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Early infantile epileptic encephalopathy 2(EIEE2)

MedGen UID:
1663579
Concept ID:
C4750718
Disease or Syndrome
Synonyms: EIEE2; INFANTILE SPASM SYNDROME, X-LINKED 2
Modes of inheritance:
X-linked dominant inheritance
MedGen UID:
376232
Concept ID:
C1847879
Finding
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for dominant traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked dominant disorders tend to manifest very severely in affected males. The severity of manifestation in females may depend on the degree of skewed X inactivation.
X-linked dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: CDKL5 (cyclin-dependent kinase-like 5) deficiency (773230003); CDKL5 deficiency disorder (773230003); Cyclin-dependent kinase-like 5 deficiency (773230003); CDKL5-related epileptic encephalopathy (773230003)
 
Gene (location): CDKL5 (Xp22.13)
OMIM®: 300672
Orphanet: ORPHA505652

Definition

Early infantile epileptic encephalopathy-2 is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in mental retardation and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but EIEE2 is considered to be a distinct entity (summary by Fehr et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350). [from OMIM]

Additional description

From GHR
CDKL5 deficiency disorder is characterized by seizures that begin in infancy, followed by significant delays in many aspects of development.Seizures in CDKL5 deficiency disorder usually begin within the first 3 months of life, and can appear as early as the first week after birth. The types of seizures change with age, and may follow a predictable pattern. The most common types are generalized tonic-clonic seizures, which involve a loss of consciousness, muscle rigidity, and convulsions; tonic seizures, which are characterized by abnormal muscle contractions; and epileptic spasms, which involve short episodes of muscle jerks. Seizures occur daily in most people with CDKL5 deficiency disorder, although they can have periods when they are seizure-free. Seizures in CDKL5 deficiency disorder are typically resistant to treatment.Development is impaired in children with CDKL5 deficiency disorder. Most have severe intellectual disability and little or no speech. The development of gross motor skills, such as sitting, standing, and walking, is delayed or not achieved. About one-third of affected individuals are able to walk independently. Fine motor skills, such as picking up small objects with the fingers, are also impaired; about half of affected individuals have purposeful use of their hands. Most people with this condition have vision problems (cortical visual impairment).Other common features of CDKL5 deficiency disorder include repetitive hand movements (stereotypies), such as clapping, hand licking, and hand sucking; teeth grinding (bruxism); disrupted sleep; feeding difficulties; and gastrointestinal problems including constipation and backflow of acidic stomach contents into the esophagus (gastroesophageal reflux). Some affected individuals have episodes of irregular breathing. Distinctive facial features in some people with CDKL5 deficiency disorder include a high and broad forehead, large and deep-set eyes, a well-defined space between the nose and upper lip (philtrum), full lips, widely spaced teeth, and a high roof of the mouth (palate). Other physical differences can also occur, such as an unusually small head size (microcephaly), side-to-side curvature of the spine (scoliosis), and tapered fingers.CDKL5 deficiency disorder was previously classified as an atypical form of Rett syndrome. These conditions have common features, including seizures, intellectual disability, and other problems with development. However, the signs and symptoms associated with CDKL5 deficiency disorder and its genetic cause are distinct from those of Rett syndrome, and CDKL5 deficiency disorder is now considered a separate condition.  https://ghr.nlm.nih.gov/condition/cdkl5-deficiency-disorder

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVEarly infantile epileptic encephalopathy 2

Recent clinical studies

Etiology

Rapaccini V, Esposito S, Strinati F, Allegretti M, Manfroi E, Miconi F, Pitzianti M, Prontera P, Principi N, Pasini A
Int J Mol Sci 2018 Jul 6;19(7) doi: 10.3390/ijms19071976. PMID: 29986434Free PMC Article
Radaelli G, de Souza Santos F, Borelli WV, Pisani L, Nunes ML, Scorza FA, da Costa JC
Epilepsy Behav 2018 Aug;85:32-36. Epub 2018 Jun 13 doi: 10.1016/j.yebeh.2018.05.015. PMID: 29906699
Zaman T, Helbig I, Božović IB, DeBrosse SD, Bergqvist AC, Wallis K, Medne L, Maver A, Peterlin B, Helbig KL, Zhang X, Goldberg EM
Ann Neurol 2018 Apr;83(4):703-717. Epub 2018 Mar 30 doi: 10.1002/ana.25188. PMID: 29466837Free PMC Article
Arafat A, Jing P, Ma Y, Pu M, Nan G, Fang H, Chen C, Fei Y
Sci Rep 2017 Apr 7;7:46227. doi: 10.1038/srep46227. PMID: 28387369Free PMC Article
Malik SI, Galliani CA, Hernandez AW, Donahue DJ
J Child Neurol 2013 Dec;28(12):1607-17. Epub 2012 Nov 8 doi: 10.1177/0883073812464395. PMID: 23143728

Diagnosis

Chen DY, Chowdhury S, Farnaes L, Friedman JR, Honold J, Dimmock DP, Gold OBOTRIJJ
Pediatr Neurol 2018 Sep;86:69-70. Epub 2018 Jul 10 doi: 10.1016/j.pediatrneurol.2018.06.002. PMID: 30107960Free PMC Article
Stowe RC, Sun Q, Elsea SH, Scaglia F
Am J Med Genet A 2018 May;176(5):1184-1189. doi: 10.1002/ajmg.a.38654. PMID: 29681092
Arafat A, Jing P, Ma Y, Pu M, Nan G, Fang H, Chen C, Fei Y
Sci Rep 2017 Apr 7;7:46227. doi: 10.1038/srep46227. PMID: 28387369Free PMC Article
Babkina N, Deignan JL, Lee H, Vilain E, Sankar R, Giurgea I, Mowat D, Graham JM Jr
Eur J Med Genet 2016 Feb;59(2):70-4. Epub 2015 Dec 22 doi: 10.1016/j.ejmg.2015.12.006. PMID: 26721324
Matsumoto H, Zaha K, Nakamura Y, Hayashi S, Inazawa J, Nonoyama S
Pediatr Neurol 2014 Jul;51(1):170-5. Epub 2014 Apr 4 doi: 10.1016/j.pediatrneurol.2014.03.013. PMID: 24938147

Therapy

Zhong M, Liao S, Li T, Wu P, Wang Y, Wu F, Li X, Hong S, Yan L, Jiang L
Medicine (Baltimore) 2019 Nov;98(44):e17749. doi: 10.1097/MD.0000000000017749. PMID: 31689829
Schwarz N, Uysal B, Rosa F, Löffler H, Mau-Holzmann UA, Liebau S, Lerche H
Stem Cell Res 2018 Dec;33:6-9. Epub 2018 Aug 31 doi: 10.1016/j.scr.2018.08.019. PMID: 30292882
Radaelli G, de Souza Santos F, Borelli WV, Pisani L, Nunes ML, Scorza FA, da Costa JC
Epilepsy Behav 2018 Aug;85:32-36. Epub 2018 Jun 13 doi: 10.1016/j.yebeh.2018.05.015. PMID: 29906699
Dilena R, Striano P, Gennaro E, Bassi L, Olivotto S, Tadini L, Mosca F, Barbieri S, Zara F, Fumagalli M
Brain Dev 2017 Apr;39(4):345-348. Epub 2016 Nov 19 doi: 10.1016/j.braindev.2016.10.015. PMID: 27876397
Komaki H, Sugai K, Sasaki M, Hashimoto T, Arai N, Takada E, Maehara T, Shimizu H
Epilepsia 1999 Mar;40(3):365-9. doi: 10.1111/j.1528-1157.1999.tb00719.x. PMID: 10080520

Prognosis

Radaelli G, de Souza Santos F, Borelli WV, Pisani L, Nunes ML, Scorza FA, da Costa JC
Epilepsy Behav 2018 Aug;85:32-36. Epub 2018 Jun 13 doi: 10.1016/j.yebeh.2018.05.015. PMID: 29906699
Shbarou R, Mikati MA
Semin Pediatr Neurol 2016 May;23(2):134-42. Epub 2016 Jun 2 doi: 10.1016/j.spen.2016.06.002. PMID: 27544470
Malik SI, Galliani CA, Hernandez AW, Donahue DJ
J Child Neurol 2013 Dec;28(12):1607-17. Epub 2012 Nov 8 doi: 10.1177/0883073812464395. PMID: 23143728
Hino-Fukuyo N, Haginoya K, Iinuma K, Uematsu M, Tsuchiya S
Epilepsy Res 2009 Dec;87(2-3):299-301. Epub 2009 Oct 13 doi: 10.1016/j.eplepsyres.2009.09.012. PMID: 19828294
Komaki H, Sugai K, Maehara T, Shimizu H
Brain Dev 2001 Nov;23(7):727-31. doi: 10.1016/s0387-7604(01)00287-x. PMID: 11701286

Clinical prediction guides

Zaman T, Helbig I, Božović IB, DeBrosse SD, Bergqvist AC, Wallis K, Medne L, Maver A, Peterlin B, Helbig KL, Zhang X, Goldberg EM
Ann Neurol 2018 Apr;83(4):703-717. Epub 2018 Mar 30 doi: 10.1002/ana.25188. PMID: 29466837Free PMC Article
Lopez-Santiago LF, Yuan Y, Wagnon JL, Hull JM, Frasier CR, O'Malley HA, Meisler MH, Isom LL
Proc Natl Acad Sci U S A 2017 Feb 28;114(9):2383-2388. Epub 2017 Feb 13 doi: 10.1073/pnas.1616821114. PMID: 28193882Free PMC Article
Devaux J, Abidi A, Roubertie A, Molinari F, Becq H, Lacoste C, Villard L, Milh M, Aniksztejn L
Epilepsia 2016 May;57(5):e87-93. Epub 2016 Mar 31 doi: 10.1111/epi.13366. PMID: 27030113
Kato M, Saitoh S, Kamei A, Shiraishi H, Ueda Y, Akasaka M, Tohyama J, Akasaka N, Hayasaka K
Am J Hum Genet 2007 Aug;81(2):361-6. Epub 2007 Jun 11 doi: 10.1086/518903. PMID: 17668384Free PMC Article
Yamatogi Y, Ohtahara S
Brain Dev 2002 Jan;24(1):13-23. doi: 10.1016/s0387-7604(01)00392-8. PMID: 11751020

Recent systematic reviews

Radaelli G, de Souza Santos F, Borelli WV, Pisani L, Nunes ML, Scorza FA, da Costa JC
Epilepsy Behav 2018 Aug;85:32-36. Epub 2018 Jun 13 doi: 10.1016/j.yebeh.2018.05.015. PMID: 29906699

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