brachini F, Apicella F, Cosenza A, Ferrari AR, Guerrini R, Muratori F, Romano MF, Santorelli FM, Tancredi R, Sicca F: Somatic overgrowth predisposes to seizures in autism spectrum disorders. / PLoS One 2013, 8:e75015. CrossRef
  17. Buxbaum JD, Cai G, Chaste P, Nygren G, Goldsmith J, Reichert J, Anckarsater H, Rastam M, Smith CJ, Silverman JM, Hollander E, Leboyer M, Gillberg C, Verloes A, Betancur C: Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. / Am J Med Genet 2007, 144B:484-91. CrossRef
  18. McBride KL, Varga EA, Pastore MT, Prior TW, Manickam K, Atkin JF, Herman GE: Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. / Autism Res 2010, 3:137-41. CrossRef
  19. Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A: Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. / Am J Med Genet 2007, 143A:589-93. CrossRef
  20. Zhou J, Parada LF: PTEN signaling in autism spectrum disorders. / Curr Opin Neurobiol 2012, 22:873-79. CrossRef
  21. Klein S, Sharifi-Hannauer P, Martinez-Agosto JA: Macrocephaly as a clinical indicator of genetic subtypes in autism. / Autism Res 2013, 6:51-6. CrossRef
  22. López-Hernández T, Ridder MC, Montolio M, Capdevila-Nortes X, Polder E, Sirisi S, Duarri A, Schulte U, Fakler B, Nunes V, Scheper GC, Martínez A, Estévez R, van der Knaap MS: Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. / Am J Hum Genet 2011, 88:422-32. CrossRef
  23. van der Knaap MS, Lai V, K?hler W, Salih MA, Fonseca MJ, Benke TA, Wilson C, Jayakar P, Aine MR, Dom L, Lynch B, Kálmánchey R, Pietsch P, Errami A, Scheper GC: Megalencephalic leukoencephalopathy with cysts without MLC1 defect. / Ann Neurol 2010, 67:834-37.
  24. van der Knaap MS, Boor I, Estévez R: Megalencephalic leukoencephalopathy with subcortical cysts: chronic white matter oedema due to a defect in brain ion and water homoeostasis. / Lancet Neurol 2012, 11:973-85. CrossRef
  25. van der Knaap MS, Scheper GC: Megalencephalic leukoencephalopathy with subcortical cysts. In / GeneReviews. Edited by: Pagon RA, Bird TD, Dolan CR, Stephens K. Seattle: University of Washington; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1116/ (accessed Aug 23, 2012)
  26. Nellhaus G: Head circumference from birth to eighteen years. Practical composite international and interracial graphs. / Pediatrics 1968, 41:106-14.
  27. Rollins JD, Collins JS, Holden KRJ: United States head circumference growth reference charts: birth to 21?years. / Pediatr 2010, 156:907-13. CrossRef
  28. Favre-Kontula L, Rolland A, Bernasconi L, Karmirantzou M, Power C, Antonsson B, Boschert U: GlialCAM, an immunoglobulin-like cell adhesion molecule is expressed in glial cells of the central nervous system. / Glia 2008, 56:633-45. CrossRef
  29. López-Hernández T, Sirisi S, Capdevila-Nortes X, Montolio M, Fernández-Due?as V, Scheper GC, van der Knaap MS, Casquero P, Ciruela F, Ferrer I, Nunes V, Estévez R: Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts. / Hum Mol Genet 2011, 20:3266-277. CrossRef
  30. Jeworutzki E, López-Hernández T, Capdevila-Nortes X, Sirisi S, Bengtsson L, Montolio M, Zifarelli G, Arnedo T, Müller CS, Schulte U, Nunes V, Martínez A, Jentsch TJ, Gasull X, Pusch M, Estévez R: GlialCAM, a protein defective in a leukodystrophy, serves as a ClC-2 Cl(? channel auxiliary subunit. / Neuron 2012, 73:951-61. CrossRef
  31. Gründer S, Thiemann A, Pusch M, Jentsch TJ: Regions involved in the opening of CIC-2 chloride channel by voltage and cell volume. / Nature 1992, 360:759-62. CrossRef
  32. Thiemann A, Gründer S, Pusch M, Jentsch TJ: A chloride channel widely expressed in epithelial and non-epithelial cells. / Nature 1992, 356:57-0. CrossRef
  33. Blanz J, Schweizer M, Auberson M, Maier H, Muenscher A, Hübner CA, Jentsch TJ: Leukoencephalopathy upon disruption of the chloride channel ClC-2. / J Neurosci 2007, 27:6581-589. CrossRef
  34. Fava M, Ferroni S, Nobile M: Osmosensitivity of an inwardly rectifying chloride current revealed by whole-cell and perforated-patch recordings in cultured rat cortical astrocytes. / FEBS Lett 2001, 492:78-3. CrossRef
  35. Makara JK, Rappert A, Matthias K, Steinh?user C, Sp?t A, Kettenmann H: Astrocytes from mouse brain slices express ClC-2-mediated Cl- currents regulated during development and after injury. / Mol Cell Neurosci 2003, 23:521-30. CrossRef
  36. Sicca F, Imbrici P, D’Adamo MC, Moro F, Bonatti F, Brovedani P, Grottesi A, Guerrini R, Masi G, Santorelli FM, Pessia M: Autism with seizures and intellectual disability: possible causative role of gain-of-function of the inwardly-rectifying K-?channel Kir4.1. / Neurobiol Dis 2011, 43:239-47. CrossRef
  37. Brignone MS, Lanciotti A, Macioce P, Macchia G, Gaetani M, Aloisi F, Petrucci TC, Ambrosini E: The beta1 subunit of the Na, K-ATPase pump interacts with megalencephalic leucoencephalopathy with subcortical cysts protein 1 (MLC1) in brain astrocytes: new insights into MLC pathogenesis. / Hum Mol Genet 2011, 20:90-03. CrossRef
  38. Duarri A, Lopez de Heredia M, Capdevila-Nortes X, Ridder MC, Montolio M, López-Hernández T, Boor I, Lien CF, Hagemann T, Messing A, Gorecki DC, Scheper GC, Martínez A, Nunes V, van der Knaap MS, Estévez R: Knockdown of MLC1 in primary astrocytes causes cell vacuolation: a MLC disease cell model. / Neurobiol Dis 2011, 43:228-38. CrossRef
  39. Butler MG, Dasouki MJ, Zhou XP, Talebizadeh Z, Brown M, Takahashi TN, Miles JH, Wang CH, Stratton R, Pilarski R, Eng C: Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. / J Med Genet 2005, 42:318-21. CrossRef
  40. O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, Carvill G, Kumar A, Lee C, Ankenman K, Munson J, Hiatt JB, Turner EH, Levy R, O’Day DR, Krumm N, Coe BP, Martin BK, Borenstein E, Nickerson DA, Mefford HC, Doherty D, Akey JM, Bernier R, Eichler EE, Shendure J: Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. / Science 2012, 338:1619-622. CrossRef
  41. Li DM, Sun H: PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. / Proc Natl Acad Sci U S A 1998, 95:15406-5411. CrossRef
  42. Pezzolesi MG, Zbuk KM, Waite KA, Eng C: Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome. / Hum Mol Genet 2007, 16:1058-071. CrossRef
  43. Potter CJ, Pedraza LG, Huang H, Xu T: The tuberous sclerosis complex (TSC) pathway and mechanism of size control. / Biochem Soc Trans 2003, 31:584-86. CrossRef
  44. Rivière JB, Mirzaa GM, O’Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM, Worthylake T, Sullivan CT, Ward TR, Butler HE, Kramer NA, Albrecht B, Armour CM, Armstrong L, Caluseriu O, Cytrynbaum C, Drolet BA, Innes AM, Lauzon JL, Lin AE, Mancini GM, Meschino WS, Reggin JD, Saggar AK, Lerman-Sagie T, Uyanik G, / et al.: De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. / Nat Genet 2012, 44:934-40. CrossRef
  45. Mirzaa GM, Rivière JB, Dobyns WB: Megalencephaly syndromes and activating mutations in the PI3K-AKT pathway: MPPH and MCAP. / Am J Med Genet 2013, 163C:122-30. CrossRef
  46. Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, Li Y, Baker SJ, Parada LF: Pten regulates neuronal arborization and social interaction in mice. / Neuron 2006, 50:377-88. CrossRef
  47. The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2350/15/26/prepub
  
• 作者单位：Maria Marchese (1)
  Valerio Conti (2)
  Giulia Valvo (3)
  Francesca Moro (1)
  Filippo Muratori (4)
  Raffaella Tancredi (4)
  Filippo M Santorelli (1)
  Renzo Guerrini (2) (3)
  Federico Sicca (3)
  
  1. Molecular Medicine Unit, IRCCS Stella Maris Foundation, Viale del Tirreno 331, Pisa, Calambrone, 56128, Italy
  2. Child Neurology Unit, A. Meyer Pediatric Hospital, Viale Pieraccini 24, Florence, 50139, Italy
  3. Clinical Neurophysiology Laboratory, IRCCS Stella Maris Foundation, Viale del Tirreno 331, Pisa, Calambrone, 56128, Italy
  4. Developmental Psychiatry Unit, IRCCS Stella Maris Foundation, Viale del Tirreno 331, Pisa, Calambrone, 56128, Italy
  
• ISSN：1471-2350

文摘

Background With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes. Comorbidity of ASD with epilepsy (or paroxysmal EEG) has long been described and seems to have strong genetic background. Macrocephaly also represents a well-known endophenotype in subgroups of ASD individuals, which suggests pathogenic mechanisms accelerating brain growth in early development and predisposing to the disorder. We attempted to estimate the association of gene variants with neurodevelopmental disorders in patients with autism-epilepsy phenotype (AEP) and cranial overgrowth, analyzing two genes previously reported to be associated with autism and macrocephaly. Methods We analyzed the coding sequences and exon-intron boundaries of GLIALCAM, encoding an IgG-like cell adhesion protein, in 81 individuals with Autism Spectrum Disorders, either with or without comorbid epilepsy, paroxysmal EEG and/or macrocephaly, and the PTEN gene in the subsample with macrocephaly. Results Among 81 individuals with ASD, 31 had concurrent macrocephaly. Head circumference, moreover, was over the 99.7th percentile (“extreme-macrocephaly) in 6/31 (19%) patients. Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one case with “extreme-macrocephaly, autism, intellectual disability and seizures. Conclusions We did not find a clear association between GLIALCAM mutations and AEP-macrocephaly comorbidity. The identification of a novel frameshift variant of PTEN in a patient with “extreme-macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in the ASD-macrocephaly endophenotype. The concurrence of epilepsy in the same patient also suggests that PTEN, and the downstream signaling pathway, might deserve to be investigated in autism-epilepsy comorbidity. Working on clinical endophenotypes might be of help to address genetic studies and establish actual causative correlations in autism-epilepsy.