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Developmental and epileptic encephalopathy, 82(EIEE82; DEE82)

MedGen UID:
1684694
Concept ID:
C5231473
Disease or Syndrome
Synonyms: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 82; GLUTAMATE OXALOACETATE TRANSAMINASE, MITOCHONDRIAL, DEFICIENCY OF; GOT2 DEFICIENCY
 
Gene (location): GOT2 (16q21)
 
Monarch Initiative: MONDO:0032880
OMIM®: 618721

Definition

Developmental and epileptic encephalopathy-82 (DEE82) is an autosomal recessive mitochondriopathy manifest as early-onset metabolic epileptic encephalopathy. Soon after birth, affected individuals exhibit hypotonia, feeding difficulties, and global developmental delay even before the onset of seizures in the first year of life. The severity is variable, but all patients have severely impaired intellectual development with absent speech and spastic tetraplegia. Other features include poor overall growth with microcephaly and recurrent infections. Brain imaging shows cerebral atrophy, thin corpus callosum, cerebellar hypoplasia, and white matter abnormalities. Laboratory studies show increased serum lactate and ammonia. Importantly, treatment with combined pyridoxine and serine can result in significant improvement in seizures as well as some mild developmental progress (summary by van Karnebeek et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Clinical features

From HPO
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Decreased body weight
MedGen UID:
1806755
Concept ID:
C5574742
Finding
Abnormally low body weight.
Feeding difficulties in infancy
MedGen UID:
436211
Concept ID:
C2674608
Finding
Impaired feeding performance of an infant as manifested by difficulties such as weak and ineffective sucking, brief bursts of sucking, and falling asleep during sucking. There may be difficulties with chewing or maintaining attention.
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.
Spastic paraparesis
MedGen UID:
52432
Concept ID:
C0037771
Sign or Symptom
Mild or moderate loss of motor function accompanied by spasticity in the lower extremities. This condition is a manifestation of CENTRAL NERVOUS SYSTEM DISEASES that cause injury to the motor cortex or descending motor pathways.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
Delayed speech and language development
MedGen UID:
105318
Concept ID:
C0454644
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
Inability to walk
MedGen UID:
107860
Concept ID:
C0560046
Finding
Incapability to ambulate.
Cerebellar vermis hypoplasia
MedGen UID:
333548
Concept ID:
C1840379
Finding
Underdevelopment of the vermis of cerebellum.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Progressive microcephaly
MedGen UID:
340542
Concept ID:
C1850456
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Recurrent infections
MedGen UID:
65998
Concept ID:
C0239998
Finding
Increased susceptibility to infections.
Increased circulating lactate concentration
MedGen UID:
332209
Concept ID:
C1836440
Finding
Abnormally increased level of blood lactate (2-hydroxypropanoic acid). Lactate is produced from pyruvate by lactate dehydrogenase during normal metabolism. The terms lactate and lactic acid are often used interchangeably but lactate (the component measured in blood) is strictly a weak base whereas lactic acid is the corresponding acid. Lactic acidosis is often used clinically to describe elevated lactate but should be reserved for cases where there is a corresponding acidosis (pH below 7.35).
Hyperammonemia
MedGen UID:
1802066
Concept ID:
C5574662
Laboratory or Test Result
An increased concentration of ammonia in the blood.

Professional guidelines

PubMed

Engel C, Valence S, Delplancq G, Maroofian R, Accogli A, Agolini E, Alkuraya FS, Baglioni V, Bagnasco I, Becmeur-Lefebvre M, Bertini E, Borggraefe I, Brischoux-Boucher E, Bruel AL, Brusco A, Bubshait DK, Cabrol C, Cilio MR, Cornet MC, Coubes C, Danhaive O, Delague V, Denommé-Pichon AS, Di Giacomo MC, Doco-Fenzy M, Engels H, Cremer K, Gérard M, Gleeson JG, Heron D, Goffeney J, Guimier A, Harms FL, Houlden H, Iacomino M, Kaiyrzhanov R, Kamien B, Karimiani EG, Kraus D, Kuentz P, Kutsche K, Lederer D, Massingham L, Mignot C, Morris-Rosendahl D, Nagarajan L, Odent S, Ormières C, Partlow JN, Pasquier L, Penney L, Philippe C, Piccolo G, Poulton C, Putoux A, Rio M, Rougeot C, Salpietro V, Scheffer I, Schneider A, Srivastava S, Straussberg R, Striano P, Valente EM, Venot P, Villard L, Vitobello A, Wagner J, Wagner M, Zaki MS, Zara F, Lesca G, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Beiraghi M, Ashrafzadeh F, Galehdari H, Walsh C, Novelli A, Tacke M, Sadykova D, Maidyrov Y, Koneev K, Shashkin C, Capra V, Zamani M, Van Maldergem L, Burglen L, Piard J
Eur J Hum Genet 2023 Sep;31(9):1023-1031. Epub 2023 Jun 21 doi: 10.1038/s41431-023-01410-z. PMID: 37344571Free PMC Article
DiBacco ML, Pop A, Salomons GS, Hanson E, Roullet JB, Gibson KM, Pearl PL
Neurology 2020 Nov 10;95(19):e2675-e2682. Epub 2020 Sep 4 doi: 10.1212/WNL.0000000000010730. PMID: 32887777Free PMC Article
McTague A, Martland T, Appleton R
Cochrane Database Syst Rev 2018 Jan 10;1(1):CD001905. doi: 10.1002/14651858.CD001905.pub3. PMID: 29320603Free PMC Article

Recent clinical studies

Etiology

Engel C, Valence S, Delplancq G, Maroofian R, Accogli A, Agolini E, Alkuraya FS, Baglioni V, Bagnasco I, Becmeur-Lefebvre M, Bertini E, Borggraefe I, Brischoux-Boucher E, Bruel AL, Brusco A, Bubshait DK, Cabrol C, Cilio MR, Cornet MC, Coubes C, Danhaive O, Delague V, Denommé-Pichon AS, Di Giacomo MC, Doco-Fenzy M, Engels H, Cremer K, Gérard M, Gleeson JG, Heron D, Goffeney J, Guimier A, Harms FL, Houlden H, Iacomino M, Kaiyrzhanov R, Kamien B, Karimiani EG, Kraus D, Kuentz P, Kutsche K, Lederer D, Massingham L, Mignot C, Morris-Rosendahl D, Nagarajan L, Odent S, Ormières C, Partlow JN, Pasquier L, Penney L, Philippe C, Piccolo G, Poulton C, Putoux A, Rio M, Rougeot C, Salpietro V, Scheffer I, Schneider A, Srivastava S, Straussberg R, Striano P, Valente EM, Venot P, Villard L, Vitobello A, Wagner J, Wagner M, Zaki MS, Zara F, Lesca G, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Beiraghi M, Ashrafzadeh F, Galehdari H, Walsh C, Novelli A, Tacke M, Sadykova D, Maidyrov Y, Koneev K, Shashkin C, Capra V, Zamani M, Van Maldergem L, Burglen L, Piard J
Eur J Hum Genet 2023 Sep;31(9):1023-1031. Epub 2023 Jun 21 doi: 10.1038/s41431-023-01410-z. PMID: 37344571Free PMC Article
Symonds JD, Elliott KS, Shetty J, Armstrong M, Brunklaus A, Cutcutache I, Diver LA, Dorris L, Gardiner S, Jollands A, Joss S, Kirkpatrick M, McLellan A, MacLeod S, O'Regan M, Page M, Pilley E, Pilz DT, Stephen E, Stewart K, Ashrafian H, Knight JC, Zuberi SM
Brain 2021 Oct 22;144(9):2879-2891. doi: 10.1093/brain/awab162. PMID: 34687210Free PMC Article
Trivisano M, Ferretti A, Bebin E, Huh L, Lesca G, Siekierska A, Takeguchi R, Carneiro M, De Palma L, Guella I, Haginoya K, Shi RM, Kikuchi A, Kobayashi T, Jung J, Lagae L, Milh M, Mathieu ML, Minassian BA, Novelli A, Pietrafusa N, Takeshita E, Tartaglia M, Terracciano A, Thompson ML, Cooper GM, Vigevano F, Villard L, Villeneuve N, Buyse GM, Demos M, Scheffer IE, Specchio N
Epilepsia 2020 Jul;61(7):e71-e78. Epub 2020 Jul 9 doi: 10.1111/epi.16582. PMID: 32645220Free PMC Article
McTague A, Martland T, Appleton R
Cochrane Database Syst Rev 2018 Jan 10;1(1):CD001905. doi: 10.1002/14651858.CD001905.pub3. PMID: 29320603Free PMC Article
Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, O'Callaghan FJ, Verity CM, Osborne JP; United Kingdom Infantile Spasms Study
Lancet Neurol 2005 Nov;4(11):712-7. doi: 10.1016/S1474-4422(05)70199-X. PMID: 16239177

Diagnosis

Çapan ÖY, Türkdoğan D, Atalay S, Çağlayan HS
Seizure 2024 Mar;116:126-132. Epub 2023 Nov 9 doi: 10.1016/j.seizure.2023.11.003. PMID: 37977948
Mammadova D, Vecko J, Hofmann M, Schüssler SC, Deiters L, Canda A, Wieland AK, Gollwitzer S, Hamer H, Trollmann R
Orphanet J Rare Dis 2023 Nov 9;18(1):349. doi: 10.1186/s13023-023-02959-0. PMID: 37946245Free PMC Article
Juanes M, Loos M, Reyes G, Veneruzzo G, García FM, Aschettino G, Calligaris S, Martín ME, Foncuberta ME, Alonso CN, Caraballo RH
Medicina (B Aires) 2022;82(6):856-865. PMID: 36571524
Symonds JD, Elliott KS, Shetty J, Armstrong M, Brunklaus A, Cutcutache I, Diver LA, Dorris L, Gardiner S, Jollands A, Joss S, Kirkpatrick M, McLellan A, MacLeod S, O'Regan M, Page M, Pilley E, Pilz DT, Stephen E, Stewart K, Ashrafian H, Knight JC, Zuberi SM
Brain 2021 Oct 22;144(9):2879-2891. doi: 10.1093/brain/awab162. PMID: 34687210Free PMC Article
Li W, Schneider AL, Scheffer IE
Epilepsia 2021 Sep;62(9):2205-2217. Epub 2021 Aug 2 doi: 10.1111/epi.17015. PMID: 34338318Free PMC Article

Therapy

Gil-Nagel A, Aledo-Serrano A, Beltrán-Corbellini Á, Martínez-Vicente L, Jimenez-Huete A, Toledano-Delgado R, Gacía-Morales I, Valls-Carbó A
Epilepsia Open 2024 Feb;9(1):164-175. Epub 2023 Nov 8 doi: 10.1002/epi4.12847. PMID: 37867433Free PMC Article
Pollack SF, Grocott OR, Parkin KA, Larson AM, Thibert RL
Epilepsy Behav 2018 May;82:170-174. Epub 2018 Mar 17 doi: 10.1016/j.yebeh.2018.02.006. PMID: 29555100
McTague A, Martland T, Appleton R
Cochrane Database Syst Rev 2018 Jan 10;1(1):CD001905. doi: 10.1002/14651858.CD001905.pub3. PMID: 29320603Free PMC Article
Siehr MS, Noebels JL
Curr Opin Neurobiol 2016 Feb;36:82-8. Epub 2015 Oct 27 doi: 10.1016/j.conb.2015.10.007. PMID: 26517286Free PMC Article
Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, O'Callaghan FJ, Verity CM, Osborne JP; United Kingdom Infantile Spasms Study
Lancet Neurol 2005 Nov;4(11):712-7. doi: 10.1016/S1474-4422(05)70199-X. PMID: 16239177

Prognosis

Cloppenborg T, van Schooneveld M, Hagemann A, Hopf JL, Kalbhenn T, Otte WM, Polster T, Bien CG, Braun KPJ
Neurology 2022 Jan 18;98(3):e225-e235. Epub 2021 Nov 18 doi: 10.1212/WNL.0000000000013065. PMID: 34795046
Symonds JD, Elliott KS, Shetty J, Armstrong M, Brunklaus A, Cutcutache I, Diver LA, Dorris L, Gardiner S, Jollands A, Joss S, Kirkpatrick M, McLellan A, MacLeod S, O'Regan M, Page M, Pilley E, Pilz DT, Stephen E, Stewart K, Ashrafian H, Knight JC, Zuberi SM
Brain 2021 Oct 22;144(9):2879-2891. doi: 10.1093/brain/awab162. PMID: 34687210Free PMC Article
Li W, Schneider AL, Scheffer IE
Epilepsia 2021 Sep;62(9):2205-2217. Epub 2021 Aug 2 doi: 10.1111/epi.17015. PMID: 34338318Free PMC Article
Mitta N, Menon RN, McTague A, Radhakrishnan A, Sundaram S, Cherian A, Madhavilatha GK, Mannan AU, Nampoothiri S, Thomas SV
Epilepsy Res 2020 Oct;166:106398. Epub 2020 Jun 18 doi: 10.1016/j.eplepsyres.2020.106398. PMID: 32593896
Siehr MS, Noebels JL
Curr Opin Neurobiol 2016 Feb;36:82-8. Epub 2015 Oct 27 doi: 10.1016/j.conb.2015.10.007. PMID: 26517286Free PMC Article

Clinical prediction guides

Çapan ÖY, Türkdoğan D, Atalay S, Çağlayan HS
Seizure 2024 Mar;116:126-132. Epub 2023 Nov 9 doi: 10.1016/j.seizure.2023.11.003. PMID: 37977948
Cloppenborg T, van Schooneveld M, Hagemann A, Hopf JL, Kalbhenn T, Otte WM, Polster T, Bien CG, Braun KPJ
Neurology 2022 Jan 18;98(3):e225-e235. Epub 2021 Nov 18 doi: 10.1212/WNL.0000000000013065. PMID: 34795046
Symonds JD, Elliott KS, Shetty J, Armstrong M, Brunklaus A, Cutcutache I, Diver LA, Dorris L, Gardiner S, Jollands A, Joss S, Kirkpatrick M, McLellan A, MacLeod S, O'Regan M, Page M, Pilley E, Pilz DT, Stephen E, Stewart K, Ashrafian H, Knight JC, Zuberi SM
Brain 2021 Oct 22;144(9):2879-2891. doi: 10.1093/brain/awab162. PMID: 34687210Free PMC Article
McTague A, Martland T, Appleton R
Cochrane Database Syst Rev 2018 Jan 10;1(1):CD001905. doi: 10.1002/14651858.CD001905.pub3. PMID: 29320603Free PMC Article
Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, O'Callaghan FJ, Verity CM, Osborne JP; United Kingdom Infantile Spasms Study
Lancet Neurol 2005 Nov;4(11):712-7. doi: 10.1016/S1474-4422(05)70199-X. PMID: 16239177

Recent systematic reviews

Goyal A, Fernandes-Torres J, Flemming KD, Williams LN, Daniels DJ
Childs Nerv Syst 2023 Jun;39(6):1545-1554. Epub 2023 Mar 14 doi: 10.1007/s00381-023-05903-6. PMID: 36917267
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
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
Zhang L, Li W, Wang C
Acta Neurol Scand 2021 Apr;143(4):339-348. Epub 2020 Dec 17 doi: 10.1111/ane.13387. PMID: 33336426
McTague A, Martland T, Appleton R
Cochrane Database Syst Rev 2018 Jan 10;1(1):CD001905. doi: 10.1002/14651858.CD001905.pub3. PMID: 29320603Free PMC Article

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