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Brunet-Wagner neurodevelopmental syndrome(BRUWAG)

MedGen UID:
1794266
Concept ID:
C5562056
Disease or Syndrome
Synonym: BRUWAG
 
Gene (location): RBL2 (16q12.2)
 
Monarch Initiative: MONDO:0859217
OMIM®: 619690

Definition

Brunet-Wagner neurodevelopmental syndrome (BRUWAG) is an autosomal recessive disorder characterized by infantile hypotonia and severely impaired development affecting both motor and cognitive skills. Affected individuals either do not achieve independent ambulation or walk with an unsteady gait; those who walk may lose the ability due to spasticity of the lower limbs. They have absent language, poor or absent social skills, and behavioral abnormalities. Most have variable ocular findings, including nystagmus, strabismus, optic atrophy, myopia, or hypermetropia (summary by Brunet et al., 2020 and Samra et al., 2021). [from OMIM]

Clinical features

From HPO
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.
Self-injurious behavior
MedGen UID:
88371
Concept ID:
C0085271
Individual Behavior
Self-aggression.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Delayed ability to walk
MedGen UID:
66034
Concept ID:
C0241726
Finding
A failure to achieve the ability to walk at an appropriate developmental stage. Most children learn to walk in a series of stages, and learn to walk short distances independently between 12 and 15 months.
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.
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.
Myoclonic seizure
MedGen UID:
1385980
Concept ID:
C4317123
Sign or Symptom
A myoclonic seizure is a type of motor seizure characterised 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.
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.
Thin corpus callosum
MedGen UID:
1785336
Concept ID:
C5441562
Anatomical Abnormality
An abnormally thin corpus callous, due to atrophy, hypoplasia or agenesis. This term is intended to be used in situations where it is not known if thinning of the corpus callosum (for instance, as visualized by magnetic resonance tomography) is due to abnormal development (e.g. a leukodystrophy) or atrophy following normal development (e.g. neurodegeneration).
Increased skull ossification
MedGen UID:
5694
Concept ID:
C0020496
Disease or Syndrome
An increase in the magnitude or amount of ossification of the skull.
Neonatal hypotonia
MedGen UID:
412209
Concept ID:
C2267233
Disease or Syndrome
Muscular hypotonia (abnormally low muscle tone) manifesting in the neonatal period.
Round face
MedGen UID:
116087
Concept ID:
C0239479
Finding
The facial appearance is more circular than usual as viewed from the front.
Thick vermilion border
MedGen UID:
332232
Concept ID:
C1836543
Finding
Increased width of the skin of vermilion border region of upper lip.
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD below the mean. Alternatively, an apparently decreased distance between the hairline and the glabella.
Wide nasal bridge
MedGen UID:
341441
Concept ID:
C1849367
Finding
Increased breadth of the nasal bridge (and with it, the nasal root).
Thin eyebrow
MedGen UID:
924116
Concept ID:
C4281771
Finding
Decreased diameter of eyebrow hairs.
Periorbital fullness
MedGen UID:
1710990
Concept ID:
C4760994
Finding
Increase in periorbital soft tissue.
Hypertelorism
MedGen UID:
9373
Concept ID:
C0020534
Finding
Although hypertelorism means an excessive distance between any paired organs (e.g., the nipples), the use of the word has come to be confined to ocular hypertelorism. Hypertelorism occurs as an isolated feature and is also a feature of many syndromes, e.g., Opitz G syndrome (see 300000), Greig cephalopolysyndactyly (175700), and Noonan syndrome (163950) (summary by Cohen et al., 1995).
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.
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.
Horizontal nystagmus
MedGen UID:
124399
Concept ID:
C0271385
Disease or Syndrome
Nystagmus consisting of horizontal to-and-fro eye movements.
Gaze-evoked horizontal nystagmus
MedGen UID:
377895
Concept ID:
C1853394
Finding
Horizontal nystagmus made apparent by looking to the right or to the left.

Professional guidelines

PubMed

Johnson KA, Worbe Y, Foote KD, Butson CR, Gunduz A, Okun MS
Lancet Neurol 2023 Feb;22(2):147-158. Epub 2022 Oct 28 doi: 10.1016/S1474-4422(22)00303-9. PMID: 36354027
Lees CC, Romero R, Stampalija T, Dall'Asta A, DeVore GA, Prefumo F, Frusca T, Visser GHA, Hobbins JC, Baschat AA, Bilardo CM, Galan HL, Campbell S, Maulik D, Figueras F, Lee W, Unterscheider J, Valensise H, Da Silva Costa F, Salomon LJ, Poon LC, Ferrazzi E, Mari G, Rizzo G, Kingdom JC, Kiserud T, Hecher K
Am J Obstet Gynecol 2022 Mar;226(3):366-378. Epub 2022 Jan 10 doi: 10.1016/j.ajog.2021.11.1357. PMID: 35026129Free PMC Article
Butler MG, Miller JL, Forster JL
Curr Pediatr Rev 2019;15(4):207-244. doi: 10.2174/1573396315666190716120925. PMID: 31333129Free PMC Article

Recent clinical studies

Etiology

Müller HL, Tauber M, Lawson EA, Özyurt J, Bison B, Martinez-Barbera JP, Puget S, Merchant TE, van Santen HM
Nat Rev Dis Primers 2022 Apr 21;8(1):24. doi: 10.1038/s41572-022-00351-z. PMID: 35449162
DelRosso LM, Picchietti DL, Spruyt K, Bruni O, Garcia-Borreguero D, Kotagal S, Owens JA, Simakajornboon N, Ferri R; International Restless Legs Syndrome Study Group (IRLSSG)
Sleep Med Rev 2021 Apr;56:101406. Epub 2020 Dec 1 doi: 10.1016/j.smrv.2020.101406. PMID: 33341437
Goldmuntz E
Am J Med Genet C Semin Med Genet 2020 Mar;184(1):64-72. Epub 2020 Feb 12 doi: 10.1002/ajmg.c.31774. PMID: 32049433
McCann ME, Soriano SG
BMJ 2019 Dec 9;367:l6459. doi: 10.1136/bmj.l6459. PMID: 31818811
Zollino M, Zweier C, Van Balkom ID, Sweetser DA, Alaimo J, Bijlsma EK, Cody J, Elsea SH, Giurgea I, Macchiaiolo M, Smigiel R, Thibert RL, Benoist I, Clayton-Smith J, De Winter CF, Deckers S, Gandhi A, Huisman S, Kempink D, Kruisinga F, Lamacchia V, Marangi G, Menke L, Mulder P, Nordgren A, Renieri A, Routledge S, Saunders CJ, Stembalska A, Van Balkom H, Whalen S, Hennekam RC
Clin Genet 2019 Apr;95(4):462-478. Epub 2019 Feb 18 doi: 10.1111/cge.13506. PMID: 30677142

Diagnosis

Raga S, Specchio N, Rheims S, Wilmshurst JM
Epileptic Disord 2021 Feb 1;23(1):40-52. doi: 10.1684/epd.2021.1244. PMID: 33632673
Harris J
Int Rev Psychiatry 2018 Feb;30(1):3-17. Epub 2018 Apr 18 doi: 10.1080/09540261.2018.1455646. PMID: 29667863
Stern JS
Pract Neurol 2018 Aug;18(4):262-270. Epub 2018 Apr 10 doi: 10.1136/practneurol-2017-001755. PMID: 29636375
Lai MC, Baron-Cohen S
Lancet Psychiatry 2015 Nov;2(11):1013-27. doi: 10.1016/S2215-0366(15)00277-1. PMID: 26544750
Kalsner L, Chamberlain SJ
Pediatr Clin North Am 2015 Jun;62(3):587-606. Epub 2015 Apr 22 doi: 10.1016/j.pcl.2015.03.004. PMID: 26022164Free PMC Article

Therapy

Lees CC, Romero R, Stampalija T, Dall'Asta A, DeVore GA, Prefumo F, Frusca T, Visser GHA, Hobbins JC, Baschat AA, Bilardo CM, Galan HL, Campbell S, Maulik D, Figueras F, Lee W, Unterscheider J, Valensise H, Da Silva Costa F, Salomon LJ, Poon LC, Ferrazzi E, Mari G, Rizzo G, Kingdom JC, Kiserud T, Hecher K
Am J Obstet Gynecol 2022 Mar;226(3):366-378. Epub 2022 Jan 10 doi: 10.1016/j.ajog.2021.11.1357. PMID: 35026129Free PMC Article
Behnke J, Lemyre B, Czernik C, Zimmer KP, Ehrhardt H, Waitz M
Dtsch Arztebl Int 2019 Mar 8;116(11):177-183. doi: 10.3238/arztebl.2019.0177. PMID: 31014448Free PMC Article
Stern JS
Pract Neurol 2018 Aug;18(4):262-270. Epub 2018 Apr 10 doi: 10.1136/practneurol-2017-001755. PMID: 29636375
Wachman EM, Schiff DM, Silverstein M
JAMA 2018 Apr 3;319(13):1362-1374. doi: 10.1001/jama.2018.2640. PMID: 29614184
Margolis SS, Sell GL, Zbinden MA, Bird LM
Neurotherapeutics 2015 Jul;12(3):641-50. doi: 10.1007/s13311-015-0361-y. PMID: 26040994Free PMC Article

Prognosis

Redline S, Cook K, Chervin RD, Ishman S, Baldassari CM, Mitchell RB, Tapia IE, Amin R, Hassan F, Ibrahim S, Ross K, Elden LM, Kirkham EM, Zopf D, Shah J, Otteson T, Naqvi K, Owens J, Young L, Furth S, Connolly H, Clark CAC, Bakker JP, Garetz S, Radcliffe J, Taylor HG, Rosen CL, Wang R; Pediatric Adenotonsillectomy Trial for Snoring (PATS) Study Team
JAMA 2023 Dec 5;330(21):2084-2095. doi: 10.1001/jama.2023.22114. PMID: 38051326Free PMC Article
McElreavey K, Pailhoux E, Bashamboo A
Sex Dev 2022;16(2-3):194-206. Epub 2022 Jul 14 doi: 10.1159/000522004. PMID: 35835064
Yehia L, Keel E, Eng C
Annu Rev Med 2020 Jan 27;71:103-116. Epub 2019 Aug 21 doi: 10.1146/annurev-med-052218-125823. PMID: 31433956
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
Alam S, Lux AL
Arch Dis Child 2012 Nov;97(11):985-92. Epub 2012 Sep 8 doi: 10.1136/archdischild-2011-301119. PMID: 22962318

Clinical prediction guides

Cediel-Ulloa A, Lindner S, Rüegg J, Broberg K
Neurotoxicology 2023 Jul;97:34-46. Epub 2023 May 8 doi: 10.1016/j.neuro.2023.05.004. PMID: 37164037
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
Weiss K, Lazar HP, Kurolap A, Martinez AF, Paperna T, Cohen L, Smeland MF, Whalen S, Heide S, Keren B, Terhal P, Irving M, Takaku M, Roberts JD, Petrovich RM, Schrier Vergano SA, Kenney A, Hove H, DeChene E, Quinonez SC, Colin E, Ziegler A, Rumple M, Jain M, Monteil D, Roeder ER, Nugent K, van Haeringen A, Gambello M, Santani A, Medne L, Krock B, Skraban CM, Zackai EH, Dubbs HA, Smol T, Ghoumid J, Parker MJ, Wright M, Turnpenny P, Clayton-Smith J, Metcalfe K, Kurumizaka H, Gelb BD, Baris Feldman H, Campeau PM, Muenke M, Wade PA, Lachlan K
Genet Med 2020 Feb;22(2):389-397. Epub 2019 Aug 7 doi: 10.1038/s41436-019-0612-0. PMID: 31388190Free PMC Article
Mocquard C, Aillet S, Riffaud L
Neurochirurgie 2019 Nov;65(5):246-251. Epub 2019 Sep 27 doi: 10.1016/j.neuchi.2019.09.014. PMID: 31568780
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

Recent systematic reviews

Petriti U, Dudman DC, Scosyrev E, Lopez-Leon S
Syst Rev 2023 Jan 16;12(1):5. doi: 10.1186/s13643-023-02169-6. PMID: 36642718Free PMC Article
Sherwood E, Vergnano S, Kakuchi I, Bruce MG, Chaurasia S, David S, Dramowski A, Georges S, Guy R, Lamagni T, Levy-Bruhl D, Lyytikäinen O, Naus M, Okaro JO, Oppegaard O, Vestrheim DF, Zulz T, Steer AC, Van Beneden CA, Seale AC
Lancet Infect Dis 2022 Jul;22(7):1076-1088. Epub 2022 Apr 4 doi: 10.1016/S1473-3099(21)00672-1. PMID: 35390294Free PMC Article
DelRosso LM, Picchietti DL, Spruyt K, Bruni O, Garcia-Borreguero D, Kotagal S, Owens JA, Simakajornboon N, Ferri R; International Restless Legs Syndrome Study Group (IRLSSG)
Sleep Med Rev 2021 Apr;56:101406. Epub 2020 Dec 1 doi: 10.1016/j.smrv.2020.101406. PMID: 33341437
Romero R, Conde-Agudelo A, Da Fonseca E, O'Brien JM, Cetingoz E, Creasy GW, Hassan SS, Nicolaides KH
Am J Obstet Gynecol 2018 Feb;218(2):161-180. Epub 2017 Nov 17 doi: 10.1016/j.ajog.2017.11.576. PMID: 29157866Free PMC Article
Grandjean P, Landrigan PJ
Lancet Neurol 2014 Mar;13(3):330-8. Epub 2014 Feb 17 doi: 10.1016/S1474-4422(13)70278-3. PMID: 24556010Free PMC Article

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