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Developmental and epileptic encephalopathy, 51(DEE51)

MedGen UID:
1372686
Concept ID:
C4479208
Disease or Syndrome
Synonyms: DEE51; Epileptic encephalopathy, early infantile, 51
 
Gene (location): MDH2 (7q11.23)
 
Monarch Initiative: MONDO:0015025
OMIM®: 617339

Definition

Developmental and epileptic encephalopathy-51 (DEE51) is an autosomal recessive severe neurodevelopmental disorder characterized by onset of intractable seizures and hypotonia in the first days or weeks of life. Affected individuals have severely delayed psychomotor development and may show abnormal movements. Brain imaging shows nonspecific abnormalities, such as cerebral atrophy, cerebellar atrophy, and delayed myelination. Laboratory studies showed increased lactate, suggesting mitochondrial dysfunction (summary by Ait-El-Mkadem et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350. [from OMIM]

Clinical features

From HPO
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Constipation
MedGen UID:
1101
Concept ID:
C0009806
Sign or Symptom
Infrequent or difficult evacuation of feces.
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.
Dyskinesia
MedGen UID:
8514
Concept ID:
C0013384
Disease or Syndrome
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
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.
Babinski sign
MedGen UID:
19708
Concept ID:
C0034935
Finding
Upturning of the big toe (and sometimes fanning of the other toes) in response to stimulation of the sole of the foot. If the Babinski sign is present it can indicate damage to the corticospinal tract.
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.
Abnormal pyramidal sign
MedGen UID:
68582
Concept ID:
C0234132
Sign or Symptom
Functional neurological abnormalities related to dysfunction of the pyramidal tract.
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.
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.
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Cerebellar atrophy
MedGen UID:
196624
Concept ID:
C0740279
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
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.
Increased CSF lactate
MedGen UID:
257904
Concept ID:
C1167918
Finding
Increased concentration of lactate in the cerebrospinal fluid.
Reduced eye contact
MedGen UID:
303190
Concept ID:
C1445953
Finding
A reduced frequency or duration of eye contact.
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
Generalized tonic seizure
MedGen UID:
322935
Concept ID:
C1836508
Disease or Syndrome
A generalized tonic seizure is a type of generalized motor seizure characterized by bilateral limb stiffening or elevation, often with neck stiffening without a subsequent clonic phase. The tonic activity can be a sustained abnormal posture, either in extension or flexion, sometimes accompanied by tremor of the extremities.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Delayed CNS myelination
MedGen UID:
867393
Concept ID:
C4021758
Anatomical Abnormality
Delayed myelination in the central nervous system.
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.
Delayed ability to sit
MedGen UID:
1368737
Concept ID:
C4476710
Finding
A failure to achieve the ability to sit at an appropriate developmental stage. Most children sit with support at 6 months of age and sit steadily without support at 9 months of age.
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Delayed ability to crawl
MedGen UID:
1772845
Concept ID:
C5421628
Finding
A failure to achieve the ability to crawl at an appropriate developmental stage. Normal infant motor development is marked by a series of postural milestones including learning to crawl on hands and knees between the ages of 6 and 10 months.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Muscular atrophy
MedGen UID:
892680
Concept ID:
C0541794
Pathologic Function
The presence of skeletal muscular atrophy (which is also known as amyotrophy).
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting. Infant head lag is observed when the head seems to flop around or lags posteriorly behind the trunk. Several articles have maintained that head lag should be absent by age 3 to 4 months.
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).
Elevated lactate:pyruvate ratio
MedGen UID:
1717835
Concept ID:
C5397670
Finding
An abnormal increase in the molar ratio of lactate to pyruvate in the blood circulation.
Supernumerary nipple
MedGen UID:
120564
Concept ID:
C0266011
Congenital Abnormality
Presence of more than two nipples.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Rod-cone dystrophy
MedGen UID:
1632921
Concept ID:
C4551714
Disease or Syndrome
An inherited retinal disease subtype in which the rod photoreceptors appear to be more severely affected than the cone photoreceptors. Typical presentation is with nyctalopia (due to rod dysfunction) followed by loss of mid-peripheral field of vision, which gradually extends and leaves many patients with a small central island of vision due to the preservation of macular cones.

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
Samanta D
Neuropediatrics 2020 Apr;51(2):135-145. Epub 2020 Feb 20 doi: 10.1055/s-0040-1701694. PMID: 32079034
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free 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
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
Vlaskamp DRM, Shaw BJ, Burgess R, Mei D, Montomoli M, Xie H, Myers CT, Bennett MF, XiangWei W, Williams D, Maas SM, Brooks AS, Mancini GMS, van de Laar IMBH, van Hagen JM, Ware TL, Webster RI, Malone S, Berkovic SF, Kalnins RM, Sicca F, Korenke GC, van Ravenswaaij-Arts CMA, Hildebrand MS, Mefford HC, Jiang Y, Guerrini R, Scheffer IE
Neurology 2019 Jan 8;92(2):e96-e107. Epub 2018 Dec 12 doi: 10.1212/WNL.0000000000006729. PMID: 30541864Free PMC Article
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
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article

Diagnosis

Dreier JW, Bjørk MH, Alvestad S, Gissler M, Igland J, Leinonen MK, Sun Y, Zoega H, Cohen JM, Furu K, Tomson T, Christensen J
JAMA Neurol 2023 Jun 1;80(6):568-577. doi: 10.1001/jamaneurol.2023.0674. PMID: 37067807Free PMC Article
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
Bastos F, Cross JH
Handb Clin Neurol 2020;174:137-158. doi: 10.1016/B978-0-444-64148-9.00011-9. PMID: 32977874
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
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article

Therapy

Dreier JW, Bjørk MH, Alvestad S, Gissler M, Igland J, Leinonen MK, Sun Y, Zoega H, Cohen JM, Furu K, Tomson T, Christensen J
JAMA Neurol 2023 Jun 1;80(6):568-577. doi: 10.1001/jamaneurol.2023.0674. PMID: 37067807Free 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
Vlaskamp DRM, Shaw BJ, Burgess R, Mei D, Montomoli M, Xie H, Myers CT, Bennett MF, XiangWei W, Williams D, Maas SM, Brooks AS, Mancini GMS, van de Laar IMBH, van Hagen JM, Ware TL, Webster RI, Malone S, Berkovic SF, Kalnins RM, Sicca F, Korenke GC, van Ravenswaaij-Arts CMA, Hildebrand MS, Mefford HC, Jiang Y, Guerrini R, Scheffer IE
Neurology 2019 Jan 8;92(2):e96-e107. Epub 2018 Dec 12 doi: 10.1212/WNL.0000000000006729. PMID: 30541864Free PMC Article
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
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
Dreier JW, Bjørk MH, Alvestad S, Gissler M, Igland J, Leinonen MK, Sun Y, Zoega H, Cohen JM, Furu K, Tomson T, Christensen J
JAMA Neurol 2023 Jun 1;80(6):568-577. doi: 10.1001/jamaneurol.2023.0674. PMID: 37067807Free PMC Article
Bastos F, Cross JH
Handb Clin Neurol 2020;174:137-158. doi: 10.1016/B978-0-444-64148-9.00011-9. PMID: 32977874
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
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article

Clinical prediction guides

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
Maroofian R, Kaiyrzhanov R, Cali E, Zamani M, Zaki MS, Ferla M, Tortora D, Sadeghian S, Saadi SM, Abdullah U, Karimiani EG, Efthymiou S, Yeşil G, Alavi S, Al Shamsi AM, Tajsharghi H, Abdel-Hamid MS, Saadi NW, Al Mutairi F, Alabdi L, Beetz C, Ali Z, Toosi MB, Rudnik-Schöneborn S, Babaei M, Isohanni P, Muhammad J, Khan S, Al Shalan M, Hickey SE, Marom D, Elhanan E, Kurian MA, Marafi D, Saberi A, Hamid M, Spaull R, Meng L, Lalani S, Maqbool S, Rahman F, Seeger J, Palculict TB, Lau T, Murphy D, Mencacci NE, Steindl K, Begemann A, Rauch A, Akbas S, Aslanger AD, Salpietro V, Yousaf H, Ben-Shachar S, Ejeskär K, Al Aqeel AI, High FA, Armstrong-Javors AE, Zahraei SM, Seifi T, Zeighami J, Shariati G, Sedaghat A, Asl SN, Shahrooei M, Zifarelli G, Burglen L, Ravelli C, Zschocke J, Schatz UA, Ghavideldarestani M, Kamel WA, Van Esch H, Hackenberg A, Taylor JC, Al-Gazali L, Bauer P, Gleeson JJ, Alkuraya FS, Lupski JR, Galehdari H, Azizimalamiri R, Chung WK, Baig SM, Houlden H, Severino M
Brain 2023 Dec 1;146(12):5031-5043. doi: 10.1093/brain/awad257. PMID: 37517035Free 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
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
O'Shea TM
Clin Obstet Gynecol 2008 Dec;51(4):816-28. doi: 10.1097/GRF.0b013e3181870ba7. PMID: 18981805Free PMC Article

Recent systematic reviews

Luisi C, Salimbene L, Pietrafusa N, Trivisano M, Marras CE, De Benedictis A, Chiarello D, Mercier M, Pepi C, de Palma L, Specchio N
Epilepsy Behav 2024 Aug;157:109846. Epub 2024 May 30 doi: 10.1016/j.yebeh.2024.109846. PMID: 38820683
Frank NA, Greuter L, Guzman R, Soleman J
Childs Nerv Syst 2023 Mar;39(3):677-688. Epub 2022 Oct 11 doi: 10.1007/s00381-022-05699-x. PMID: 36219224
Batson S, Shankar R, Conry J, Boggs J, Radtke R, Mitchell S, Barion F, Murphy J, Danielson V
J Neurol 2022 Jun;269(6):2874-2891. Epub 2022 Jan 16 doi: 10.1007/s00415-022-10967-6. PMID: 35034187Free 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
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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