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Developmental and epileptic encephalopathy, 81(EIEE81; DEE81)

MedGen UID:
1684681
Concept ID:
C5231450
Disease or Syndrome
Synonym: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 81
 
Gene (location): DMXL2 (15q21.2)
 
Monarch Initiative: MONDO:0032858
OMIM®: 618663

Definition

Developmental and epileptic encephalopathy-81 (DEE81) is an autosomal recessive neurodevelopmental disorder typically characterized by onset of severe refractory seizures soon after birth or in the first months of life. Affected individuals show little developmental progress with no eye contact and no motor or cognitive development. Other features may include facial dysmorphism, such as hypotonic facies and epicanthal folds, as well as sensorineural hearing loss and peripheral neuropathy. Brain imaging shows cerebral atrophy, impaired myelination, thin corpus callosum, and progressive leukoencephalopathy (summary by Esposito et al., 2019; Maddirevula et al., 2019). For a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Clinical features

From HPO
Sensorineural hearing loss disorder
MedGen UID:
9164
Concept ID:
C0018784
Disease or Syndrome
A type of hearing impairment in one or both ears related to an abnormal functionality of the cochlear nerve.
Peripheral neuropathy
MedGen UID:
18386
Concept ID:
C0031117
Disease or Syndrome
Peripheral neuropathy is a general term for any disorder of the peripheral nervous system. The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
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.
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.
Focal clonic seizure
MedGen UID:
155749
Concept ID:
C0752323
Disease or Syndrome
A focal clonic seizure is a type of focal motor seizure characterized by sustained rhythmic jerking, that is regularly repetitive.
EEG with burst suppression
MedGen UID:
369943
Concept ID:
C1969156
Finding
The burst suppression pattern in electroencephalography refers to a characteristic periodic pattern of low voltage (<10 microvolts) suppressed background and a relatively shorter pattern of higher amplitude slow, sharp, and spiking complexes.
Intellectual disability, profound
MedGen UID:
892508
Concept ID:
C3161330
Mental or Behavioral Dysfunction
Profound mental retardation is defined as an intelligence quotient (IQ) below 20.
Infantile spasms
MedGen UID:
854616
Concept ID:
C3887898
Disease or Syndrome
Infantile spasms represent a subset of "epileptic spasms". Infantile Spasms are epileptic spasms starting in the first year of life (infancy).
Myoclonic seizure
MedGen UID:
1385980
Concept ID:
C4317123
Sign or Symptom
A myoclonic seizure is a type of motor seizure characterized by sudden, brief (<100 ms) involuntary single or multiple contraction of muscles or muscle groups of variable topography (axial, proximal limb, distal). Myoclonus is less regularly repetitive and less sustained than is clonus.
Dolichocephaly
MedGen UID:
65142
Concept ID:
C0221358
Congenital Abnormality
An abnormality of skull shape characterized by a increased anterior-posterior diameter, i.e., an increased antero-posterior dimension of the skull. Cephalic index less than 76%. Alternatively, an apparently increased antero-posterior length of the head compared to width. Often due to premature closure of the sagittal suture.
Severe muscular hypotonia
MedGen UID:
326544
Concept ID:
C1839630
Finding
A severe degree of muscular hypotonia characterized by markedly reduced muscle tone.
High palate
MedGen UID:
66814
Concept ID:
C0240635
Congenital Abnormality
Height of the palate more than 2 SD above the mean (objective) or palatal height at the level of the first permanent molar more than twice the height of the teeth (subjective).
Concave nasal ridge
MedGen UID:
78105
Concept ID:
C0264169
Finding
Nasal ridge curving posteriorly to an imaginary line that connects the nasal root and tip.
Myopathic facies
MedGen UID:
90695
Concept ID:
C0332615
Finding
A facial appearance characteristic of myopathic conditions. The face appears expressionless with sunken cheeks, bilateral ptosis, and inability to elevate the corners of the mouth, due to muscle weakness.
Downslanted palpebral fissures
MedGen UID:
98391
Concept ID:
C0423110
Finding
The palpebral fissure inclination is more than two standard deviations below the mean.
Epicanthus
MedGen UID:
151862
Concept ID:
C0678230
Congenital Abnormality
Epicanthus is a condition in which a fold of skin stretches from the upper to the lower eyelid, partially covering the inner canthus. Usher (1935) noted that epicanthus is a normal finding in the fetus of all races. Epicanthus also occurs in association with hereditary ptosis (110100).
Small forehead
MedGen UID:
336888
Concept ID:
C1845250
Finding
The presence of a forehead that is abnormally small.

Professional guidelines

PubMed

D'Gama AM, Mulhern S, Sheidley BR, Boodhoo F, Buts S, Chandler NJ, Cobb J, Curtis M, Higginbotham EJ, Holland J, Khan T, Koh J, Liang NSY, McRae L, Nesbitt SE, Oby BT, Paternoster B, Patton A, Rose G, Scotchman E, Valentine R, Wiltrout KN; Gene-STEPS Study Group; IPCHiP Executive Committee, Hayeems RZ, Jain P, Lunke S, Marshall CR, Rockowitz S, Sebire NJ, Stark Z, White SM, Chitty LS, Cross JH, Scheffer IE, Chau V, Costain G, Poduri A, Howell KB, McTague A
Lancet Neurol 2023 Sep;22(9):812-825. doi: 10.1016/S1474-4422(23)00246-6. PMID: 37596007
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
Sánchez Fernández I, Abend NS, Amengual-Gual M, Anderson A, Arya R, Barcia Aguilar C, Brenton JN, Carpenter JL, Chapman KE, Clark J, Farias-Moeller R, Gaillard WD, Gaínza-Lein M, Glauser T, Goldstein J, Goodkin HP, Guerriero RM, Lai YC, McDonough T, Mikati MA, Morgan LA, Novotny E Jr, Payne E, Peariso K, Piantino J, Ostendorf A, Sands TT, Sannagowdara K, Tasker RC, Tchapyjnikov D, Topjian AA, Vasquez A, Wainwright MS, Wilfong A, Williams K, Loddenkemper T; pSERG
Neurology 2020 Sep 1;95(9):e1222-e1235. Epub 2020 Jul 1 doi: 10.1212/WNL.0000000000010174. PMID: 32611646Free PMC Article

Recent clinical studies

Etiology

D'Gama AM, Mulhern S, Sheidley BR, Boodhoo F, Buts S, Chandler NJ, Cobb J, Curtis M, Higginbotham EJ, Holland J, Khan T, Koh J, Liang NSY, McRae L, Nesbitt SE, Oby BT, Paternoster B, Patton A, Rose G, Scotchman E, Valentine R, Wiltrout KN; Gene-STEPS Study Group; IPCHiP Executive Committee, Hayeems RZ, Jain P, Lunke S, Marshall CR, Rockowitz S, Sebire NJ, Stark Z, White SM, Chitty LS, Cross JH, Scheffer IE, Chau V, Costain G, Poduri A, Howell KB, McTague A
Lancet Neurol 2023 Sep;22(9):812-825. doi: 10.1016/S1474-4422(23)00246-6. PMID: 37596007
Casas-Alba D, Aguilar A, Alonso I, García MT, Cilio MR, Fons C; BIO-KCNQ2-Spanish Study Group
Pediatr Neurol 2023 Jul;144:11-15. Epub 2023 Mar 9 doi: 10.1016/j.pediatrneurol.2023.03.004. PMID: 37099824
Oshino S, Tani N, Khoo HM, Kagitani-Shimono K, Nabatame S, Tominaga K, Yanagisawa T, Hirata M, Kishima H
Neurol Med Chir (Tokyo) 2023 May 15;63(5):173-178. Epub 2023 Apr 6 doi: 10.2176/jns-nmc.2022-0300. PMID: 37019652Free PMC Article
Berg AT, Coffman K, Gaebler-Spira D
Dev Med Child Neurol 2021 Dec;63(12):1433-1440. Epub 2021 Jul 11 doi: 10.1111/dmcn.14990. PMID: 34247387
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

D'Gama AM, Mulhern S, Sheidley BR, Boodhoo F, Buts S, Chandler NJ, Cobb J, Curtis M, Higginbotham EJ, Holland J, Khan T, Koh J, Liang NSY, McRae L, Nesbitt SE, Oby BT, Paternoster B, Patton A, Rose G, Scotchman E, Valentine R, Wiltrout KN; Gene-STEPS Study Group; IPCHiP Executive Committee, Hayeems RZ, Jain P, Lunke S, Marshall CR, Rockowitz S, Sebire NJ, Stark Z, White SM, Chitty LS, Cross JH, Scheffer IE, Chau V, Costain G, Poduri A, Howell KB, McTague A
Lancet Neurol 2023 Sep;22(9):812-825. doi: 10.1016/S1474-4422(23)00246-6. PMID: 37596007
Nagarajan B, Gowda VK, Yoganathan S, Sharawat IK, Srivastava K, Vora N, Badheka R, Danda S, Kalane U, Kaur A, Madaan P, Mehta S, Negi S, Panda PK, Rajadhyaksha S, Saini AG, Saini L, Shah S, Srinivasan VM, Suthar R, Thomas M, Vyas S, Sankhyan N, Sahu JK
Epilepsia Open 2023 Dec;8(4):1383-1404. Epub 2023 Aug 25 doi: 10.1002/epi4.12811. PMID: 37583270Free 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
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
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

Therapy

Valls Carbó A, Beltrán Á, Sánchez-Miranda Román I, Cabal B, Gómez-Porro P, Aledo-Serrano Á, López Sobrino G, Ayuga F, Gómez Eguilaz M, Gil-Nagel A
Epilepsy Behav 2024 Feb;151:109620. Epub 2024 Jan 8 doi: 10.1016/j.yebeh.2024.109620. PMID: 38194770
Terada K, Kubota Y, Dimova S, Elmoufti S, Floricel F, Chellun D, O'Brien TJ
Seizure 2023 Nov;112:62-67. Epub 2023 Sep 13 doi: 10.1016/j.seizure.2023.09.011. PMID: 37769545
Scheffer IE, Hulihan J, Messenheimer J, Ali S, Keenan N, Griesser J, Gutterman DL, Sebree T, Sadleir LG
JAMA Netw Open 2021 Sep 1;4(9):e2123930. doi: 10.1001/jamanetworkopen.2021.23930. PMID: 34477852Free PMC Article
Ko A, Youn SE, Chung HJ, Kim SH, Lee JS, Kim HD, Kang HC
Epilepsy Res 2018 Sep;145:127-133. Epub 2018 Jun 23 doi: 10.1016/j.eplepsyres.2018.06.013. PMID: 29966811
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

D'Gama AM, Mulhern S, Sheidley BR, Boodhoo F, Buts S, Chandler NJ, Cobb J, Curtis M, Higginbotham EJ, Holland J, Khan T, Koh J, Liang NSY, McRae L, Nesbitt SE, Oby BT, Paternoster B, Patton A, Rose G, Scotchman E, Valentine R, Wiltrout KN; Gene-STEPS Study Group; IPCHiP Executive Committee, Hayeems RZ, Jain P, Lunke S, Marshall CR, Rockowitz S, Sebire NJ, Stark Z, White SM, Chitty LS, Cross JH, Scheffer IE, Chau V, Costain G, Poduri A, Howell KB, McTague A
Lancet Neurol 2023 Sep;22(9):812-825. doi: 10.1016/S1474-4422(23)00246-6. PMID: 37596007
Liu X, Zhu Y, Liu Q, Zhang S, Wu P, Sun Y, Zhang J, Wang R, Ji T, Wang S, Liu X, Jiang Y, Cai L, Wu Y
Epilepsia Open 2023 Sep;8(3):898-911. Epub 2023 May 16 doi: 10.1002/epi4.12755. PMID: 37144544Free PMC Article
Oshino S, Tani N, Khoo HM, Kagitani-Shimono K, Nabatame S, Tominaga K, Yanagisawa T, Hirata M, Kishima H
Neurol Med Chir (Tokyo) 2023 May 15;63(5):173-178. Epub 2023 Apr 6 doi: 10.2176/jns-nmc.2022-0300. PMID: 37019652Free 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
Spencer SS, Theodore WH, Berkovic SF
Magn Reson Imaging 1995;13(8):1119-24. doi: 10.1016/0730-725x(95)02021-k. PMID: 8750325

Clinical prediction guides

Nagarajan B, Gowda VK, Yoganathan S, Sharawat IK, Srivastava K, Vora N, Badheka R, Danda S, Kalane U, Kaur A, Madaan P, Mehta S, Negi S, Panda PK, Rajadhyaksha S, Saini AG, Saini L, Shah S, Srinivasan VM, Suthar R, Thomas M, Vyas S, Sankhyan N, Sahu JK
Epilepsia Open 2023 Dec;8(4):1383-1404. Epub 2023 Aug 25 doi: 10.1002/epi4.12811. PMID: 37583270Free PMC Article
Liu X, Zhu Y, Liu Q, Zhang S, Wu P, Sun Y, Zhang J, Wang R, Ji T, Wang S, Liu X, Jiang Y, Cai L, Wu Y
Epilepsia Open 2023 Sep;8(3):898-911. Epub 2023 May 16 doi: 10.1002/epi4.12755. PMID: 37144544Free PMC Article
Casas-Alba D, Aguilar A, Alonso I, García MT, Cilio MR, Fons C; BIO-KCNQ2-Spanish Study Group
Pediatr Neurol 2023 Jul;144:11-15. Epub 2023 Mar 9 doi: 10.1016/j.pediatrneurol.2023.03.004. PMID: 37099824
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
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

Cutillo G, Masnada S, Lesca G, Ville D, Accorsi P, Giordano L, Pichiecchio A, Valente M, Borrelli P, Ferraro OE, Veggiotti P
Epilepsia Open 2024 Feb;9(1):106-121. Epub 2023 Nov 27 doi: 10.1002/epi4.12837. PMID: 37842880Free PMC Article
Schmidlechner T, Zaddach M, Heinen F, Cornell S, Ramantani G, Rémi J, Vollmar C, Kunz M, Borggraefe I
J Neurol 2024 Jan;271(1):177-187. Epub 2023 Sep 28 doi: 10.1007/s00415-023-12002-8. PMID: 37770569Free PMC Article
Iranmehr A, Dabbagh Ohadi MA, Chavoshi M, Jahanbakhshi A, Slavin KV
Neurosurg Focus 2022 Oct;53(4):E8. doi: 10.3171/2022.7.FOCUS22296. PMID: 36183177
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
Lukmanji S, Manji SA, Kadhim S, Sauro KM, Wirrell EC, Kwon CS, Jetté N
Epilepsy Behav 2019 Sep;98(Pt A):238-248. Epub 2019 Aug 6 doi: 10.1016/j.yebeh.2019.07.037. PMID: 31398688

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