SEARCH WITHIN CONTENT
Citation Information : Journal of Epileptology. Volume 25, Issue 1-2, Pages 47-51, DOI: https://doi.org/10.1515/joepi-2017-0002
License : (CC BY 4.0)
Received Date : 04-July-2017 / Accepted: 20-July-2017 / Published Online: 08-August-2017
Introduction. There are some genetic disorders with combination of mental retardation, epilepsy and autism in which the abnormal mammalian Target of Rapamycin (m-TOR) signaling is implicated. The most important of them is tuberous sclerosis complex (TSC), but the disturbances of the m-TOR pathway can also be detected in Rett syndrome (RS), Fragile X syndrome and Down syndrome. We describe the rare case of co-occurrence of TSC and RS.
Case study. The female child was born at term by normal delivery after a non-complicated pregnancy. Family history was negative for epilepsy and mental retardation. The neonatal period was uneventful and psychomotor development was normal before the child became 1.5 years old. At the age of 18 months the girl developed hand-wringing stereotypes, facial hypotonia, ataxia and gait apraxia. She lost eye-to-eye contact and verbal contact with relatives, and became indifferent to the surrounding environment. When she was 2 years old, focal adversive seizures started which were readily controlled with carbamazepine. Cerebral cortical and subcortical tubers, cerebral white-matter radial migration lines and subependymal nodules on brain MRI together with hypomelanotic macules suggested the presence of TSC. Diagnosis was confirmed at age of 3 years by a heterozygous mutation c.5161-2A>G in TSC2 gene on chromosome 16p13. But the rude regression of psychomotor development and speech, autistic features alongside with characteristic hand-wringing stereotypes were unexplained until at age of 4.5 years RS was diagnosed by finding a heterozygous missense mutation in exon 4 of the MECP2 gene c.455C>T, resulting in a P152R substitution in the methyl-binding domain of the protein. At age of 5 the patient is not able to walk independently and has no expressive speech, she is autistic, has ataxia, limb rigidity, hyperreflexia, lack of purposeful hand movements, verbal and motor stereotypies.
Discussion. The presence of two mutations (one characteristic for TSC2 and one – characteristic for RS) significantly worsened the developmental and motor delay and autistic features in our patient. Dysregulation of m-TOR way is well established in TSC and recently described in RS, Down syndrome and Fragile X syndrome.
Cheadle J.P., Gill H., Fleming N., Maynard J., Kerr A., Leonard H. et al.: Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum. Mol. Genet., 2000, 9: 1119–1129.
Curatolo P., Bombardieri R., Jozwiak S.: Tuberous sclerosis. Lancet, 2008, 372: 657–668.
Davis P.E., Peters J.M., Krueger D.A., Sahin M.: Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism. Neurotherapeutics, 2015, 12: 572–583. doi: 10.1007/s13311- 015-0359-5.
Davydov E.V., Goode D.L., Sirota M., Cooper G.M., Sidow A., Batzoglou S.: Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput. Biol., 2010, 6: e1001025.
Della Sala G., Pizzorusso T.: Synaptic plasticity and signaling in Rett syndrome. Dev. Neurobiol., 2014, 74: 178–196.
Dolce A., Ben-Zeev B., Naidu S., Kossoff E.H.: Rett syndrome and epilepsy: an update for child neurologists. Pediatr. Neurol., 2013, 48: 337–345.
Gadalla K.K., Bailey M.E., Cobb S.R.: MeCP2 and Rett syndrome: reversibility and potential avenues for therapy. Biochem. J., 2011, 439: 1–14.
Khwaja O.S., Sahin M.: Translational research: Rett syndrome and Tuberous Sclerosis Complex. Curr. Opin. Pediatr., 2011, 23: 633–639.
Kothare S.V., Singh K., Chalifoux J.R., Staley B.A., Weiner H.L., Menzer K.: Severity of manifestations in tuberous sclerosis complex in relation to genotype. Epilepsia, 2014, 55: 1025– 1029. doi: 10.1111/epi.12680.
Krueger D.A., Northrup H. on behalf of the International Tuberous Sclerosis Complex Consensus Group: Tuberous Sclerosis Complex Surveillance and Management: Recommendations of the 2012 International Tuberous Sclerosis. Pediatr. Neurol., 2013, 49: 255–265.
Neul J.L.: The relationship of Rett syndrome and MECP2 disorders to autism. Dialogues Clin. Neurosci., 2012, 14: 253–262.
Philippart M.: Rett syndrome associated with tuberous sclerosis in a male and in a female: evidence for arrested motor and mental development. Am. J. Med. Genet., 1993, 48: 229–230.
Ricciardi S., Boggio E.M., Grosso S., Lonetti G., Forlani G., Stefanelli G. et al.: Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum. Mol. Gen., 2011, 20: 1182–1196.
Roach E.S., Sparagana S.P.: Diagnosis of tuberous sclerosis complex. J. Child. Neurol., 2004, 19: 643–649.
Schwarz J.M., Cooper D.N., Schuelke M., Seelow D.: MutationTaster2: mutation prediction for the deep-sequencing age. Nat. Methods., 2014, 11: 361–362.
Sheen V., Valencia I.M., Torres A.R.: Atypical features in MECP2 P152R-associated Rett syndrome. Pediatr. Neurol., 2013, 49: 124–126.
Troca-Marín J.A., Casañas J.J., Benito I., Montesinos M.L.: The Akt-mTOR pathway in Down’s syndrome: the potential use of rapamycin/rapalogs for treating cognitive deficits. CNS Neurol. Disord. Drug Targets, 2014, 13: 34–40.