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Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity(NEDMCMS)

MedGen UID:
1684695
Concept ID:
C5231480
Disease or Syndrome
Synonym: VANDERVORE-SCHOT SYNDROME
 
Gene (location): TMX2 (11q12.1)
 
Monarch Initiative: MONDO:0032887
OMIM®: 618730

Definition

Neurodevelopmental disorder with microcephaly, cortical malformations, and spasticity (NEDMCMS) is an autosomal recessive disorder characterized by severe to profound global developmental delay, early-onset seizures, microcephaly, and polymicrogyria and/or cerebral atrophy on brain imaging. Most affected individuals are unable to walk or speak and have profoundly impaired intellectual development, as well as axial hypotonia and peripheral spasticity. Rare individuals may be less severely affected (summary by Vandervore et al., 2019). [from OMIM]

Clinical features

From HPO
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.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Cerebral atrophy
MedGen UID:
116012
Concept ID:
C0235946
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
Lissencephaly
MedGen UID:
78604
Concept ID:
C0266463
Finding
A spectrum of malformations of cortical development caused by insufficient neuronal migration that subsumes the terms agyria, pachygyria and subcortical band heterotopia. See also neuropathological definitions for 2-, 3-, and 4-layered lissencephaly.
Polymicrogyria
MedGen UID:
78605
Concept ID:
C0266464
Congenital Abnormality
Polymicrogyria is a congenital malformation of the cerebral cortex characterized by abnormal cortical layering (lamination) and an excessive number of small gyri (folds).
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.
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.
Hypoplasia of the brainstem
MedGen UID:
334226
Concept ID:
C1842688
Finding
Underdevelopment of the brainstem.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Cerebral white matter hypoplasia
MedGen UID:
892337
Concept ID:
C4022908
Finding
Underdevelopment of the cerebral white matter.
Bilateral tonic-clonic seizure with generalized onset
MedGen UID:
1368929
Concept ID:
C4476643
Sign or Symptom
A bilateral tonic-clonic seizure with generalized onset is a type of bilateral tonic-clonic seizure characterised by generalized onset; these seizures rapidly engage networks in both hemispheres at the start of the seizure.
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.
Hypertonia
MedGen UID:
10132
Concept ID:
C0026826
Finding
A condition in which there is increased muscle tone so that arms or legs, for example, are stiff and difficult to move.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.

Recent clinical studies

Etiology

Gouvea LA, Martins M, Vivacqua D, Rosseto J, Lima G, Frota AC, Abreu T, Araujo A, Hofer CB
J Child Neurol 2021 Jun;36(7):537-544. Epub 2021 Jan 7 doi: 10.1177/0883073820983163. PMID: 33406966
Cavallin M, Maillard C, Hully M, Philbert M, Boddaert N, Reilly ML, Nitschké P, Bery A, Bahi-Buisson N
Eur J Med Genet 2018 Dec;61(12):729-732. Epub 2018 May 25 doi: 10.1016/j.ejmg.2018.05.002. PMID: 29758293
Grønborg S, Kjaergaard S, Hove H, Larsen VA, Kirchhoff M
Am J Med Genet A 2015 Nov;167A(11):2731-6. Epub 2015 Jun 24 doi: 10.1002/ajmg.a.37227. PMID: 26109418
Leventer RJ, Jansen A, Pilz DT, Stoodley N, Marini C, Dubeau F, Malone J, Mitchell LA, Mandelstam S, Scheffer IE, Berkovic SF, Andermann F, Andermann E, Guerrini R, Dobyns WB
Brain 2010 May;133(Pt 5):1415-27. Epub 2010 Apr 19 doi: 10.1093/brain/awq078. PMID: 20403963Free PMC Article
Barkovich AJ, Kjos BO
AJNR Am J Neuroradiol 1992 Jan-Feb;13(1):95-103. PMID: 1375803Free PMC Article

Diagnosis

Gouvea LA, Martins M, Vivacqua D, Rosseto J, Lima G, Frota AC, Abreu T, Araujo A, Hofer CB
J Child Neurol 2021 Jun;36(7):537-544. Epub 2021 Jan 7 doi: 10.1177/0883073820983163. PMID: 33406966
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
Leventer RJ, Jansen A, Pilz DT, Stoodley N, Marini C, Dubeau F, Malone J, Mitchell LA, Mandelstam S, Scheffer IE, Berkovic SF, Andermann F, Andermann E, Guerrini R, Dobyns WB
Brain 2010 May;133(Pt 5):1415-27. Epub 2010 Apr 19 doi: 10.1093/brain/awq078. PMID: 20403963Free PMC Article
Grosso S, Cerase A, De Stefano N, Marco LD, Galluzzi P, Galimberti D, Morgese G, Balestri P
Brain Dev 2005 Jan;27(1):73-7. doi: 10.1016/j.braindev.2004.04.009. PMID: 15626547
Barkovich AJ, Kjos BO
AJNR Am J Neuroradiol 1992 Jan-Feb;13(1):95-103. PMID: 1375803Free PMC Article

Prognosis

Calame DG, Bakhtiari S, Logan R, Coban-Akdemir Z, Du H, Mitani T, Fatih JM, Hunter JV, Herman I, Pehlivan D, Jhangiani SN, Person R, Schnur RE, Jin SC, Bilguvar K, Posey JE, Koh S, Firouzabadi SG, Alehabib E, Tafakhori A, Esmkhani S, Gibbs RA, Noureldeen MM, Zaki MS, Marafi D, Darvish H, Kruer MC, Lupski JR
Genet Med 2021 Dec;23(12):2455-2460. Epub 2021 Aug 12 doi: 10.1038/s41436-021-01291-x. PMID: 34385670Free PMC Article
Gouvea LA, Martins M, Vivacqua D, Rosseto J, Lima G, Frota AC, Abreu T, Araujo A, Hofer CB
J Child Neurol 2021 Jun;36(7):537-544. Epub 2021 Jan 7 doi: 10.1177/0883073820983163. PMID: 33406966
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
Mavili E, Coskun A, Per H, Donmez H, Kumandas S, Yikilmaz A
Childs Nerv Syst 2012 Jun;28(6):905-9. doi: 10.1007/s00381-012-1703-2. PMID: 22286201
Leventer RJ, Jansen A, Pilz DT, Stoodley N, Marini C, Dubeau F, Malone J, Mitchell LA, Mandelstam S, Scheffer IE, Berkovic SF, Andermann F, Andermann E, Guerrini R, Dobyns WB
Brain 2010 May;133(Pt 5):1415-27. Epub 2010 Apr 19 doi: 10.1093/brain/awq078. PMID: 20403963Free PMC Article

Clinical prediction guides

Calame DG, Bakhtiari S, Logan R, Coban-Akdemir Z, Du H, Mitani T, Fatih JM, Hunter JV, Herman I, Pehlivan D, Jhangiani SN, Person R, Schnur RE, Jin SC, Bilguvar K, Posey JE, Koh S, Firouzabadi SG, Alehabib E, Tafakhori A, Esmkhani S, Gibbs RA, Noureldeen MM, Zaki MS, Marafi D, Darvish H, Kruer MC, Lupski JR
Genet Med 2021 Dec;23(12):2455-2460. Epub 2021 Aug 12 doi: 10.1038/s41436-021-01291-x. PMID: 34385670Free PMC Article
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
Tanaka AJ, Cho MT, Millan F, Juusola J, Retterer K, Joshi C, Niyazov D, Garnica A, Gratz E, Deardorff M, Wilkins A, Ortiz-Gonzalez X, Mathews K, Panzer K, Brilstra E, van Gassen KL, Volker-Touw CM, van Binsbergen E, Sobreira N, Hamosh A, McKnight D, Monaghan KG, Chung WK
Am J Hum Genet 2015 Sep 3;97(3):457-64. Epub 2015 Aug 20 doi: 10.1016/j.ajhg.2015.07.014. PMID: 26299366Free PMC Article
Mavili E, Coskun A, Per H, Donmez H, Kumandas S, Yikilmaz A
Childs Nerv Syst 2012 Jun;28(6):905-9. doi: 10.1007/s00381-012-1703-2. PMID: 22286201
Grosso S, Cerase A, De Stefano N, Marco LD, Galluzzi P, Galimberti D, Morgese G, Balestri P
Brain Dev 2005 Jan;27(1):73-7. doi: 10.1016/j.braindev.2004.04.009. PMID: 15626547

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