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Cortical dysplasia, complex, with other brain malformations 9(CDCBM9)

MedGen UID:
1648399
Concept ID:
C4748540
Disease or Syndrome
Synonyms: CDCBM9; CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 9
 
Gene (location): CTNNA2 (2p12)
 
Monarch Initiative: MONDO:0032578
OMIM®: 618174

Definition

Complex cortical dysplasia with other brain malformations-9 is a severe autosomal recessive disorder characterized by profoundly impaired motor and cognitive development apparent from early infancy. Affected individuals develop intractable seizures and are unable to speak or ambulate. Brain imaging shows pachygyria as well as hypogenesis of the corpus callosum and other variable brain abnormalities. The phenotype results from impaired cortical neuronal migration (summary by Schaffer et al., 2018). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039). [from OMIM]

Clinical features

From HPO
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
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.
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Spastic tetraplegia
MedGen UID:
98433
Concept ID:
C0426970
Disease or Syndrome
Spastic paralysis affecting all four limbs.
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.
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 brainstem
MedGen UID:
334226
Concept ID:
C1842688
Finding
Underdevelopment of the brainstem.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Pachygyria
MedGen UID:
504794
Concept ID:
CN001193
Finding
Pachygyria is a malformation of cortical development with abnormally wide gyri with sulci 1,5-3 cm apart and abnormally thick cortex measuring more than 5 mm (radiological definition). See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Secondary microcephaly
MedGen UID:
608952
Concept ID:
C0431352
Finding
Head circumference which falls below 2 standard deviations below the mean for age and gender because of insufficient head growth after birth.
Generalized hypotonia
MedGen UID:
346841
Concept ID:
C1858120
Finding
Generalized muscular hypotonia (abnormally low muscle tone).

Professional guidelines

PubMed

Schwartz RA, Fernández G, Kotulska K, Jóźwiak S
J Am Acad Dermatol 2007 Aug;57(2):189-202. doi: 10.1016/j.jaad.2007.05.004. PMID: 17637444
Guerreiro MM, Andermann F, Andermann E, Palmini A, Hwang P, Hoffman HJ, Otsubo H, Bastos A, Dubeau F, Snipes GJ, Olivier A, Rasmussen T
Neurology 1998 Nov;51(5):1263-9. doi: 10.1212/wnl.51.5.1263. PMID: 9818843

Recent clinical studies

Etiology

Zöllner JP, Grau J, Rosenow F, Sauter M, Knuf M, Kurlemann G, Mayer T, Hertzberg C, Bertsche A, Immisch I, Klein KM, Knake S, Marquard K, Meyer S, Noda AH, von Podewils F, Schäfer H, Thiels C, Willems LM, Zukunft B, Schubert-Bast S, Strzelczyk A
Orphanet J Rare Dis 2021 Jun 2;16(1):250. doi: 10.1186/s13023-021-01838-w. PMID: 34078440Free PMC Article
Thiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, O'Callaghan FJ, Wong M, Sahebkar F, Checketts D, Knappertz V; GWPCARE6 Study Group
JAMA Neurol 2021 Mar 1;78(3):285-292. doi: 10.1001/jamaneurol.2020.4607. PMID: 33346789Free PMC Article
Steiner JE, McCoy GN, Hess CP, Dobyns WB, Metry DW, Drolet BA, Maheshwari M, Siegel DH
Am J Med Genet A 2018 Jan;176(1):48-55. Epub 2017 Nov 24 doi: 10.1002/ajmg.a.38523. PMID: 29171184Free PMC Article
Li J, Wang L, Guo H, Shi L, Zhang K, Tang M, Hu S, Dong S, Liu Y, Wang T, Yu P, He X, Hu Z, Zhao J, Liu C, Sun ZS, Xia K
Mol Psychiatry 2017 Sep;22(9):1282-1290. Epub 2017 Jul 25 doi: 10.1038/mp.2017.140. PMID: 28831199
Prather P, de Vries PJ
J Child Neurol 2004 Sep;19(9):666-74. doi: 10.1177/08830738040190090601. PMID: 15563012

Diagnosis

Klonowska K, Thiele EA, Grevelink JM, Thorner AR, Kwiatkowski DJ
J Med Genet 2022 Sep;59(9):920-923. Epub 2021 Oct 11 doi: 10.1136/jmedgenet-2021-108160. PMID: 34635572
Thiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, O'Callaghan FJ, Wong M, Sahebkar F, Checketts D, Knappertz V; GWPCARE6 Study Group
JAMA Neurol 2021 Mar 1;78(3):285-292. doi: 10.1001/jamaneurol.2020.4607. PMID: 33346789Free PMC Article
Steiner JE, McCoy GN, Hess CP, Dobyns WB, Metry DW, Drolet BA, Maheshwari M, Siegel DH
Am J Med Genet A 2018 Jan;176(1):48-55. Epub 2017 Nov 24 doi: 10.1002/ajmg.a.38523. PMID: 29171184Free PMC Article
Islam MP, Roach ES
Handb Clin Neurol 2015;132:97-109. doi: 10.1016/B978-0-444-62702-5.00006-8. PMID: 26564073
Schwartz RA, Fernández G, Kotulska K, Jóźwiak S
J Am Acad Dermatol 2007 Aug;57(2):189-202. doi: 10.1016/j.jaad.2007.05.004. PMID: 17637444

Therapy

Leitner DF, Kanshin E, Askenazi M, Siu Y, Friedman D, Devore S, Jones D, Ueberheide B, Wisniewski T, Devinsky O
PLoS One 2022;17(5):e0268597. Epub 2022 May 19 doi: 10.1371/journal.pone.0268597. PMID: 35587487Free PMC Article
Zöllner JP, Grau J, Rosenow F, Sauter M, Knuf M, Kurlemann G, Mayer T, Hertzberg C, Bertsche A, Immisch I, Klein KM, Knake S, Marquard K, Meyer S, Noda AH, von Podewils F, Schäfer H, Thiels C, Willems LM, Zukunft B, Schubert-Bast S, Strzelczyk A
Orphanet J Rare Dis 2021 Jun 2;16(1):250. doi: 10.1186/s13023-021-01838-w. PMID: 34078440Free PMC Article
Thiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, O'Callaghan FJ, Wong M, Sahebkar F, Checketts D, Knappertz V; GWPCARE6 Study Group
JAMA Neurol 2021 Mar 1;78(3):285-292. doi: 10.1001/jamaneurol.2020.4607. PMID: 33346789Free PMC Article
Sasongko TH, Ismail NF, Zabidi-Hussin Z
Cochrane Database Syst Rev 2016 Jul 13;7(7):CD011272. doi: 10.1002/14651858.CD011272.pub2. PMID: 27409709Free PMC Article
Schwartz RA, Fernández G, Kotulska K, Jóźwiak S
J Am Acad Dermatol 2007 Aug;57(2):189-202. doi: 10.1016/j.jaad.2007.05.004. PMID: 17637444

Prognosis

d'Orio P, Pelliccia V, Biondi D, Scarpa P, Gozzo F, Revay M, Cardinale F, Tassi L, Cossu M
Seizure 2022 Apr;97:8-14. Epub 2022 Feb 27 doi: 10.1016/j.seizure.2022.02.013. PMID: 35247673
Willems LM, Schubert-Bast S, Grau J, Hertzberg C, Kurlemann G, Wiemer-Kruel A, Bast T, Bertsche A, Bettendorf U, Fiedler B, Hahn A, Hartmann H, Hornemann F, Immisch I, Jacobs J, Kieslich M, Klein KM, Klotz KA, Kluger G, Knuf M, Mayer T, Marquard K, Meyer S, Muhle H, Müller-Schlüter K, Noda AH, Ruf S, Sauter M, Schlump JU, Syrbe S, Thiels C, Trollmann R, Wilken B, Zöllner JP, Rosenow F, Strzelczyk A
Eur J Paediatr Neurol 2021 Nov;35:111-122. Epub 2021 Oct 7 doi: 10.1016/j.ejpn.2021.10.003. PMID: 34673401
Thiele EA, Bebin EM, Bhathal H, Jansen FE, Kotulska K, Lawson JA, O'Callaghan FJ, Wong M, Sahebkar F, Checketts D, Knappertz V; GWPCARE6 Study Group
JAMA Neurol 2021 Mar 1;78(3):285-292. doi: 10.1001/jamaneurol.2020.4607. PMID: 33346789Free PMC Article
van der Poest Clement EA, Sahin M, Peters JM
J Child Neurol 2018 Jul;33(8):519-524. Epub 2018 Apr 24 doi: 10.1177/0883073818768309. PMID: 29687739
Kotulska K, Jurkiewicz E, Domańska-Pakieła D, Grajkowska W, Mandera M, Borkowska J, Jóźwiak S
Eur J Paediatr Neurol 2014 Nov;18(6):714-21. Epub 2014 Jul 5 doi: 10.1016/j.ejpn.2014.06.009. PMID: 25030328

Clinical prediction guides

Musante L, Faletra F, Meier K, Tomoum H, Najarzadeh Torbati P, Blair E, North S, Gärtner J, Diegmann S, Beiraghi Toosi M, Ashrafzadeh F, Ghayoor Karimiani E, Murphy D, Murru FM, Zanus C, Magnolato A, La Bianca M, Feresin A, Girotto G, Gasparini P, Costa P, Carrozzi M
Am J Med Genet A 2022 Sep;188(9):2652-2665. Epub 2022 Jun 7 doi: 10.1002/ajmg.a.62852. PMID: 35670379Free PMC Article
d'Orio P, Pelliccia V, Biondi D, Scarpa P, Gozzo F, Revay M, Cardinale F, Tassi L, Cossu M
Seizure 2022 Apr;97:8-14. Epub 2022 Feb 27 doi: 10.1016/j.seizure.2022.02.013. PMID: 35247673
Willems LM, Schubert-Bast S, Grau J, Hertzberg C, Kurlemann G, Wiemer-Kruel A, Bast T, Bertsche A, Bettendorf U, Fiedler B, Hahn A, Hartmann H, Hornemann F, Immisch I, Jacobs J, Kieslich M, Klein KM, Klotz KA, Kluger G, Knuf M, Mayer T, Marquard K, Meyer S, Muhle H, Müller-Schlüter K, Noda AH, Ruf S, Sauter M, Schlump JU, Syrbe S, Thiels C, Trollmann R, Wilken B, Zöllner JP, Rosenow F, Strzelczyk A
Eur J Paediatr Neurol 2021 Nov;35:111-122. Epub 2021 Oct 7 doi: 10.1016/j.ejpn.2021.10.003. PMID: 34673401
Huang Q, Zhou J, Wang X, Li T, Wang M, Wang J, Teng P, Qi X, Zhu M, Luan G, Zhai F
Seizure 2021 May;88:45-52. Epub 2021 Mar 25 doi: 10.1016/j.seizure.2021.03.022. PMID: 33812307
Steiner JE, McCoy GN, Hess CP, Dobyns WB, Metry DW, Drolet BA, Maheshwari M, Siegel DH
Am J Med Genet A 2018 Jan;176(1):48-55. Epub 2017 Nov 24 doi: 10.1002/ajmg.a.38523. PMID: 29171184Free PMC Article

Recent systematic reviews

Romero VI, Arias-Almeida B, Aguiar SA
BMC Genomics 2022 Dec 22;23(1):849. doi: 10.1186/s12864-022-09071-w. PMID: 36550402Free PMC Article
Sasongko TH, Ismail NF, Zabidi-Hussin Z
Cochrane Database Syst Rev 2016 Jul 13;7(7):CD011272. doi: 10.1002/14651858.CD011272.pub2. PMID: 27409709Free PMC Article

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