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Developmental and epileptic encephalopathy, 12(DEE12)

MedGen UID:
462338
Concept ID:
C3150988
Disease or Syndrome
Synonyms: DEE12; Early infantile epileptic encephalopathy 12
 
Gene (location): PLCB1 (20p12.3)
 
Monarch Initiative: MONDO:0013389
OMIM®: 613722

Definition

Developmental and epileptic encephalopathy-12 (DEE12) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first year of life. Affected infants may have normal or mildly delayed development before the onset of seizures, but thereafter show severe developmental regression and stagnation. Seizure types vary: focal seizures, infantile spasms, and generalized tonic-clonic seizures may occur, even within the same patient. EEG may show hypsarrhythmia, consistent with West syndrome, or a pattern consistent with 'malignant migrating partial seizures in infancy' (MMPSI). Patients have little or no developmental progress: there is absent speech, hypotonia, poor motor skills, peripheral spasticity, and impaired visual fixation (summary by Kurian et al., 2010 and Poduri et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of developmental and epileptic encephalopathy, see 308350. [from OMIM]

Clinical features

From HPO
Spasticity
MedGen UID:
7753
Concept ID:
C0026838
Sign or Symptom
A motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with increased muscle tone, exaggerated (hyperexcitable) tendon reflexes.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Tonic seizure
MedGen UID:
82855
Concept ID:
C0270844
Disease or Syndrome
A tonic seizure is a type of motor seizure characterized by unilateral or bilateral limb stiffening or elevation, often with neck stiffening.
Bilateral tonic-clonic seizure
MedGen UID:
141670
Concept ID:
C0494475
Sign or Symptom
A bilateral tonic-clonic seizure is a seizure defined by a tonic (bilateral increased tone, lasting seconds to minutes) and then a clonic (bilateral sustained rhythmic jerking) phase.
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.
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).
Focal-onset seizure
MedGen UID:
199670
Concept ID:
C0751495
Disease or Syndrome
A focal-onset seizure is a type of seizure originating within networks limited to one hemisphere. They may be discretely localized or more widely distributed, and may originate in subcortical structures.
Epileptic spasm
MedGen UID:
315948
Concept ID:
C1527366
Disease or Syndrome
A sudden flexion, extension, or mixed extension-flexion of predominantly proximal and truncal muscles that is usually more sustained than a myoclonic movement but not as sustained as a tonic seizure. Limited forms may occur
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.

Professional guidelines

PubMed

Bayat A, Bayat M, Rubboli G, Møller RS
Genes (Basel) 2021 Jul 8;12(7) doi: 10.3390/genes12071051. PMID: 34356067Free PMC Article
Pop-Jordanova N
Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2019 May 1;40(1):5-40. doi: 10.2478/prilozi-2019-0001. PMID: 31152643
van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ
Orphanet J Rare Dis 2017 Oct 12;12(1):162. doi: 10.1186/s13023-017-0685-2. PMID: 29025426Free 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
Morsy H, Benkirane M, Cali E, Rocca C, Zhelcheska K, Cipriani V, Galanaki E, Maroofian R, Efthymiou S, Murphy D, O'Driscoll M, Suri M, Banka S, Clayton-Smith J, Wright T, Redman M, Bassetti JA, Nizon M, Cogne B, Jamra RA, Bartolomaeus T, Heruth M, Krey I, Gburek-Augustat J, Wieczorek D, Gattermann F, Mcentagart M, Goldenberg A, Guyant-Marechal L, Garcia-Moreno H, Giunti P, Chabrol B, Bacrot S, Buissonnière R, Magry V, Gowda VK, Srinivasan VM, Melegh B, Szabó A, Sümegi K, Cossée M, Ziff M, Butterfield R, Hunt D, Bird-Lieberman G, Hanna M, Koenig M, Stankewich M, Vandrovcova J, Houlden H; Genomics England Research Consortium
Genet Med 2023 Jan;25(1):76-89. Epub 2022 Nov 4 doi: 10.1016/j.gim.2022.09.013. PMID: 36331550Free PMC Article
Xian J, Parthasarathy S, Ruggiero SM, Balagura G, Fitch E, Helbig K, Gan J, Ganesan S, Kaufman MC, Ellis CA, Lewis-Smith D, Galer P, Cunningham K, O'Brien M, Cosico M, Baker K, Darling A, Veiga de Goes F, El Achkar CM, Doering JH, Furia F, García-Cazorla Á, Gardella E, Geertjens L, Klein C, Kolesnik-Taylor A, Lammertse H, Lee J, Mackie A, Misra-Isrie M, Olson H, Sexton E, Sheidley B, Smith L, Sotero L, Stamberger H, Syrbe S, Thalwitzer KM, van Berkel A, van Haelst M, Yuskaitis C, Weckhuysen S, Prosser B, Son Rigby C, Demarest S, Pierce S, Zhang Y, Møller RS, Bruining H, Poduri A, Zara F, Verhage M, Striano P, Helbig I
Brain 2022 Jun 3;145(5):1668-1683. doi: 10.1093/brain/awab327. PMID: 35190816Free PMC Article
Bonardi CM, Heyne HO, Fiannacca M, Fitzgerald MP, Gardella E, Gunning B, Olofsson K, Lesca G, Verbeek N, Stamberger H, Striano P, Zara F, Mancardi MM, Nava C, Syrbe S, Buono S, Baulac S, Coppola A, Weckhuysen S, Schoonjans AS, Ceulemans B, Sarret C, Baumgartner T, Muhle H, Portes VD, Toulouse J, Nougues MC, Rossi M, Demarquay G, Ville D, Hirsch E, Maurey H, Willems M, de Bellescize J, Altuzarra CD, Villeneuve N, Bartolomei F, Picard F, Hornemann F, Koolen DA, Kroes HY, Reale C, Fenger CD, Tan WH, Dibbens L, Bearden DR, Møller RS, Rubboli G
Brain 2021 Dec 31;144(12):3635-3650. doi: 10.1093/brain/awab219. PMID: 34114611
Bar C, Kuchenbuch M, Barcia G, Schneider A, Jennesson M, Le Guyader G, Lesca G, Mignot C, Montomoli M, Parrini E, Isnard H, Rolland A, Keren B, Afenjar A, Dorison N, Sadleir LG, Breuillard D, Levy R, Rio M, Dupont S, Negrin S, Danieli A, Scalais E, De Saint Martin A, El Chehadeh S, Chelly J, Poisson A, Lebre AS, Nica A, Odent S, Sekhara T, Brankovic V, Goldenberg A, Vrielynck P, Lederer D, Maurey H, Terrone G, Besmond C, Hubert L, Berquin P, Billette de Villemeur T, Isidor B, Freeman JL, Mefford HC, Myers CT, Howell KB, Rodríguez-Sacristán Cascajo A, Meyer P, Genevieve D, Guët A, Doummar D, Durigneux J, van Dooren MF, de Wit MCY, Gerard M, Marey I, Munnich A, Guerrini R, Scheffer IE, Kabashi E, Nabbout R
Epilepsia 2020 Nov;61(11):2461-2473. Epub 2020 Sep 21 doi: 10.1111/epi.16679. PMID: 32954514

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
Bayat A, Bayat M, Rubboli G, Møller RS
Genes (Basel) 2021 Jul 8;12(7) doi: 10.3390/genes12071051. PMID: 34356067Free PMC Article
Pavone P, Polizzi A, Marino SD, Corsello G, Falsaperla R, Marino S, Ruggieri M
Neurol Sci 2020 Dec;41(12):3547-3562. Epub 2020 Aug 22 doi: 10.1007/s10072-020-04600-5. PMID: 32827285Free PMC Article
van Wegberg AMJ, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ
Orphanet J Rare Dis 2017 Oct 12;12(1):162. doi: 10.1186/s13023-017-0685-2. PMID: 29025426Free PMC Article

Therapy

Knupp KG, Scheffer IE, Ceulemans B, Sullivan J, Nickels KC, Lagae L, Guerrini R, Zuberi SM, Nabbout R, Riney K, Agarwal A, Lock M, Dai D, Farfel GM, Galer BS, Gammaitoni AR, Polega S, Davis R, Gil-Nagel A
Epilepsia 2023 Jan;64(1):139-151. Epub 2022 Nov 9 doi: 10.1111/epi.17431. PMID: 36196777Free PMC Article
Hahn CD, Jiang Y, Villanueva V, Zolnowska M, Arkilo D, Hsiao S, Asgharnejad M, Dlugos D
Epilepsia 2022 Oct;63(10):2671-2683. Epub 2022 Aug 4 doi: 10.1111/epi.17367. PMID: 35841234Free 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
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
Veroniki AA, Rios P, Cogo E, Straus SE, Finkelstein Y, Kealey R, Reynen E, Soobiah C, Thavorn K, Hutton B, Hemmelgarn BR, Yazdi F, D'Souza J, MacDonald H, Tricco AC
BMJ Open 2017 Jul 20;7(7):e017248. doi: 10.1136/bmjopen-2017-017248. PMID: 28729328Free PMC Article

Prognosis

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
Vetro A, Nielsen HN, Holm R, Hevner RF, Parrini E, Powis Z, Møller RS, Bellan C, Simonati A, Lesca G, Helbig KL, Palmer EE, Mei D, Ballardini E, Van Haeringen A, Syrbe S, Leuzzi V, Cioni G, Curry CJ, Costain G, Santucci M, Chong K, Mancini GMS, Clayton-Smith J, Bigoni S, Scheffer IE, Dobyns WB, Vilsen B, Guerrini R; ATP1A2/A3-collaborators
Brain 2021 Jun 22;144(5):1435-1450. doi: 10.1093/brain/awab052. PMID: 33880529
Santoro JD, Pagarkar D, Chu DT, Rosso M, Paulsen KC, Levitt P, Rafii MS
J Neurol 2021 Dec;268(12):4495-4509. Epub 2020 Sep 12 doi: 10.1007/s00415-020-10179-w. PMID: 32920658
Bar C, Kuchenbuch M, Barcia G, Schneider A, Jennesson M, Le Guyader G, Lesca G, Mignot C, Montomoli M, Parrini E, Isnard H, Rolland A, Keren B, Afenjar A, Dorison N, Sadleir LG, Breuillard D, Levy R, Rio M, Dupont S, Negrin S, Danieli A, Scalais E, De Saint Martin A, El Chehadeh S, Chelly J, Poisson A, Lebre AS, Nica A, Odent S, Sekhara T, Brankovic V, Goldenberg A, Vrielynck P, Lederer D, Maurey H, Terrone G, Besmond C, Hubert L, Berquin P, Billette de Villemeur T, Isidor B, Freeman JL, Mefford HC, Myers CT, Howell KB, Rodríguez-Sacristán Cascajo A, Meyer P, Genevieve D, Guët A, Doummar D, Durigneux J, van Dooren MF, de Wit MCY, Gerard M, Marey I, Munnich A, Guerrini R, Scheffer IE, Kabashi E, Nabbout R
Epilepsia 2020 Nov;61(11):2461-2473. Epub 2020 Sep 21 doi: 10.1111/epi.16679. PMID: 32954514
Pavone P, Polizzi A, Marino SD, Corsello G, Falsaperla R, Marino S, Ruggieri M
Neurol Sci 2020 Dec;41(12):3547-3562. Epub 2020 Aug 22 doi: 10.1007/s10072-020-04600-5. PMID: 32827285Free PMC Article

Clinical prediction guides

Zhou Y, Su Y, Li S, Kennedy BC, Zhang DY, Bond AM, Sun Y, Jacob F, Lu L, Hu P, Viaene AN, Helbig I, Kessler SK, Lucas T, Salinas RD, Gu X, Chen HI, Wu H, Kleinman JE, Hyde TM, Nauen DW, Weinberger DR, Ming GL, Song H
Nature 2022 Jul;607(7919):527-533. Epub 2022 Jul 6 doi: 10.1038/s41586-022-04912-w. PMID: 35794479Free 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
Xian J, Parthasarathy S, Ruggiero SM, Balagura G, Fitch E, Helbig K, Gan J, Ganesan S, Kaufman MC, Ellis CA, Lewis-Smith D, Galer P, Cunningham K, O'Brien M, Cosico M, Baker K, Darling A, Veiga de Goes F, El Achkar CM, Doering JH, Furia F, García-Cazorla Á, Gardella E, Geertjens L, Klein C, Kolesnik-Taylor A, Lammertse H, Lee J, Mackie A, Misra-Isrie M, Olson H, Sexton E, Sheidley B, Smith L, Sotero L, Stamberger H, Syrbe S, Thalwitzer KM, van Berkel A, van Haelst M, Yuskaitis C, Weckhuysen S, Prosser B, Son Rigby C, Demarest S, Pierce S, Zhang Y, Møller RS, Bruining H, Poduri A, Zara F, Verhage M, Striano P, Helbig I
Brain 2022 Jun 3;145(5):1668-1683. doi: 10.1093/brain/awab327. PMID: 35190816Free PMC Article
Bonardi CM, Heyne HO, Fiannacca M, Fitzgerald MP, Gardella E, Gunning B, Olofsson K, Lesca G, Verbeek N, Stamberger H, Striano P, Zara F, Mancardi MM, Nava C, Syrbe S, Buono S, Baulac S, Coppola A, Weckhuysen S, Schoonjans AS, Ceulemans B, Sarret C, Baumgartner T, Muhle H, Portes VD, Toulouse J, Nougues MC, Rossi M, Demarquay G, Ville D, Hirsch E, Maurey H, Willems M, de Bellescize J, Altuzarra CD, Villeneuve N, Bartolomei F, Picard F, Hornemann F, Koolen DA, Kroes HY, Reale C, Fenger CD, Tan WH, Dibbens L, Bearden DR, Møller RS, Rubboli G
Brain 2021 Dec 31;144(12):3635-3650. doi: 10.1093/brain/awab219. PMID: 34114611
Vetro A, Nielsen HN, Holm R, Hevner RF, Parrini E, Powis Z, Møller RS, Bellan C, Simonati A, Lesca G, Helbig KL, Palmer EE, Mei D, Ballardini E, Van Haeringen A, Syrbe S, Leuzzi V, Cioni G, Curry CJ, Costain G, Santucci M, Chong K, Mancini GMS, Clayton-Smith J, Bigoni S, Scheffer IE, Dobyns WB, Vilsen B, Guerrini R; ATP1A2/A3-collaborators
Brain 2021 Jun 22;144(5):1435-1450. doi: 10.1093/brain/awab052. PMID: 33880529

Recent systematic reviews

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
Huber R, Weber P
Eur J Paediatr Neurol 2022 May;38:1-6. Epub 2022 Feb 26 doi: 10.1016/j.ejpn.2022.01.021. PMID: 35248913
Craiu D, Rener Primec Z, Lagae L, Vigevano F, Trinka E, Specchio N, Bakhtadze S, Cazacu C, Golli T, Zuberi SM
Eur J Paediatr Neurol 2022 Jan;36:57-68. Epub 2021 Dec 3 doi: 10.1016/j.ejpn.2021.11.014. PMID: 34922162
Santoro JD, Pagarkar D, Chu DT, Rosso M, Paulsen KC, Levitt P, Rafii MS
J Neurol 2021 Dec;268(12):4495-4509. Epub 2020 Sep 12 doi: 10.1007/s00415-020-10179-w. PMID: 32920658
Veroniki AA, Rios P, Cogo E, Straus SE, Finkelstein Y, Kealey R, Reynen E, Soobiah C, Thavorn K, Hutton B, Hemmelgarn BR, Yazdi F, D'Souza J, MacDonald H, Tricco AC
BMJ Open 2017 Jul 20;7(7):e017248. doi: 10.1136/bmjopen-2017-017248. PMID: 28729328Free PMC Article

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