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Early-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome(PEBAS)

MedGen UID:
1798652
Concept ID:
C5567229
Disease or Syndrome
Synonym: ENCEPHALOPATHY, PROGRESSIVE, EARLY-ONSET, WITH BRAIN ATROPHY AND SPASTICITY
SNOMED CT: Early-onset progressive encephalopathy, hearing loss, pons hypoplasia, brain atrophy syndrome (1169356004)
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): TRAPPC12 (2p25.3)
 
Monarch Initiative: MONDO:0044696
OMIM®: 617669
Orphanet: ORPHA500144

Definition

A rare genetic neurological disorder with characteristics of early-onset severe global developmental delay with regression, congenital or acquired microcephaly, hearing loss, truncal hypotonia, appendicular spasticity, and dystonia and/or myoclonus. Additional reported manifestations include seizures, optic atrophy, cortical visual impairment, scoliosis, and dysphagia. Brain imaging shows pontine hypoplasia, partial agenesis of the corpus callosum, and diffuse cerebral atrophy with relative sparing of the cerebellum. [from SNOMEDCT_US]

Clinical features

From HPO
Neurogenic bladder
MedGen UID:
595
Concept ID:
C0005697
Disease or Syndrome
A type of bladder dysfunction caused by neurologic damage. Neurogenic bladder can be flaccid or spastic. Common manifestatios of neurogenic bladder are overflow incontinence, frequency, urgency, urge incontinence, and retention.
Dysphagia
MedGen UID:
41440
Concept ID:
C0011168
Disease or Syndrome
Difficulty in swallowing.
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.
Hearing impairment
MedGen UID:
235586
Concept ID:
C1384666
Disease or Syndrome
A decreased magnitude of the sensory perception of sound.
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.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Finding
Very brief, involuntary random muscular contractions occurring at rest, in response to sensory stimuli, or accompanying voluntary movements.
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.
Encephalopathy
MedGen UID:
39314
Concept ID:
C0085584
Disease or Syndrome
Encephalopathy is a term that means brain disease, damage, or malfunction. In general, encephalopathy is manifested by an altered mental state.
Corpus callosum, agenesis of
MedGen UID:
104498
Concept ID:
C0175754
Congenital Abnormality
The corpus callosum is the largest fiber tract in the central nervous system and the major interhemispheric fiber bundle in the brain. Formation of the corpus callosum begins as early as 6 weeks' gestation, with the first fibers crossing the midline at 11 to 12 weeks' gestation, and completion of the basic shape by age 18 to 20 weeks (Schell-Apacik et al., 2008). Agenesis of the corpus callosum (ACC) is one of the most frequent malformations in brain with a reported incidence ranging between 0.5 and 70 in 10,000 births. ACC is a clinically and genetically heterogeneous condition, which can be observed either as an isolated condition or as a manifestation in the context of a congenital syndrome (see MOLECULAR GENETICS and Dobyns, 1996). Also see mirror movements-1 and/or agenesis of the corpus callosum (MRMV1; 157600). Schell-Apacik et al. (2008) noted that there is confusion in the literature regarding radiologic terminology concerning partial absence of the corpus callosum, where various designations have been used, including hypogenesis, hypoplasia, partial agenesis, or dysgenesis.
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
Hypsarrhythmia
MedGen UID:
195766
Concept ID:
C0684276
Finding
Hypsarrhythmia is abnormal interictal high amplitude waves and a background of irregular spikes. There is continuous (during wakefulness), high-amplitude (>200 Hz), generalized polymorphic slowing with no organized background and multifocal spikes demonstrated by electroencephalography (EEG).
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
Developmental regression
MedGen UID:
324613
Concept ID:
C1836830
Disease or Syndrome
Loss of developmental skills, as manifested by loss of developmental milestones.
Severe global developmental delay
MedGen UID:
332436
Concept ID:
C1837397
Finding
A severe delay in the achievement of motor or mental milestones in the domains of development of a child.
Hypoplasia of the pons
MedGen UID:
341246
Concept ID:
C1848529
Finding
Underdevelopment of the pons.
Simplified gyral pattern
MedGen UID:
413664
Concept ID:
C2749675
Finding
An abnormality of the cerebral cortex with fewer gyri but with normal cortical thickness. This pattern is usually often associated with congenital microcephaly.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Extra-axial cerebrospinal fluid accumulation
MedGen UID:
868477
Concept ID:
C4022871
Finding
An increased amount of cerebrospinal fluid (CSF) in the subarachnoid space.
Appendicular spasticity
MedGen UID:
937224
Concept ID:
C4313257
Finding
A type of spasticity that affects one or more limbs (arms or legs).
Cerebral cortical atrophy
MedGen UID:
1646740
Concept ID:
C4551583
Disease or Syndrome
Atrophy of the cortex of the cerebrum.
Scoliosis
MedGen UID:
11348
Concept ID:
C0036439
Disease or Syndrome
The presence of an abnormal lateral curvature of the spine.
Axial hypotonia
MedGen UID:
342959
Concept ID:
C1853743
Finding
Muscular hypotonia (abnormally low muscle tone) affecting the musculature of the trunk.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Optic atrophy
MedGen UID:
18180
Concept ID:
C0029124
Disease or Syndrome
Atrophy of the optic nerve. Optic atrophy results from the death of the retinal ganglion cell axons that comprise the optic nerve and manifesting as a pale optic nerve on fundoscopy.
Hypoplastic optic chiasm
MedGen UID:
767486
Concept ID:
C3554572
Finding
Developmental defect characterized by undergrowth of the optic chiasm.
Cerebral visual impairment
MedGen UID:
890568
Concept ID:
C4048268
Pathologic Function
A form of loss of vision caused by damage to the visual cortex rather than a defect in the eye.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVEarly-onset progressive encephalopathy-hearing loss-pons hypoplasia-brain atrophy syndrome

Professional guidelines

PubMed

Na JH, Lee YM
Acta Neurol Scand 2022 Apr;145(4):414-422. Epub 2021 Dec 7 doi: 10.1111/ane.13566. PMID: 34877647
Tohyama J, Nakashima M, Nabatame S, Gaik-Siew C, Miyata R, Rener-Primec Z, Kato M, Matsumoto N, Saitsu H
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Recent clinical studies

Etiology

Calikusu FZ, Akkus S, Kochan Kizilkilic E, Poyraz BC, Altunç AT, Kiziltan G, Gunduz A
Clin Neurol Neurosurg 2023 Oct;233:107975. Epub 2023 Sep 17 doi: 10.1016/j.clineuro.2023.107975. PMID: 37734268
Polsinelli AJ, Apostolova LG
Continuum (Minneap Minn) 2022 Jun 1;28(3):676-701. doi: 10.1212/CON.0000000000001082. PMID: 35678398Free PMC Article
Ferreras C, Gorito V, Pedro J, Ferreira S, Costa C, Santos Silva R, Castro Correia C
Endokrynol Pol 2021;72(4):353-356. Epub 2021 May 19 doi: 10.5603/EP.a2021.0038. PMID: 34010437
Villain N, Dubois B
Semin Neurol 2019 Apr;39(2):213-226. Epub 2019 Mar 29 doi: 10.1055/s-0039-1681041. PMID: 30925614
Bertini E, Zanni G, Boltshauser E
Handb Clin Neurol 2018;155:91-103. doi: 10.1016/B978-0-444-64189-2.00006-8. PMID: 29891079

Diagnosis

Best J, Chapleau M, Rabinovici GD
Expert Rev Neurother 2023 Mar;23(3):227-236. Epub 2023 Mar 15 doi: 10.1080/14737175.2023.2190885. PMID: 36920752
Polsinelli AJ, Apostolova LG
Continuum (Minneap Minn) 2022 Jun 1;28(3):676-701. doi: 10.1212/CON.0000000000001082. PMID: 35678398Free PMC Article
Risacher SL, Saykin AJ
Handb Clin Neurol 2019;167:191-227. doi: 10.1016/B978-0-12-804766-8.00012-1. PMID: 31753134Free PMC Article
Villain N, Dubois B
Semin Neurol 2019 Apr;39(2):213-226. Epub 2019 Mar 29 doi: 10.1055/s-0039-1681041. PMID: 30925614
Perry DC, Miller BL
Semin Neurol 2013 Sep;33(4):336-41. Epub 2013 Nov 14 doi: 10.1055/s-0033-1359316. PMID: 24234354

Therapy

You FL, Xia GF, Cai J
Curr Alzheimer Res 2023;20(5):371-378. doi: 10.2174/1567205020666230811092906. PMID: 37872794
Stallworth JY, Blair DR, Slavotinek A, Moore AT, Duncan JL, de Alba Campomanes AG
Ophthalmic Genet 2023 Oct;44(5):486-490. Epub 2022 Nov 24 doi: 10.1080/13816810.2022.2141792. PMID: 36420660Free PMC Article
Grande V, Ornaghi F, Comerio L, Restelli E, Masone A, Corbelli A, Tolomeo D, Capone V, Axten JM, Laping NJ, Fiordaliso F, Sallese M, Chiesa R
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Wenning GK, Ben Shlomo Y, Magalhães M, Daniel SE, Quinn NP
Brain 1994 Aug;117 ( Pt 4):835-45. doi: 10.1093/brain/117.4.835. PMID: 7922469

Prognosis

Garcia-Moreno H, Langbehn DR, Abiona A, Garrood I, Fleszar Z, Manes MA, Morley AMS, Craythorne E, Mohammed S, Henshaw T, Turner S, Naik H, Bodi I, Sarkany RPE, Fassihi H, Lehmann AR, Giunti P
Brain 2023 Dec 1;146(12):5044-5059. doi: 10.1093/brain/awad266. PMID: 38040034Free PMC Article
Catsman-Berrevoets CE, Koudijs SM, Buijze MSJ, de Laat PCJ, Pasmans SGMA, Dremmen MHG
Eur J Paediatr Neurol 2022 May;38:66-72. Epub 2022 Apr 13 doi: 10.1016/j.ejpn.2022.04.002. PMID: 35461064
Chiari A, Vinceti G, Adani G, Tondelli M, Galli C, Fiondella L, Costa M, Molinari MA, Filippini T, Zamboni G, Vinceti M
Alzheimers Dement 2021 Jan;17(1):81-88. Epub 2020 Sep 11 doi: 10.1002/alz.12177. PMID: 32914938
Georgiou M, Robson AG, Singh N, Pontikos N, Kane T, Hirji N, Ripamonti C, Rotsos T, Dubra A, Kalitzeos A, Webster AR, Carroll J, Michaelides M
Invest Ophthalmol Vis Sci 2019 Dec 2;60(15):5112-5123. doi: 10.1167/iovs.19-27761. PMID: 31826238Free PMC Article
Bertini E, Zanni G, Boltshauser E
Handb Clin Neurol 2018;155:91-103. doi: 10.1016/B978-0-444-64189-2.00006-8. PMID: 29891079

Clinical prediction guides

Jiang Y, Zhou L, Wang Y, Ouyang J, Li S, Xiao X, Jia X, Wang J, Yi Z, Sun W, Jiao X, Wang P, Hejtmancik JF, Zhang Q
Invest Ophthalmol Vis Sci 2023 Mar 1;64(3):14. doi: 10.1167/iovs.64.3.24. PMID: 36917121Free PMC Article
Catsman-Berrevoets CE, Koudijs SM, Buijze MSJ, de Laat PCJ, Pasmans SGMA, Dremmen MHG
Eur J Paediatr Neurol 2022 May;38:66-72. Epub 2022 Apr 13 doi: 10.1016/j.ejpn.2022.04.002. PMID: 35461064
Izquierdo-Serra M, Fernández-Fernández JM, Serrano M
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Sferra A, Baillat G, Rizza T, Barresi S, Flex E, Tasca G, D'Amico A, Bellacchio E, Ciolfi A, Caputo V, Cecchetti S, Torella A, Zanni G, Diodato D, Piermarini E, Niceta M, Coppola A, Tedeschi E, Martinelli D, Dionisi-Vici C, Nigro V, Dallapiccola B, Compagnucci C, Tartaglia M, Haase G, Bertini E
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Tohyama J, Nakashima M, Nabatame S, Gaik-Siew C, Miyata R, Rener-Primec Z, Kato M, Matsumoto N, Saitsu H
J Hum Genet 2015 Apr;60(4):167-73. Epub 2015 Jan 29 doi: 10.1038/jhg.2015.5. PMID: 25631096

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