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Developmental and epileptic encephalopathy, 69(EIEE69; DEE69)

MedGen UID:
1648381
Concept ID:
C4748988
Disease or Syndrome
Synonym: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 69
 
Gene (location): CACNA1E (1q25.3)
 
Monarch Initiative: MONDO:0032657
OMIM®: 618285

Definition

Developmental and epileptic encephalopathy-69 (DEE69) is an autosomal dominant severe neurodevelopmental encephalopathic disorder characterized by early-onset refractory seizures, hypotonia, and profoundly impaired development often associated with macrocephaly, hyperkinetic movements, and contractures. The disorder can sometimes result in early death. Some patients may have a favorable seizure response to topiramate medication (summary by Helbig et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Clinical features

From HPO
Dystonic disorder
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
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.
EEG abnormality
MedGen UID:
56235
Concept ID:
C0151611
Finding
Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Corpus callosum atrophy
MedGen UID:
96560
Concept ID:
C0431370
Finding
The presence of atrophy (wasting) of the corpus callosum.
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.
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).
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Hyperkinetic movements
MedGen UID:
854367
Concept ID:
C3887506
Disease or Syndrome
Motor hyperactivity with excessive movement of muscles of the body as a whole.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Congenital contracture
MedGen UID:
83066
Concept ID:
C0332878
Congenital Abnormality
One or more flexion contractures (a bent joint that cannot be straightened actively or passively) that are present at birth.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Arthrogryposis multiplex congenita
MedGen UID:
1830310
Concept ID:
C5779613
Disease or Syndrome
Multiple congenital contractures in different body areas.
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.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Professional guidelines

PubMed

Menon RN, Nambiar PN, Keni RR, Baishya J, Radhakrishnan A, Cherian A, Nampoothiri S, Madhavilatha GK, Kotecha UH, Thomas SV
Neurol India 2021 Nov-Dec;69(6):1701-1705. doi: 10.4103/0028-3886.333508. PMID: 34979672
Nickels K, Kossoff EH, Eschbach K, Joshi C
Epilepsia 2021 Jan;62(1):120-127. Epub 2020 Nov 14 doi: 10.1111/epi.16752. PMID: 33190223
Ream MA, Mikati MA
Epilepsy Behav 2014 Aug;37:241-8. Epub 2014 Aug 9 doi: 10.1016/j.yebeh.2014.06.018. PMID: 25108116

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
Knight EMP, Amin S, Bahi-Buisson N, Benke TA, Cross JH, Demarest ST, Olson HE, Specchio N, Fleming TR, Aimetti AA, Gasior M, Devinsky O; Marigold Trial Group
Lancet Neurol 2022 May;21(5):417-427. doi: 10.1016/S1474-4422(22)00077-1. PMID: 35429480
Bar C, Barcia G, Jennesson M, Le Guyader G, Schneider A, Mignot C, Lesca G, Breuillard D, Montomoli M, Keren B, Doummar D, Billette de Villemeur T, Afenjar A, Marey I, Gerard M, Isnard H, Poisson A, Dupont S, Berquin P, Meyer P, Genevieve D, De Saint Martin A, El Chehadeh S, Chelly J, Guët A, Scalais E, Dorison N, Myers CT, Mefford HC, Howell KB, Marini C, Freeman JL, Nica A, Terrone G, Sekhara T, Lebre AS, Odent S, Sadleir LG, Munnich A, Guerrini R, Scheffer IE, Kabashi E, Nabbout R
Hum Mutat 2020 Jan;41(1):69-80. Epub 2019 Oct 4 doi: 10.1002/humu.23915. PMID: 31513310
Burgess R, Wang S, McTague A, Boysen KE, Yang X, Zeng Q, Myers KA, Rochtus A, Trivisano M, Gill D; EIMFS Consortium, Sadleir LG, Specchio N, Guerrini R, Marini C, Zhang YH, Mefford HC, Kurian MA, Poduri AH, Scheffer IE
Ann Neurol 2019 Dec;86(6):821-831. doi: 10.1002/ana.25619. PMID: 31618474Free PMC Article
Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K; GWPCARE4 Study Group
Lancet 2018 Mar 17;391(10125):1085-1096. Epub 2018 Jan 26 doi: 10.1016/S0140-6736(18)30136-3. PMID: 29395273

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
Brunklaus A, Brünger T, Feng T, Fons C, Lehikoinen A, Panagiotakaki E, Vintan MA, Symonds J, Andrew J, Arzimanoglou A, Delima S, Gallois J, Hanrahan D, Lesca G, MacLeod S, Marjanovic D, McTague A, Nuñez-Enamorado N, Perez-Palma E, Scott Perry M, Pysden K, Russ-Hall SJ, Scheffer IE, Sully K, Syrbe S, Vaher U, Velayutham M, Vogt J, Weiss S, Wirrell E, Zuberi SM, Lal D, Møller RS, Mantegazza M, Cestèle S
Brain 2022 Nov 21;145(11):3816-3831. doi: 10.1093/brain/awac210. PMID: 35696452Free PMC Article
Bar C, Barcia G, Jennesson M, Le Guyader G, Schneider A, Mignot C, Lesca G, Breuillard D, Montomoli M, Keren B, Doummar D, Billette de Villemeur T, Afenjar A, Marey I, Gerard M, Isnard H, Poisson A, Dupont S, Berquin P, Meyer P, Genevieve D, De Saint Martin A, El Chehadeh S, Chelly J, Guët A, Scalais E, Dorison N, Myers CT, Mefford HC, Howell KB, Marini C, Freeman JL, Nica A, Terrone G, Sekhara T, Lebre AS, Odent S, Sadleir LG, Munnich A, Guerrini R, Scheffer IE, Kabashi E, Nabbout R
Hum Mutat 2020 Jan;41(1):69-80. Epub 2019 Oct 4 doi: 10.1002/humu.23915. PMID: 31513310
Burgess R, Wang S, McTague A, Boysen KE, Yang X, Zeng Q, Myers KA, Rochtus A, Trivisano M, Gill D; EIMFS Consortium, Sadleir LG, Specchio N, Guerrini R, Marini C, Zhang YH, Mefford HC, Kurian MA, Poduri AH, Scheffer IE
Ann Neurol 2019 Dec;86(6):821-831. doi: 10.1002/ana.25619. PMID: 31618474Free PMC Article
D'Antonio F, Pagani G, Familiari A, Khalil A, Sagies TL, Malinger G, Leibovitz Z, Garel C, Moutard ML, Pilu G, Bhide A, Acharya G, Leombroni M, Manzoli L, Papageorghiou A, Prefumo F
Pediatrics 2016 Sep;138(3) doi: 10.1542/peds.2016-0445. PMID: 27581855

Therapy

Coughlin CR, Tseng LA, Bok LA, Hartmann H, Footitt E, Striano P, Tabarki BM, Lunsing RJ, Stockler-Ipsiroglu S, Gordon S, Van Hove JLK, Abdenur JE, Boyer M, Longo N, Andrews A, Janssen MCH, van Wegberg A, Prasad C, Prasad AN, Lamb MM, Wijburg FA, Gospe SM Jr, van Karnebeek C; International PDE Consortium
Neurology 2022 Dec 5;99(23):e2627-e2636. doi: 10.1212/WNL.0000000000201222. PMID: 36008148Free PMC Article
Knight EMP, Amin S, Bahi-Buisson N, Benke TA, Cross JH, Demarest ST, Olson HE, Specchio N, Fleming TR, Aimetti AA, Gasior M, Devinsky O; Marigold Trial Group
Lancet Neurol 2022 May;21(5):417-427. doi: 10.1016/S1474-4422(22)00077-1. PMID: 35429480
Nickels K, Kossoff EH, Eschbach K, Joshi C
Epilepsia 2021 Jan;62(1):120-127. Epub 2020 Nov 14 doi: 10.1111/epi.16752. PMID: 33190223
Aaberg KM, Bakken IJ, Lossius MI, Lund Søraas C, Tallur KK, Stoltenberg C, Chin R, Surén P
Pediatrics 2018 Jun;141(6) Epub 2018 May 22 doi: 10.1542/peds.2017-4016. PMID: 29789444
Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K; GWPCARE4 Study Group
Lancet 2018 Mar 17;391(10125):1085-1096. Epub 2018 Jan 26 doi: 10.1016/S0140-6736(18)30136-3. PMID: 29395273

Prognosis

Koh HY, Smith L, Wiltrout KN, Podury A, Chourasia N, D'Gama AM, Park M, Knight D, Sexton EL, Koh JJ, Oby B, Pinsky R, Shao DD, French CE, Shao W, Rockowitz S, Sliz P, Zhang B, Mahida S, Moufawad El Achkar C, Yuskaitis CJ, Olson HE, Sheidley BR, Poduri AH; BCH Neurology Referral and Phenotyping Group
JAMA Netw Open 2023 Jul 3;6(7):e2324380. doi: 10.1001/jamanetworkopen.2023.24380. PMID: 37471090Free PMC Article
Yoshitomi S, Hamano SI, Hayashi M, Sakuma H, Hirose S, Ishii A, Honda R, Ikeda A, Imai K, Jin K, Kada A, Kakita A, Kato M, Kawai K, Kawakami T, Kobayashi K, Matsuishi T, Matsuo T, Nabatame S, Okamoto N, Ito S, Okumura A, Saito A, Shiraishi H, Shirozu H, Saito T, Sugano H, Takahashi Y, Yamamoto H, Fukuyama T, Kuki I, Inoue Y
Epileptic Disord 2021 Aug 1;23(4):579-589. doi: 10.1684/epd.2021.1301. PMID: 34269179
Nickels K, Kossoff EH, Eschbach K, Joshi C
Epilepsia 2021 Jan;62(1):120-127. Epub 2020 Nov 14 doi: 10.1111/epi.16752. PMID: 33190223
Bar C, Barcia G, Jennesson M, Le Guyader G, Schneider A, Mignot C, Lesca G, Breuillard D, Montomoli M, Keren B, Doummar D, Billette de Villemeur T, Afenjar A, Marey I, Gerard M, Isnard H, Poisson A, Dupont S, Berquin P, Meyer P, Genevieve D, De Saint Martin A, El Chehadeh S, Chelly J, Guët A, Scalais E, Dorison N, Myers CT, Mefford HC, Howell KB, Marini C, Freeman JL, Nica A, Terrone G, Sekhara T, Lebre AS, Odent S, Sadleir LG, Munnich A, Guerrini R, Scheffer IE, Kabashi E, Nabbout R
Hum Mutat 2020 Jan;41(1):69-80. Epub 2019 Oct 4 doi: 10.1002/humu.23915. PMID: 31513310
Ramantani G, Maillard LG, Bast T, Husain RA, Niggemann P, Kohlhase J, Hertzberg C, Ungerath K, Innes MA, Walkenhorst H, Bevot A, von Stülpnagel C, Thomas K, Niemann F, Ergun MA, Tacke U, Häusler M, Ikonomidou C, Korinthenberg R, Lee-Kirsch MA
Eur J Paediatr Neurol 2014 Jan;18(1):30-7. Epub 2013 Sep 5 doi: 10.1016/j.ejpn.2013.07.005. PMID: 24011626

Clinical prediction guides

Thalwitzer KM, Driedger JH, Xian J, Saffari A, Zacher P, Bölsterli BK, Ruggiero SM, Sullivan KR, Datta AN, Kellinghaus C, Althaus J, Wiemer-Kruel A, van Baalen A, Pampel A, Alber M, Braakman HMH, Debus OM, Denecke J, Hobbiebrunken E, Breitweg I, Diehl D, Eitel H, Gburek-Augustat J, Preisel M, Schlump JU, Laufs M, Mammadova D, Wurst C, Prager C, Löhr-Nilles C, Martin P, Garbade SF, Platzer K, Benkel-Herrenbrueck I, Egler K, Fazeli W, Lemke JR, Runkel E, Klein B, Linden T, Schröter J, Steffeck H, Thies B, von Deimling F, Illsinger S, Borggraefe I, Classen G, Wieczorek D, Ramantani G, Koelker S, Hoffmann GF, Ries M, Helbig I, Syrbe S
Neurology 2023 Aug 29;101(9):e879-e891. Epub 2023 Jul 5 doi: 10.1212/WNL.0000000000207550. PMID: 37407264Free PMC Article
Sivathamboo S, Myers KA, Pattichis A, White EJ, Ku KN, O'Brien TJ, Perucca P, Kwan P
Epilepsia Open 2023 Sep;8(3):1157-1168. Epub 2023 Jun 12 doi: 10.1002/epi4.12772. PMID: 37277988Free PMC Article
Coughlin CR, Tseng LA, Bok LA, Hartmann H, Footitt E, Striano P, Tabarki BM, Lunsing RJ, Stockler-Ipsiroglu S, Gordon S, Van Hove JLK, Abdenur JE, Boyer M, Longo N, Andrews A, Janssen MCH, van Wegberg A, Prasad C, Prasad AN, Lamb MM, Wijburg FA, Gospe SM Jr, van Karnebeek C; International PDE Consortium
Neurology 2022 Dec 5;99(23):e2627-e2636. doi: 10.1212/WNL.0000000000201222. PMID: 36008148Free PMC Article
Burgess R, Wang S, McTague A, Boysen KE, Yang X, Zeng Q, Myers KA, Rochtus A, Trivisano M, Gill D; EIMFS Consortium, Sadleir LG, Specchio N, Guerrini R, Marini C, Zhang YH, Mefford HC, Kurian MA, Poduri AH, Scheffer IE
Ann Neurol 2019 Dec;86(6):821-831. doi: 10.1002/ana.25619. PMID: 31618474Free PMC Article
D'Antonio F, Pagani G, Familiari A, Khalil A, Sagies TL, Malinger G, Leibovitz Z, Garel C, Moutard ML, Pilu G, Bhide A, Acharya G, Leombroni M, Manzoli L, Papageorghiou A, Prefumo F
Pediatrics 2016 Sep;138(3) doi: 10.1542/peds.2016-0445. PMID: 27581855

Recent systematic reviews

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
Vasilica AM, Winsor A, Chari A, Scott R, Baldeweg T, Tisdall M
Epilepsy Res 2023 May;192:107132. Epub 2023 Mar 30 doi: 10.1016/j.eplepsyres.2023.107132. PMID: 37023554
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
Sharawat IK, Panda PK, Kasinathan A, Panda P, Dawman L, Joshi K
Seizure 2021 Feb;85:119-126. Epub 2021 Jan 11 doi: 10.1016/j.seizure.2020.12.016. PMID: 33461030
Griessenauer CJ, Salam S, Hendrix P, Patel DM, Tubbs RS, Blount JP, Winkler PA
J Neurosurg Pediatr 2015 Jan;15(1):34-44. doi: 10.3171/2014.10.PEDS14155. PMID: 25380174

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