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Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy(NEDESBA)

MedGen UID:
1717952
•Concept ID:
C5394027
•
Disease or Syndrome
Synonyms: NEDESBA; NEURODEVELOPMENTAL DISORDER WITH EPILEPSY, SPASTICITY, AND BRAIN ATROPHY
 
Gene (location): TRAPPC4 (11q23.3)
 
Monarch Initiative: MONDO:0032894
OMIM®: 618741

Definition

Neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA) is an autosomal recessive disorder characterized by severely impaired global development apparent soon after birth. Affected individuals develop seizures in the first year of life and achieve almost no psychomotor progress, resulting in feeding difficulties and an inability to walk or speak. Other features include hypotonia, peripheral spasticity with contractures, cortical visual impairment, and dysmorphic features, including microcephaly. Death in childhood may occur (summary by Van Bergen et al., 2020). Van Bergen et al. (2020) noted that the molecular mechanism of this disorder can be classified into a group of similar phenotypes resulting from mutations in genes associated with transport protein particles, sometimes referred to as 'TRAPPopathies' (review by Sacher et al., 2019). [from OMIM]

Clinical features

From HPO
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.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
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.
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Spastic tetraparesis
MedGen UID:
658719
•Concept ID:
C0575059
•
Disease or Syndrome
Spastic weakness affecting all four limbs.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
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.
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Brain atrophy
MedGen UID:
1643639
•Concept ID:
C4551584
•
Disease or Syndrome
Partial or complete wasting (loss) of brain tissue that was once present.
See: Feature record | Search on this feature
Scoliosis
MedGen UID:
11348
•Concept ID:
C0036439
•
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
See: Feature record | Search on this feature
Microcephaly
MedGen UID:
1644158
•Concept ID:
C4551563
•
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
See: Feature record | Search on this feature
Narrow forehead
MedGen UID:
326956
•Concept ID:
C1839758
•
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
See: Feature record | Search on this feature
Long philtrum
MedGen UID:
351278
•Concept ID:
C1865014
•
Finding
Distance between nasal base and midline upper lip vermilion border more than 2 SD above the mean. Alternatively, an apparently increased distance between nasal base and midline upper lip vermilion border.
See: Feature record | Search on this feature
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Recent clinical studies

Etiology

Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.
Salpietro V, Maroofian R, Zaki MS, Wangen J, Ciolfi A, Barresi S, Efthymiou S, Lamaze A, Aughey GN, Al Mutairi F, Rad A, Rocca C, Calì E, Accogli A, Zara F, Striano P, Mojarrad M, Tariq H, Giacopuzzi E, Taylor JC, Oprea G, Skrahina V, Rehman KU, Abd Elmaksoud M, Bassiony M, El Said HG, Abdel-Hamid MS, Al Shalan M, Seo G, Kim S, Lee H, Khang R, Issa MY, Elbendary HM, Rafat K, Marinakis NM, Traeger-Synodinos J, Ververi A, Sourmpi M, Eslahi A, Khadivi Zand F, Beiraghi Toosi M, Babaei M, Jackson A; SYNAPS Study Group, Bertoli-Avella A, Pagnamenta AT, Niceta M, Battini R, Corsello A, Leoni C, Chiarelli F, Dallapiccola B, Faqeih EA, Tallur KK, Alfadhel M, Alobeid E, Maddirevula S, Mankad K, Banka S, Ghayoor-Karimiani E, Tartaglia M, Chung WK, Green R, Alkuraya FS, Jepson JEC, Houlden H
Am J Hum Genet 2024 Jan 4;111(1):200-210. Epub 2023 Dec 20 doi: 10.1016/j.ajhg.2023.11.012. PMID: 38118446Free PMC Article
Progressive cerebral atrophies in three children with COL4A1 mutations.
Nakamura Y, Okanishi T, Yamada H, Okazaki T, Hosoda C, Itai T, Miyatake S, Saitsu H, Matsumoto N, Maegaki Y
Brain Dev 2021 Nov;43(10):1033-1038. Epub 2021 Jul 17 doi: 10.1016/j.braindev.2021.06.008. PMID: 34281745
Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.
Nicita F, Ginevrino M, Travaglini L, D'Arrigo S, Zorzi G, Borgatti R, Terrone G, Catteruccia M, Vasco G, Brankovic V, Siliquini S, Romano S, Veredice C, Pedemonte M, Armando M, Lettori D, Stregapede F, Bosco L, Sferra A, Tessarollo V, Romaniello R, Ristori G, Bertini E, Valente EM, Zanni G
J Med Genet 2021 Jul;58(7):475-483. Epub 2020 Jul 31 doi: 10.1136/jmedgenet-2020-107007. PMID: 32737135
Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.
Chelban V, Alsagob M, Kloth K, Chirita-Emandi A, Vandrovcova J, Maroofian R, Davagnanam I, Bakhtiari S, AlSayed MD, Rahbeeni Z, AlZaidan H, Malintan NT, Johannsen J, Efthymiou S, Ghayoor Karimiani E, Mankad K, Al-Shahrani SA, Beiraghi Toosi M, AlShammari M, Groppa S, Haridy NA, AlQuait L, Qari A, Huma R, Salih MA, Almass R, Almutairi FB, Hamad MH, Alorainy IA, Ramzan K, Imtiaz F, Puiu M, Kruer MC, Bierhals T, Wood NW, Colak D, Houlden H, Kaya N
Eur J Neurol 2020 Feb;27(2):334-342. Epub 2019 Oct 17 doi: 10.1111/ene.14082. PMID: 31509304Free PMC Article
Congenital Disorders of Autophagy: What a Pediatric Neurologist Should Know.
Ebrahimi-Fakhari D
Neuropediatrics 2018 Feb;49(1):18-25. Epub 2017 Nov 7 doi: 10.1055/s-0037-1608652. PMID: 29112993

Diagnosis

Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
Franchino CA, Brughera M, Baderna V, De Ritis D, Rocco A, Seneca S, Regal L, Podini P, D'Antonio M, Toro C, Quattrini A, Scalais E, Maltecca F
Brain 2024 Mar 1;147(3):1043-1056. doi: 10.1093/brain/awad340. PMID: 37804316Free PMC Article
Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.
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
Delineation of the phenotype of MED17-related disease in Caucasus-Jewish families.
Fattal-Valevski A, Ben Sira L, Lerman-Sagie T, Strausberg R, Bloch-Mimouni A, Edvardson S, Kaufman R, Chernuha V, Schneebaum Sender N, Heimer G, Ben Zeev B
Eur J Paediatr Neurol 2021 May;32:40-45. Epub 2021 Mar 5 doi: 10.1016/j.ejpn.2020.08.011. PMID: 33756211
Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.
Chelban V, Alsagob M, Kloth K, Chirita-Emandi A, Vandrovcova J, Maroofian R, Davagnanam I, Bakhtiari S, AlSayed MD, Rahbeeni Z, AlZaidan H, Malintan NT, Johannsen J, Efthymiou S, Ghayoor Karimiani E, Mankad K, Al-Shahrani SA, Beiraghi Toosi M, AlShammari M, Groppa S, Haridy NA, AlQuait L, Qari A, Huma R, Salih MA, Almass R, Almutairi FB, Hamad MH, Alorainy IA, Ramzan K, Imtiaz F, Puiu M, Kruer MC, Bierhals T, Wood NW, Colak D, Houlden H, Kaya N
Eur J Neurol 2020 Feb;27(2):334-342. Epub 2019 Oct 17 doi: 10.1111/ene.14082. PMID: 31509304Free PMC Article
BRAT1 mutations present with a spectrum of clinical severity.
Srivastava S, Olson HE, Cohen JS, Gubbels CS, Lincoln S, Davis BT, Shahmirzadi L, Gupta S, Picker J, Yu TW, Miller DT, Soul JS, Poretti A, Naidu S
Am J Med Genet A 2016 Sep;170(9):2265-73. Epub 2016 Jun 9 doi: 10.1002/ajmg.a.37783. PMID: 27282546Free PMC Article

Therapy

A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination.
Miyamoto S, Nakashima M, Ohashi T, Hiraide T, Kurosawa K, Yamamoto T, Takanashi J, Osaka H, Inoue K, Miyazaki T, Wada Y, Okamoto N, Saitsu H
Mol Genet Genomic Med 2019 Aug;7(8):e814. Epub 2019 Jun 23 doi: 10.1002/mgg3.814. PMID: 31231989Free PMC Article
Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy.
Fichera M, Failla P, Saccuzzo L, Miceli M, Salvo E, Castiglia L, Galesi O, Grillo L, Calì F, Greco D, Amato C, Romano C, Elia M
Hum Genet 2019 Feb;138(2):187-198. Epub 2019 Jan 17 doi: 10.1007/s00439-019-01972-3. PMID: 30656450
Novel features in the evolution of adenylosuccinate lyase deficiency.
Pérez-Dueñas B, Sempere A, Campistol J, Alonso-Colmenero I, Díez M, González V, Merinero B, Desviat LR, Artuch R
Eur J Paediatr Neurol 2012 Jul;16(4):343-8. Epub 2011 Sep 7 doi: 10.1016/j.ejpn.2011.08.008. PMID: 21903433
Sterotactic hypothalamotomy in erethic children.
Arjona VE
Acta Neurochir (Wien) 1974;Suppl 21:185-91. doi: 10.1007/978-3-7091-8355-7_25. PMID: 4213397

Prognosis

Deficiencies in vesicular transport mediated by TRAPPC4 are associated with severe syndromic intellectual disability.
Van Bergen NJ, Guo Y, Al-Deri N, Lipatova Z, Stanga D, Zhao S, Murtazina R, Gyurkovska V, Pehlivan D, Mitani T, Gezdirici A, Antony J, Collins F, Willis MJH, Coban Akdemir ZH, Liu P, Punetha J, Hunter JV, Jhangiani SN, Fatih JM, Rosenfeld JA, Posey JE, Gibbs RA, Karaca E, Massey S, Ranasinghe TG, Sleiman P, Troedson C, Lupski JR, Sacher M, Segev N, Hakonarson H, Christodoulou J
Brain 2020 Jan 1;143(1):112-130. doi: 10.1093/brain/awz374. PMID: 31794024Free PMC Article
Genetic and phenotypic characterization of NKX6-2-related spastic ataxia and hypomyelination.
Chelban V, Alsagob M, Kloth K, Chirita-Emandi A, Vandrovcova J, Maroofian R, Davagnanam I, Bakhtiari S, AlSayed MD, Rahbeeni Z, AlZaidan H, Malintan NT, Johannsen J, Efthymiou S, Ghayoor Karimiani E, Mankad K, Al-Shahrani SA, Beiraghi Toosi M, AlShammari M, Groppa S, Haridy NA, AlQuait L, Qari A, Huma R, Salih MA, Almass R, Almutairi FB, Hamad MH, Alorainy IA, Ramzan K, Imtiaz F, Puiu M, Kruer MC, Bierhals T, Wood NW, Colak D, Houlden H, Kaya N
Eur J Neurol 2020 Feb;27(2):334-342. Epub 2019 Oct 17 doi: 10.1111/ene.14082. PMID: 31509304Free PMC Article
Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy.
Fichera M, Failla P, Saccuzzo L, Miceli M, Salvo E, Castiglia L, Galesi O, Grillo L, Calì F, Greco D, Amato C, Romano C, Elia M
Hum Genet 2019 Feb;138(2):187-198. Epub 2019 Jan 17 doi: 10.1007/s00439-019-01972-3. PMID: 30656450
A homozygous canonical splice acceptor site mutation in PRUNE1 is responsible for a rare childhood neurodegenerative disease in Manitoba Cree families.
Hartley JN, Simard LR, Ly V, Del Bigio MR, Frosk P
Am J Med Genet A 2019 Feb;179(2):206-218. Epub 2018 Dec 17 doi: 10.1002/ajmg.a.60690. PMID: 30556349
PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum.
Alhaddad B, Schossig A, Haack TB, Kovács-Nagy R, Braunisch MC, Makowski C, Senderek J, Vill K, Müller-Felber W, Strom TM, Krabichler B, Freisinger P, Deshpande C, Polster T, Wolf NI, Desguerre I, Wörmann F, Rötig A, Ahting U, Kopajtich R, Prokisch H, Meitinger T, Feichtinger RG, Mayr JA, Jungbluth H, Hubmann M, Zschocke J, Distelmaier F, Koch J
Neuropediatrics 2018 Oct;49(5):330-338. Epub 2018 Jun 25 doi: 10.1055/s-0038-1661396. PMID: 29940663

Clinical prediction guides

Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.
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
Further evidence of muscle involvement in neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy.
Majethia P, Do Rosario MC, Kaur P, Karanvir, Shankar R, Sharma S, Siddiqui S, Shukla A
Ann Hum Genet 2022 Mar;86(2):94-101. Epub 2021 Dec 8 doi: 10.1111/ahg.12452. PMID: 34878169Free PMC Article
Mutations in ACTL6B, coding for a subunit of the neuron-specific chromatin remodeling complex nBAF, cause early onset severe developmental and epileptic encephalopathy with brain hypomyelination and cerebellar atrophy.
Fichera M, Failla P, Saccuzzo L, Miceli M, Salvo E, Castiglia L, Galesi O, Grillo L, Calì F, Greco D, Amato C, Romano C, Elia M
Hum Genet 2019 Feb;138(2):187-198. Epub 2019 Jan 17 doi: 10.1007/s00439-019-01972-3. PMID: 30656450
PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum.
Alhaddad B, Schossig A, Haack TB, Kovács-Nagy R, Braunisch MC, Makowski C, Senderek J, Vill K, Müller-Felber W, Strom TM, Krabichler B, Freisinger P, Deshpande C, Polster T, Wolf NI, Desguerre I, Wörmann F, Rötig A, Ahting U, Kopajtich R, Prokisch H, Meitinger T, Feichtinger RG, Mayr JA, Jungbluth H, Hubmann M, Zschocke J, Distelmaier F, Koch J
Neuropediatrics 2018 Oct;49(5):330-338. Epub 2018 Jun 25 doi: 10.1055/s-0038-1661396. PMID: 29940663
Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination.
Chelban V, Patel N, Vandrovcova J, Zanetti MN, Lynch DS, Ryten M, Botía JA, Bello O, Tribollet E, Efthymiou S, Davagnanam I; SYNAPSE Study Group, Bashiri FA, Wood NW, Rothman JE, Alkuraya FS, Houlden H
Am J Hum Genet 2017 Jun 1;100(6):969-977. doi: 10.1016/j.ajhg.2017.05.009. PMID: 28575651Free PMC Article

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