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Intellectual disability-epilepsy-extrapyramidal syndrome(NEDHELS)

MedGen UID:
934650
Concept ID:
C4310683
Disease or Syndrome
Synonyms: Dyskinesia, seizures, and intellectual developmental disorder; NEDHELS
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): DEAF1 (11p15.5)
 
Monarch Initiative: MONDO:0014952
OMIM®: 617171
Orphanet: ORPHA468620

Definition

Neurodevelopmental disorder with hypotonia and impaired expressive language and with or without seizures (NEDHELS) is an autosomal recessive disorder characterized by hypotonia, poor feeding, and global developmental delay apparent from infancy. Most patients have poor overall growth, poor eye contact, sleep disturbances, and severely impaired expressive language. Affected individuals also tend to have behavioral problems, microcephaly, and variable dysmorphic features; many develop seizures. Brain imaging may show enlarged ventricles, thin corpus callosum and brainstem, and white matter abnormalities. The phenotype is variable (summary by Nabais Sa et al., 2019). [from OMIM]

Clinical features

From HPO
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
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.
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.
Motor stereotypies
MedGen UID:
21318
Concept ID:
C0038271
Individual Behavior
Use of the same abnormal action in response to certain triggers or at random. They may be used as a way to regulate one's internal state but must otherwise have no apparent functional purpose.
Agitation
MedGen UID:
88447
Concept ID:
C0085631
Sign or Symptom
A state of extreme restlessness and excessive motor activity is associated with mental distress or a feeling of inner tension.
Emotional lability
MedGen UID:
39319
Concept ID:
C0085633
Mental or Behavioral Dysfunction
Unstable emotional experiences and frequent mood changes; emotions that are easily aroused, intense, and/or disproportionate to events and circumstances.
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.
Involuntary movements
MedGen UID:
140884
Concept ID:
C0427086
Sign or Symptom
Involuntary contractions of muscle leading to involuntary movements of extremities, neck, trunk, or face.
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.
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
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.
Drooling
MedGen UID:
8484
Concept ID:
C0013132
Finding
Habitual flow of saliva out of the mouth.

Professional guidelines

PubMed

Salcedo-Arellano MJ, Hagerman RJ, Martínez-Cerdeño V
Gac Med Mex 2020;156(1):60-66. doi: 10.24875/GMM.19005275. PMID: 32026885
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J
Circulation 2019 Jun 18;139(25):e1082-e1143. Epub 2018 Nov 10 doi: 10.1161/CIR.0000000000000625. PMID: 30586774Free PMC Article
Sanchack KE, Thomas CA
Am Fam Physician 2016 Dec 15;94(12):972-979. PMID: 28075089

Recent clinical studies

Etiology

Lui JC, Baron J
J Clin Endocrinol Metab 2024 Jan 18;109(2):312-320. doi: 10.1210/clinem/dgad420. PMID: 37450557
Miroševič Š, Khandelwal S, Sušjan P, Žakelj N, Gosar D, Forstnerič V, Lainšček D, Jerala R, Osredkar D
Int J Mol Sci 2022 Oct 19;23(20) doi: 10.3390/ijms232012564. PMID: 36293418Free PMC Article
Aref-Eshghi E, Kerkhof J, Pedro VP; Groupe DI France, Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Héron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B
Am J Hum Genet 2020 Mar 5;106(3):356-370. Epub 2020 Feb 27 doi: 10.1016/j.ajhg.2020.01.019. PMID: 32109418Free PMC Article
Van Dijck A, Vulto-van Silfhout AT, Cappuyns E, van der Werf IM, Mancini GM, Tzschach A, Bernier R, Gozes I, Eichler EE, Romano C, Lindstrand A, Nordgren A; ADNP Consortium, Kvarnung M, Kleefstra T, de Vries BBA, Küry S, Rosenfeld JA, Meuwissen ME, Vandeweyer G, Kooy RF
Biol Psychiatry 2019 Feb 15;85(4):287-297. Epub 2018 Mar 15 doi: 10.1016/j.biopsych.2018.02.1173. PMID: 29724491Free PMC Article
Renier D, Lajeunie E, Arnaud E, Marchac D
Childs Nerv Syst 2000 Nov;16(10-11):645-58. doi: 10.1007/s003810000320. PMID: 11151714

Diagnosis

Hills S, Pugacheva A, Weltin P, Maughan A, Morton SU, Feldman HA, Klinge PM, Agrawal PB
Am J Med Genet A 2023 May;191(5):1222-1226. Epub 2023 Feb 1 doi: 10.1002/ajmg.a.63128. PMID: 36722669
Carvalho LML, Pinto CF, de Oliveira Scliar M, Otto PA, Krepischi ACV, Rosenberg C
Am J Med Genet A 2023 Feb;191(2):570-574. Epub 2022 Nov 5 doi: 10.1002/ajmg.a.63032. PMID: 36333968
Wilson KD, Porter EG, Garcia BA
Crit Rev Biochem Mol Biol 2022 Feb;57(1):73-112. Epub 2021 Oct 2 doi: 10.1080/10409238.2021.1979457. PMID: 34601997Free PMC Article
Aref-Eshghi E, Kerkhof J, Pedro VP; Groupe DI France, Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Héron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B
Am J Hum Genet 2020 Mar 5;106(3):356-370. Epub 2020 Feb 27 doi: 10.1016/j.ajhg.2020.01.019. PMID: 32109418Free PMC Article
Renier D, Lajeunie E, Arnaud E, Marchac D
Childs Nerv Syst 2000 Nov;16(10-11):645-58. doi: 10.1007/s003810000320. PMID: 11151714

Therapy

Liu SH, Saldanha IJ, Abraham AG, Rittiphairoj T, Hauswirth S, Gregory D, Ifantides C, Li T
Cochrane Database Syst Rev 2022 Oct 21;10(10):CD015070. doi: 10.1002/14651858.CD015070.pub2. PMID: 36269562Free PMC Article
Bruno LP, Doddato G, Valentino F, Baldassarri M, Tita R, Fallerini C, Bruttini M, Lo Rizzo C, Mencarelli MA, Mari F, Pinto AM, Fava F, Fabbiani A, Lamacchia V, Carrer A, Caputo V, Granata S, Benetti E, Zguro K, Furini S, Renieri A, Ariani F
Int J Mol Sci 2021 Dec 14;22(24) doi: 10.3390/ijms222413439. PMID: 34948243Free PMC Article
Montouris G, Aboumatar S, Burdette D, Kothare S, Kuzniecky R, Rosenfeld W, Chung S
Epilepsy Behav 2020 Sep;110:107146. Epub 2020 Jun 18 doi: 10.1016/j.yebeh.2020.107146. PMID: 32563898
Samanta D
Pediatr Neurol 2020 Apr;105:3-9. Epub 2019 Nov 30 doi: 10.1016/j.pediatrneurol.2019.10.009. PMID: 32057594
Devinsky O, Cilio MR, Cross H, Fernandez-Ruiz J, French J, Hill C, Katz R, Di Marzo V, Jutras-Aswad D, Notcutt WG, Martinez-Orgado J, Robson PJ, Rohrback BG, Thiele E, Whalley B, Friedman D
Epilepsia 2014 Jun;55(6):791-802. Epub 2014 May 22 doi: 10.1111/epi.12631. PMID: 24854329Free PMC Article

Prognosis

Wilson KD, Porter EG, Garcia BA
Crit Rev Biochem Mol Biol 2022 Feb;57(1):73-112. Epub 2021 Oct 2 doi: 10.1080/10409238.2021.1979457. PMID: 34601997Free PMC Article
Nazha A, Komrokji R, Meggendorfer M, Jia X, Radakovich N, Shreve J, Hilton CB, Nagata Y, Hamilton BK, Mukherjee S, Al Ali N, Walter W, Hutter S, Padron E, Sallman D, Kuzmanovic T, Kerr C, Adema V, Steensma DP, Dezern A, Roboz G, Garcia-Manero G, Erba H, Haferlach C, Maciejewski JP, Haferlach T, Sekeres MA
J Clin Oncol 2021 Nov 20;39(33):3737-3746. Epub 2021 Aug 18 doi: 10.1200/JCO.20.02810. PMID: 34406850Free PMC Article
Cogné B, Ehresmann S, Beauregard-Lacroix E, Rousseau J, Besnard T, Garcia T, Petrovski S, Avni S, McWalter K, Blackburn PR, Sanders SJ, Uguen K, Harris J, Cohen JS, Blyth M, Lehman A, Berg J, Li MH, Kini U, Joss S, von der Lippe C, Gordon CT, Humberson JB, Robak L, Scott DA, Sutton VR, Skraban CM, Johnston JJ, Poduri A, Nordenskjöld M, Shashi V, Gerkes EH, Bongers EMHF, Gilissen C, Zarate YA, Kvarnung M, Lally KP, Kulch PA, Daniels B, Hernandez-Garcia A, Stong N, McGaughran J, Retterer K, Tveten K, Sullivan J, Geisheker MR, Stray-Pedersen A, Tarpinian JM, Klee EW, Sapp JC, Zyskind J, Holla ØL, Bedoukian E, Filippini F, Guimier A, Picard A, Busk ØL, Punetha J, Pfundt R, Lindstrand A, Nordgren A, Kalb F, Desai M, Ebanks AH, Jhangiani SN, Dewan T, Coban Akdemir ZH, Telegrafi A, Zackai EH, Begtrup A, Song X, Toutain A, Wentzensen IM, Odent S, Bonneau D, Latypova X, Deb W; CAUSES Study, Redon S, Bilan F, Legendre M, Troyer C, Whitlock K, Caluseriu O, Murphree MI, Pichurin PN, Agre K, Gavrilova R, Rinne T, Park M, Shain C, Heinzen EL, Xiao R, Amiel J, Lyonnet S, Isidor B, Biesecker LG, Lowenstein D, Posey JE, Denommé-Pichon AS; Deciphering Developmental Disorders study, Férec C, Yang XJ, Rosenfeld JA, Gilbert-Dussardier B, Audebert-Bellanger S, Redon R, Stessman HAF, Nellaker C, Yang Y, Lupski JR, Goldstein DB, Eichler EE, Bolduc F, Bézieau S, Küry S, Campeau PM
Am J Hum Genet 2019 Mar 7;104(3):530-541. Epub 2019 Feb 28 doi: 10.1016/j.ajhg.2019.01.010. PMID: 30827496Free PMC Article
Marshall JD, Beck S, Maffei P, Naggert JK
Eur J Hum Genet 2007 Dec;15(12):1193-202. Epub 2007 Oct 17 doi: 10.1038/sj.ejhg.5201933. PMID: 17940554
Renier D, Lajeunie E, Arnaud E, Marchac D
Childs Nerv Syst 2000 Nov;16(10-11):645-58. doi: 10.1007/s003810000320. PMID: 11151714

Clinical prediction guides

Dingemans AJM, Truijen KMG, Kim JH, Alaçam Z, Faivre L, Collins KM, Gerkes EH, van Haelst M, van de Laar IMBH, Lindstrom K, Nizon M, Pauling J, Heropolitańska-Pliszka E, Plomp AS, Racine C, Sachdev R, Sinnema M, Skranes J, Veenstra-Knol HE, Verberne EA, Vulto-van Silfhout AT, Wilsterman MEF, Ahn EE, de Vries BBA, Vissers LELM
Eur J Hum Genet 2022 Mar;30(3):271-281. Epub 2021 Sep 15 doi: 10.1038/s41431-021-00960-4. PMID: 34521999Free PMC Article
Sanchez-Jimeno C, Blanco-Kelly F, López-Grondona F, Losada-Del Pozo R, Moreno B, Rodrigo-Moreno M, Martinez-Cayuelas E, Riveiro-Alvarez R, Fenollar-Cortés M, Ayuso C, Rodríguez de Alba M, Lorda-Sanchez I, Almoguera B
Genes (Basel) 2021 Aug 30;12(9) doi: 10.3390/genes12091360. PMID: 34573342Free PMC Article
Inuzuka LM, Macedo-Souza LI, Della-Rippa B, Monteiro FP, Delgado DS, Godoy LF, Ramos L, de Athayde Costa LS, Garzon E, Kok F
Epileptic Disord 2020 Jun 1;22(3):317-322. doi: 10.1684/epd.2020.1166. PMID: 32597767
Agaimy A, Foulkes WD
Semin Diagn Pathol 2018 May;35(3):193-198. Epub 2018 Feb 1 doi: 10.1053/j.semdp.2018.01.002. PMID: 29397238
Moortgat S, Berland S, Aukrust I, Maystadt I, Baker L, Benoit V, Caro-Llopis A, Cooper NS, Debray FG, Faivre L, Gardeitchik T, Haukanes BI, Houge G, Kivuva E, Martinez F, Mehta SG, Nassogne MC, Powell-Hamilton N, Pfundt R, Rosello M, Prescott T, Vasudevan P, van Loon B, Verellen-Dumoulin C, Verloes A, Lippe CV, Wakeling E, Wilkie AOM, Wilson L, Yuen A, Study D, Low KJ, Newbury-Ecob RA
Eur J Hum Genet 2018 Jan;26(1):64-74. Epub 2017 Nov 27 doi: 10.1038/s41431-017-0038-6. PMID: 29180823Free PMC Article

Recent systematic reviews

Santomasso BD, Nastoupil LJ, Adkins S, Lacchetti C, Schneider BJ, Anadkat M, Atkins MB, Brassil KJ, Caterino JM, Chau I, Davies MJ, Ernstoff MS, Fecher L, Funchain P, Jaiyesimi I, Mammen JS, Naidoo J, Naing A, Phillips T, Porter LD, Reichner CA, Seigel C, Song JM, Spira A, Suarez-Almazor M, Swami U, Thompson JA, Vikas P, Wang Y, Weber JS, Bollin K, Ghosh M
J Clin Oncol 2021 Dec 10;39(35):3978-3992. Epub 2021 Nov 1 doi: 10.1200/JCO.21.01992. PMID: 34724386
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
Ruiz-González L, Lucena-Antón D, Salazar A, Martín-Valero R, Moral-Munoz JA
J Intellect Disabil Res 2019 Aug;63(8):1041-1067. Epub 2019 Feb 20 doi: 10.1111/jir.12606. PMID: 30788876
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J
Circulation 2019 Jun 18;139(25):e1082-e1143. Epub 2018 Nov 10 doi: 10.1161/CIR.0000000000000625. PMID: 30586774Free PMC Article
Anders PL, Davis EL
Spec Care Dentist 2010 May-Jun;30(3):110-7. doi: 10.1111/j.1754-4505.2010.00136.x. PMID: 20500706

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