Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR.
AKT3
MTOR
PIK3CA
PIK3R2
megalencephaly
Journal
American journal of medical genetics. Part C, Seminars in medical genetics
ISSN: 1552-4876
Titre abrégé: Am J Med Genet C Semin Med Genet
Pays: United States
ID NLM: 101235745
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
13
05
2019
revised:
15
07
2019
accepted:
16
07
2019
pubmed:
24
8
2019
medline:
6
5
2020
entrez:
24
8
2019
Statut:
ppublish
Résumé
Megalencephaly (MEG) is a developmental abnormality of brain growth characterized by early onset, often progressive, brain overgrowth. Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K-AKT-MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype-phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and/or autism spectrum disorder; moderately activating variants (that are typically high-level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low-level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K-AKT-MTOR pathway inhibitors.
Identifiants
pubmed: 31441589
doi: 10.1002/ajmg.c.31736
doi:
Substances chimiques
MTOR protein, human
EC 2.7.1.1
AKT3 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
582-590Subventions
Organisme : NINDS NIH HHS
ID : R01 NS092772
Pays : United States
Organisme : NINDS NIH HHS
ID : K08NS092898
Pays : United States
Informations de copyright
© 2019 Wiley Periodicals, Inc.
Références
Alcantara, D., Timms, A. E., Gripp, K., Baker, L., Park, K., Collins, S., … Mirzaa, G. M. (2017). Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly. Brain, 140(10), 2610-2622.
Assogba, K., Ferlazzo, E., Striano, P., Calarese, T., Villeneuve, N., Ivanov, I., … Genton, P. (2010). Heterogeneous seizure manifestations in Hypomelanosis of Ito: Report of four new cases and review of the literature. Neurological Sciences, 31(1), 9-16.
Auriemma, A., Agostinis, C., Bianchi, P., Bellan, C., Salvoni, L., Manara, O., & Colombo, A. (2000). Hemimegalencephaly in hypomelanosis of Ito: Early sonographic pattern and peculiar MR findings in a newborn. European Journal of Ultrasound, 12(1), 61-67.
Battistella, P. A., Peserico, A., Bertoli, P., Drigo, P., Laverda, A. M., & Casara, G. L. (1990). Hypomelanosis of Ito and hemimegalencephaly. Child's Nervous System, 6(7), 421-423.
Blumcke, I., Thom, M., Aronica, E., Armstrong, D. D., Vinters, H. V., Palmini, A., … Spreafico, R. (2011). The clinicopathologic spectrum of focal cortical dysplasias: A consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia, 52(1), 158-174.
Chapman, K., & Cardenas, J. F. (2008). Hemimegalencephaly in a patient with a neurocutaneous syndrome. Seminars in Pediatric Neurology, 15(4), 190-193.
Clayton-Smith, J., Kerr, B., Brunner, H., Tranebjaerg, L., Magee, A., Hennekam, R. C., … Donnai, D. (1997). Macrocephaly with cutis marmorata, haemangioma and syndactyly-A distinctive overgrowth syndrome. Clinical Dysmorphology, 6(4), 291-302.
Cohen, M. M., Jr. (1990). Bannayan-Riley-Ruvalcaba syndrome: Renaming three formerly recognized syndromes as one etiologic entity. American Journal of Medical Genetics, 35(2), 291-292.
DeMyer, W. (1972). Megalencephaly in children. Clinical syndromes, genetic patterns, and differential diagnosis from other causes of megalocephaly. Neurology, 22(6), 634-643.
DeMyer, W. (1986). Megalencephaly: Types, clinical syndromes, and management. Pediatric Neurology, 2(6), 321-328.
Fruman, D. A., Chiu, H., Hopkins, B. D., Bagrodia, S., Cantley, L. C., & Abraham, R. T. (2017). The PI3K pathway in human disease. Cell, 170(4), 605-635.
Gucev, Z. S., Tasic, V., Jancevska, A., Konstantinova, M. K., Pop-Jordanova, N., Trajkovski, Z., & Biesecker, L. G. (2008). Congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE) syndrome: CNS malformations and seizures may be a component of this disorder. American Journal of Medical Genetics, 146A(20), 2688-2690.
Fletcher, H. M. (1900). A case of megalencephaly. Transactions of the Pathological Society, 51, 230-232.
Janku, F., Yap, T. A., & Meric-Bernstam, F. (2018). Targeting the PI3K pathway in cancer: Are we making headway? Nature Reviews. Clinical Oncology, 15(5), 273-291.
Jansen, L. A., Mirzaa, G. M., Ishak, G. E., O'Roak, B. J., Hiatt, J. B., Roden, W. H., … Dobyns, W. B. (2015). PI3K/AKT pathway mutations cause a spectrum of brain malformations from megalencephaly to focal cortical dysplasia. Brain, 138(Pt 6), 1613-1628.
Laurence, K. M. (1964). A case of unilateral megalencephaly. Developmental Medicine and Child Neurology, 6, 585-590.
Liaw, D., Marsh, D. J., Li, J., Dahia, P. L., Wang, S. I., Zheng, Z., … Parsons, R. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genetics, 16(1), 64-67.
Malherbe, V., Pariente, D., Tardieu, M., Lacroix, C., Venencie, P. Y., Hibon, D., … Landrieu, P. (1993). Central nervous system lesions in hypomelanosis of Ito: An MRI and pathological study. Journal of Neurology, 240(5), 302-304.
Manjila, S., Miller, B. R., Goodman, A., Bahuleyan, B., Basha, M., Munyon, C., … Miller, J. P. (2014). Pharmacoresistant epilepsy in hypomelanosis of Ito: Palliative surgical treatment with modified anatomic posterior quadrantic resection. Clinical Neurology and Neurosurgery, 123, 15-17.
Marsh, D. J., Dahia, P. L., Zheng, Z., Liaw, D., Parsons, R., Gorlin, R. J., & Eng, C. (1997). Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nature Genetics, 16(4), 333-334.
Mirzaa, G., Dodge, N. N., Glass, I., Day, C., Gripp, K., Nicholson, L., … Dobyns, W. B. (2004). Megalencephaly and perisylvian polymicrogyria with postaxial polydactyly and hydrocephalus: A rare brain malformation syndrome associated with mental retardation and seizures. Neuropediatrics, 35(6), 353-359.
Mirzaa, G., Timms, A. E., Conti, V., Boyle, E. A., Girisha, K. M., Martin, B., … Dobyns, W. B. (2016a). PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight, 1(9), e87623.
Mirzaa, G. M., Campbell, C. D., Solovieff, N., Goold, C., Jansen, L. A., Menon, S., … Dobyns, W. B. (2016b). Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurology, 73(7), 836-845.
Mirzaa, G. M., Conti, V., Timms, A. E., Smyser, C. D., Ahmed, S., Carter, M., … Guerrini, R. (2015). Characterisation of mutations of the phosphoinositide-3-kinase regulatory subunit, PIK3R2, in perisylvian polymicrogyria: A next-generation sequencing study. Lancet Neurology, 14(12), 1182-1195.
Mirzaa, G. M., Conway, R. L., Gripp, K. W., Lerman-Sagie, T., Siegel, D. H., deVries, L. S., … Dobyns, W. B. (2012). Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: Two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. American Journal of Medical Genetics. Part A, 158A(2), 269-291.
Mirzaa, G. M., Parry, D. A., Fry, A. E., Giamanco, K. A., Schwartzentruber, J., Vanstone, M., … Sheridan, E. G. (2014). De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome. Nature Genetics, 46(5), 510-515.
Moore, C. A., Toriello, H. V., Abuelo, D. N., Bull, M. J., Curry, C. J., Hall, B. D., … Dobyns, W. B. (1997). Macrocephaly-cutis marmorata telangiectatica congenita: A distinct disorder with developmental delay and connective tissue abnormalities. American Journal of Medical Genetics, 70(1), 67-73.
Nakamura, K., Kato, M., Tohyama, J., Shiohama, T., Hayasaka, K., Nishiyama, K., … Saitsu, H. (2013). AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. Clinical Genetics, 85(4), 396-398.
Okanari, K., Miyahara, H., Itoh, M., Takahashi, A., Aizaki, K., Nakagawa, E., … Izumi, T. (2014). Hemimegalencephaly in a patient with coexisting trisomy 21 and hypomelanosis of Ito. Journal of Child Neurology, 29(3), 415-420.
Placantonakis, D. G., Ney, G., Edgar, M., Souweidane, M., Hosain, S., & Schwartz, T. H. (2005). Neurosurgical management of medically intractable epilepsy associated with hypomelanosis of Ito. Epilepsia, 46(2), 329-331.
Riviere, J. B., Mirzaa, G. M., O'Roak, B. J., Beddaoui, M., Alcantara, D., Conway, R. L., … Dobyns, W. B. (2012). De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nature Genetics, 44(8), 934-940.
Ross, D. L., Liwnicz, B. H., Chun, R. W. M., & Gilbert, E. (1982). Hypomelanosis of Ito (incontinentia pigmenti achromians)-A clinicopathologic study: Macrocephaly and gray matter heterotopias. Neurology, 32, 1013-1016.
Rutland, B. M., Edgar, M. A., & Horenstein, M. G. (2006). Hypomelanosis of Ito associated with precocious puberty. Pediatric Neurology, 34(1), 51-54.
Scott, A., Micallef, C., Hale, S. L., & Watts, P. (2008). Cortical visual impairment in hypomelanosis of Ito. Journal of Pediatric Ophthalmology and Strabismus, 45(4), 240-241.
Sharma, S., Sankhyan, N., Kabra, M., & Kumar, A. (2009). Hypomelanosis of Ito with hemimegalencephaly. Dermatology Online Journal, 15(11), 12.
Sims, J. (1835). On hypertrophy and atrophy of the brain. Medico-Chirurgical Transactions, 19, 315-380.
Stevenson, R. E., Schroer, R. J., Skinner, C., Fender, D., & Simensen, R. J. (1997). Autism and macrocephaly. Lancet, 349(9067), 1744-1745.
Tagawa, T., Otani, K., Futagi, Y., Wakayama, A., Morimoto, K., & Morita, Y. (1994). Serial IMP-SPECT and EEG studies in an infant with hemimegalencephaly. Brain & Development, 16(6), 475-479.
Terrone, G., Voisin, N., Abdullah Alfaiz, A., Cappuccio, G., Vitiello, G., Guex, N., … Reymond, A. (2016). De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia. European Journal of Human Genetics, 24(9), 1359-1362.
Venot, Q., Blanc, T., Rabia, S. H., Berteloot, L., Ladraa, S., Duong, J. P., … Canaud, G. (2018). Targeted therapy in patients with PIK3CA-related overgrowth syndrome. Nature, 558(7711), 540-546.
Wilson, S. A. (1934). Megalencephaly. Journal of Neurology and Psychopathology, 14(55), 193-216.