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Developmental and epileptic encephalopathy, 58(EIEE58; DEE58)

MedGen UID:
1646861
Concept ID:
C4693367
Disease or Syndrome
Synonym: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 58
 
Gene (location): NTRK2 (9q21.33)
 
Monarch Initiative: MONDO:0033367
OMIM®: 617830

Definition

Developmental and epileptic encephalopathy-58 (DEE58) is a severe neurodevelopmental disorder characterized by the onset of infantile spasms and refractory seizures in the first days or months of life. Affected individuals have global developmental delay with impaired intellectual development, usually with absent speech and inability to walk. Additional features include optic atrophy with poor or absent visual fixation, hypotonia, feeding difficulties, and spasticity (summary by Hamdan et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Clinical features

From HPO
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Spastic diplegia
MedGen UID:
44181
Concept ID:
C0023882
Disease or Syndrome
Spasticity (neuromuscular hypertonia) primarily in the muscles of the legs, hips, and pelvis.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Status epilepticus
MedGen UID:
11586
Concept ID:
C0038220
Disease or Syndrome
Status epilepticus is a type of prolonged seizure resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t1). It is a condition that can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.
Motor stereotypies
MedGen UID:
21318
Concept ID:
C0038271
Individual Behavior
Use of the same abnormal action in response to certain triggers or at random. They may be used as a way to regulate one's internal state but must otherwise have no apparent functional purpose.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Epileptic encephalopathy
MedGen UID:
452596
Concept ID:
C0543888
Disease or Syndrome
A condition in which epileptiform abnormalities are believed to contribute to the progressive disturbance in cerebral function. Epileptic encephalaopathy is characterized by (1) electrographic EEG paroxysmal activity that is often aggressive, (2) seizures that are usually multiform and intractable, (3) cognitive, behavioral and neurological deficits that may be relentless, and (4) sometimes early death.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
Delayed myelination
MedGen UID:
224820
Concept ID:
C1277241
Finding
Delayed myelination.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Rhythmic, involuntary oscillations of one or both eyes related to abnormality in fixation, conjugate gaze, or vestibular mechanisms.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Visual impairment
MedGen UID:
777085
Concept ID:
C3665347
Finding
Visual impairment (or vision impairment) is vision loss (of a person) to such a degree as to qualify as an additional support need through a significant limitation of visual capability resulting from either disease, trauma, or congenital or degenerative conditions that cannot be corrected by conventional means, such as refractive correction, medication, or surgery.

Professional guidelines

PubMed

Du X, Wang J, Li S, Ma Y, Wang T, Wu B, Zhou Y, Yu L, Wang Y
Genes (Basel) 2022 Aug 14;13(8) doi: 10.3390/genes13081447. PMID: 36011358Free PMC Article
Frank NA, Greuter L, Dill PE, Guzman R, Soleman J
Neurosurg Focus 2022 May;52(5):E4. doi: 10.3171/2022.2.FOCUS21788. PMID: 35535828
Poudel P, Kafle SP, Pokharel R
Epilepsia Open 2021 Mar;6(1):206-215. Epub 2021 Feb 8 doi: 10.1002/epi4.12470. PMID: 33681663Free PMC Article

Recent clinical studies

Etiology

Poke G, Stanley J, Scheffer IE, Sadleir LG
Neurology 2023 Mar 28;100(13):e1363-e1375. Epub 2022 Dec 29 doi: 10.1212/WNL.0000000000206758. PMID: 36581463Free PMC Article
Knupp KG, Scheffer IE, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, Guerrini R, Zuberi SM, Nabbout R, Riney K, Shore S, Agarwal A, Lock M, Farfel GM, Galer BS, Gammaitoni AR, Davis R, Gil-Nagel A
JAMA Neurol 2022 Jun 1;79(6):554-564. doi: 10.1001/jamaneurol.2022.0829. PMID: 35499850Free PMC Article
Roston A, Evans D, Gill H, McKinnon M, Isidor B, Cogné B, Mwenifumbo J, van Karnebeek C, An J, Jones SJM, Farrer M, Demos M, Connolly M, Gibson WT; CAUSES Study; EPGEN Study
J Med Genet 2021 Mar;58(3):196-204. Epub 2020 Jun 16 doi: 10.1136/jmedgenet-2019-106756. PMID: 32546566
Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM
Epilepsia 2017 Apr;58(4):512-521. Epub 2017 Mar 8 doi: 10.1111/epi.13709. PMID: 28276062Free PMC Article
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M
JAMA 2013 Apr 24;309(16):1696-703. doi: 10.1001/jama.2013.2270. PMID: 23613074Free PMC Article

Diagnosis

Poke G, Stanley J, Scheffer IE, Sadleir LG
Neurology 2023 Mar 28;100(13):e1363-e1375. Epub 2022 Dec 29 doi: 10.1212/WNL.0000000000206758. PMID: 36581463Free PMC Article
Knupp KG, Scheffer IE, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, Guerrini R, Zuberi SM, Nabbout R, Riney K, Shore S, Agarwal A, Lock M, Farfel GM, Galer BS, Gammaitoni AR, Davis R, Gil-Nagel A
JAMA Neurol 2022 Jun 1;79(6):554-564. doi: 10.1001/jamaneurol.2022.0829. PMID: 35499850Free PMC Article
Coursimault J, Guerrot AM, Morrow MM, Schramm C, Zamora FM, Shanmugham A, Liu S, Zou F, Bilan F, Le Guyader G, Bruel AL, Denommé-Pichon AS, Faivre L, Tran Mau-Them F, Tessarech M, Colin E, El Chehadeh S, Gérard B, Schaefer E, Cogne B, Isidor B, Nizon M, Doummar D, Valence S, Héron D, Keren B, Mignot C, Coutton C, Devillard F, Alaix AS, Amiel J, Colleaux L, Munnich A, Poirier K, Rio M, Rondeau S, Barcia G, Callewaert B, Dheedene A, Kumps C, Vergult S, Menten B, Chung WK, Hernan R, Larson A, Nori K, Stewart S, Wheless J, Kresge C, Pletcher BA, Caumes R, Smol T, Sigaudy S, Coubes C, Helm M, Smith R, Morrison J, Wheeler PG, Kritzer A, Jouret G, Afenjar A, Deleuze JF, Olaso R, Boland A, Poitou C, Frebourg T, Houdayer C, Saugier-Veber P, Nicolas G, Lecoquierre F
Hum Genet 2022 Jan;141(1):65-80. Epub 2021 Nov 8 doi: 10.1007/s00439-021-02383-z. PMID: 34748075
Takata A, Nakashima M, Saitsu H, Mizuguchi T, Mitsuhashi S, Takahashi Y, Okamoto N, Osaka H, Nakamura K, Tohyama J, Haginoya K, Takeshita S, Kuki I, Okanishi T, Goto T, Sasaki M, Sakai Y, Miyake N, Miyatake S, Tsuchida N, Iwama K, Minase G, Sekiguchi F, Fujita A, Imagawa E, Koshimizu E, Uchiyama Y, Hamanaka K, Ohba C, Itai T, Aoi H, Saida K, Sakaguchi T, Den K, Takahashi R, Ikeda H, Yamaguchi T, Tsukamoto K, Yoshitomi S, Oboshi T, Imai K, Kimizu T, Kobayashi Y, Kubota M, Kashii H, Baba S, Iai M, Kira R, Hara M, Ohta M, Miyata Y, Miyata R, Takanashi JI, Matsui J, Yokochi K, Shimono M, Amamoto M, Takayama R, Hirabayashi S, Aiba K, Matsumoto H, Nabatame S, Shiihara T, Kato M, Matsumoto N
Nat Commun 2019 Jun 7;10(1):2506. doi: 10.1038/s41467-019-10482-9. PMID: 31175295Free PMC Article
Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, Hirsch E, Jain S, Mathern GW, Moshé SL, Nordli DR, Perucca E, Tomson T, Wiebe S, Zhang YH, Zuberi SM
Epilepsia 2017 Apr;58(4):512-521. Epub 2017 Mar 8 doi: 10.1111/epi.13709. PMID: 28276062Free PMC Article

Therapy

Juliá-Palacios N, Olivella M, Sigatullina Bondarenko M, Ibáñez-Micó S, Muñoz-Cabello B, Alonso-Luengo O, Soto-Insuga V, García-Navas D, Cuesta-Herraiz L, Andreo-Lillo P, Aguilera-Albesa S, Hedrera-Fernández A, González Alguacil E, Sánchez-Carpintero R, Martín Del Valle F, Jiménez González E, Cean Cabrera L, Medina-Rivera I, Perez-Ordoñez M, Colomé R, Lopez L, Engracia Cazorla M, Fornaguera M, Ormazabal A, Alonso-Colmenero I, Illescas KS, Balsells-Mejía S, Mari-Vico R, Duffo Viñas M, Cappuccio G, Terrone G, Romano R, Manti F, Mastrangelo M, Alfonsi C, de Siqueira Barros B, Nizon M, Gjerulfsen CE, Muro VL, Karall D, Zeiner F, Masnada S, Peterlongo I, Oyarzábal A, Santos-Gómez A, Altafaj X, García-Cazorla Á
Brain 2024 May 3;147(5):1653-1666. doi: 10.1093/brain/awae041. PMID: 38380699
Schoeler NE, Marston L, Lyons L, Halsall S, Jain R, Titre-Johnson S, Balogun M, Heales SJR, Eaton S, Orford M, Neal E, Reilly C, Eltze C, Stephen E, Mallick AA, O'Callaghan F, Agrawal S, Parker A, Kirkpatrick M, Brunklaus A, McLellan A, McCullagh H, Samanta R, Kneen R, Tan HJ, Devlin A, Prasad M, Rattihalli R, Basu H, Desurkar A, Williams R, Fallon P, Nazareth I, Freemantle N, Cross JH; KIWE study group
Lancet Neurol 2023 Dec;22(12):1113-1124. doi: 10.1016/S1474-4422(23)00370-8. PMID: 37977712
Räikkönen K, Gissler M, Tapiainen T, Kajantie E
JAMA Netw Open 2022 Aug 1;5(8):e2228518. doi: 10.1001/jamanetworkopen.2022.28518. PMID: 36001315Free PMC Article
Knupp KG, Scheffer IE, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, Guerrini R, Zuberi SM, Nabbout R, Riney K, Shore S, Agarwal A, Lock M, Farfel GM, Galer BS, Gammaitoni AR, Davis R, Gil-Nagel A
JAMA Neurol 2022 Jun 1;79(6):554-564. doi: 10.1001/jamaneurol.2022.0829. PMID: 35499850Free PMC Article
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M
JAMA 2013 Apr 24;309(16):1696-703. doi: 10.1001/jama.2013.2270. PMID: 23613074Free PMC Article

Prognosis

Schoeler NE, Marston L, Lyons L, Halsall S, Jain R, Titre-Johnson S, Balogun M, Heales SJR, Eaton S, Orford M, Neal E, Reilly C, Eltze C, Stephen E, Mallick AA, O'Callaghan F, Agrawal S, Parker A, Kirkpatrick M, Brunklaus A, McLellan A, McCullagh H, Samanta R, Kneen R, Tan HJ, Devlin A, Prasad M, Rattihalli R, Basu H, Desurkar A, Williams R, Fallon P, Nazareth I, Freemantle N, Cross JH; KIWE study group
Lancet Neurol 2023 Dec;22(12):1113-1124. doi: 10.1016/S1474-4422(23)00370-8. PMID: 37977712
Kaya Özçora GD, Söbü E, Gümüş U
Neurol Res 2023 Mar;45(3):226-233. Epub 2023 Feb 2 doi: 10.1080/01616412.2023.2170917. PMID: 36731496
Stamberger H, Crosiers D, Balagura G, Bonardi CM, Basu A, Cantalupo G, Chiesa V, Christensen J, Dalla Bernardina B, Ellis CA, Furia F, Gardiner F, Giron C, Guerrini R, Klein KM, Korff C, Krijtova H, Leffler M, Lerche H, Lesca G, Lewis-Smith D, Marini C, Marjanovic D, Mazzola L, McKeown Ruggiero S, Mochel F, Ramond F, Reif PS, Richard-Mornas A, Rosenow F, Schropp C, Thomas RH, Vignoli A, Weber Y, Palmer E, Helbig I, Scheffer IE, Striano P, Møller RS, Gardella E, Weckhuysen S
Neurology 2022 Jul 19;99(3):e221-e233. Epub 2022 Jun 3 doi: 10.1212/WNL.0000000000200715. PMID: 35851549Free PMC Article
Liu Q, Ma J, Yu G, Zhang Q, Zhu Y, Wang R, Yu H, Liu C, Sun Y, Wang W, Wang S, Ji T, Li M, Liu X, Jiang Y, Cai L, Wu Y
Seizure 2021 Nov;92:29-35. Epub 2021 Aug 14 doi: 10.1016/j.seizure.2021.08.006. PMID: 34416421
Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, Vestergaard M
JAMA 2013 Apr 24;309(16):1696-703. doi: 10.1001/jama.2013.2270. PMID: 23613074Free PMC Article

Clinical prediction guides

Stamberger H, Crosiers D, Balagura G, Bonardi CM, Basu A, Cantalupo G, Chiesa V, Christensen J, Dalla Bernardina B, Ellis CA, Furia F, Gardiner F, Giron C, Guerrini R, Klein KM, Korff C, Krijtova H, Leffler M, Lerche H, Lesca G, Lewis-Smith D, Marini C, Marjanovic D, Mazzola L, McKeown Ruggiero S, Mochel F, Ramond F, Reif PS, Richard-Mornas A, Rosenow F, Schropp C, Thomas RH, Vignoli A, Weber Y, Palmer E, Helbig I, Scheffer IE, Striano P, Møller RS, Gardella E, Weckhuysen S
Neurology 2022 Jul 19;99(3):e221-e233. Epub 2022 Jun 3 doi: 10.1212/WNL.0000000000200715. PMID: 35851549Free PMC Article
Guerrini R, Mei D, Kerti-Szigeti K, Pepe S, Koenig MK, Von Allmen G, Cho MT, McDonald K, Baker J, Bhambhani V, Powis Z, Rodan L, Nabbout R, Barcia G, Rosenfeld JA, Bacino CA, Mignot C, Power LH, Harris CJ, Marjanovic D, Møller RS, Hammer TB; DDD Study, Keski Filppula R, Vieira P, Hildebrandt C, Sacharow S; Undiagnosed Diseases Network, Maragliano L, Benfenati F, Lachlan K, Benneche A, Petit F, de Sainte Agathe JM, Hallinan B, Si Y, Wentzensen IM, Zou F, Narayanan V, Matsumoto N, Boncristiano A, la Marca G, Kato M, Anderson K, Barba C, Sturiale L, Garozzo D, Bei R; ATP6V1A collaborators, Masuelli L, Conti V, Novarino G, Fassio A
Brain 2022 Aug 27;145(8):2687-2703. doi: 10.1093/brain/awac145. PMID: 35675510Free PMC Article
Knupp KG, Scheffer IE, Ceulemans B, Sullivan JE, Nickels KC, Lagae L, Guerrini R, Zuberi SM, Nabbout R, Riney K, Shore S, Agarwal A, Lock M, Farfel GM, Galer BS, Gammaitoni AR, Davis R, Gil-Nagel A
JAMA Neurol 2022 Jun 1;79(6):554-564. doi: 10.1001/jamaneurol.2022.0829. PMID: 35499850Free PMC Article
Takata A, Nakashima M, Saitsu H, Mizuguchi T, Mitsuhashi S, Takahashi Y, Okamoto N, Osaka H, Nakamura K, Tohyama J, Haginoya K, Takeshita S, Kuki I, Okanishi T, Goto T, Sasaki M, Sakai Y, Miyake N, Miyatake S, Tsuchida N, Iwama K, Minase G, Sekiguchi F, Fujita A, Imagawa E, Koshimizu E, Uchiyama Y, Hamanaka K, Ohba C, Itai T, Aoi H, Saida K, Sakaguchi T, Den K, Takahashi R, Ikeda H, Yamaguchi T, Tsukamoto K, Yoshitomi S, Oboshi T, Imai K, Kimizu T, Kobayashi Y, Kubota M, Kashii H, Baba S, Iai M, Kira R, Hara M, Ohta M, Miyata Y, Miyata R, Takanashi JI, Matsui J, Yokochi K, Shimono M, Amamoto M, Takayama R, Hirabayashi S, Aiba K, Matsumoto H, Nabatame S, Shiihara T, Kato M, Matsumoto N
Nat Commun 2019 Jun 7;10(1):2506. doi: 10.1038/s41467-019-10482-9. PMID: 31175295Free PMC Article
Ravizza T, Onat FY, Brooks-Kayal AR, Depaulis A, Galanopoulou AS, Mazarati A, Numis AL, Sankar R, Friedman A
Epilepsia 2017 Mar;58(3):331-342. Epub 2016 Dec 30 doi: 10.1111/epi.13652. PMID: 28035782Free PMC Article

Recent systematic reviews

Sullivan J, Benítez A, Roth J, Andrews JS, Shah D, Butcher E, Jones A, Cross JH
Epilepsia 2024 May;65(5):1240-1263. Epub 2024 Jan 22 doi: 10.1111/epi.17866. PMID: 38252068
Stefanos-Yakoub I, Wingeier K, Held U, Latal B, Wirrell E, Smith ML, Ramantani G
Epilepsia 2024 Feb;65(2):251-265. Epub 2023 Dec 9 doi: 10.1111/epi.17834. PMID: 38031640
Lattanzi S, Trinka E, Russo E, Del Giovane C, Matricardi S, Meletti S, Striano P, Damavandi PT, Silvestrini M, Brigo F
Drugs 2023 Oct;83(15):1409-1424. Epub 2023 Sep 11 doi: 10.1007/s40265-023-01936-y. PMID: 37695433Free PMC Article
Rondão MBA, Hsu BRRHS, Centeno RS, de Aguiar PHP
Seizure 2023 Aug;110:58-68. Epub 2023 Jun 3 doi: 10.1016/j.seizure.2023.04.020. PMID: 37327751
Yates CF, Malone S, Riney K, Shah U, Wood MJ
Pediatr Neurosurg 2023;58(1):18-28. Epub 2023 Jan 13 doi: 10.1159/000529098. PMID: 36693334Free PMC Article

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