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Mental retardation, autosomal dominant 5(MRD5)

MedGen UID:
382611
Concept ID:
C2675473
Disease or Syndrome
Synonyms: MRD5
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, 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 heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
 
Gene (location): SYNGAP1 (6p21.32)
OMIM®: 612621

Definition

MRD5 is characterized by moderate to severe intellectual disability with delayed psychomotor development apparent in the first years of life. Most patients develop variable types of seizures, some have autism or autism spectrum disorder (see 209850), and some have acquired microcephaly (summary by Berryer et al., 2013). [from GTR]

Additional descriptions

From OMIM
MRD5 is characterized by moderate to severe intellectual disability with delayed psychomotor development apparent in the first years of life. Most patients develop variable types of seizures, some have autism or autism spectrum disorder (see 209850), and some have acquired microcephaly (summary by Berryer et al., 2013).  http://www.omim.org/entry/612621
From GHR
SYNGAP1-related intellectual disability is a neurological disorder characterized by moderate to severe intellectual disability that is evident in early childhood. The earliest features are typically delayed development of speech and motor skills, such as sitting, standing, and walking. Many people with this condition have weak muscle tone (hypotonia), which contributes to the difficulty with motor skills. Some affected individuals lose skills they had already acquired (developmental regression). Other features of SYNGAP1-related intellectual disability include recurrent seizures (epilepsy), hyperactivity, and autism spectrum disorder, which is characterized by impaired communication and social interaction; almost everyone with SYNGAP1-related intellectual disability develops epilepsy, and about half have autism spectrum disorder.  https://ghr.nlm.nih.gov/condition/syngap1-related-intellectual-disability

Clinical features

Seizure Disorders
MedGen UID:
4506
Concept ID:
C0014544
Disease or Syndrome
A brain disorder characterized by episodes of abnormally increased neuronal discharge resulting in transient episodes of sensory or motor neurological dysfunction, or psychic dysfunction. These episodes may or may not be associated with loss of consciousness or convulsions.
Language impairment
MedGen UID:
44069
Concept ID:
C0023015
Mental or Behavioral Dysfunction
A category of disorders characterized by an impairment in the development of an individual's language capabilities, which is in contrast to his/her non-verbal intellect.
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.
Spasmodic torticollis
MedGen UID:
101818
Concept ID:
C0152116
Sign or Symptom
Involuntary contractions of the neck musculature resulting in an abnormal posture of or abnormal movements of the head.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Epileptic encephalopathy
MedGen UID:
452596
Concept ID:
C0543888
Disease or Syndrome
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
A disorder beginning in childhood. It is marked by the presence of markedly abnormal or impaired development in social interaction and communication and a markedly restricted repertoire of activity and interest. Manifestations of the disorder vary greatly depending on the developmental level and chronological age of the individual (DSM-IV).
Psychomotor regression, progressive
MedGen UID:
340556
Concept ID:
C1850493
Finding
Loss of developmental skills, as manifested by loss of developmental milestones.
Cognitive delay
MedGen UID:
351243
Concept ID:
C1864897
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.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Subnormal intellectual functioning which originates during the developmental period. Intellectual disability, previously referred to as mental retardation, has been defined as an IQ score below 70.
No development of motor milestones
MedGen UID:
892432
Concept ID:
C4020874
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Muscular hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
A condition of decreased tone of the skeletal muscles and diminished resistance to passive stretching.
Spasmodic torticollis
MedGen UID:
101818
Concept ID:
C0152116
Sign or Symptom
Involuntary contractions of the neck musculature resulting in an abnormal posture of or abnormal movements of the head.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.
Spasmodic torticollis
MedGen UID:
101818
Concept ID:
C0152116
Sign or Symptom
Involuntary contractions of the neck musculature resulting in an abnormal posture of or abnormal movements of the head.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.

Recent clinical studies

Etiology

Delplanque J, Devos D, Huin V, Genet A, Sand O, Moreau C, Goizet C, Charles P, Anheim M, Monin ML, Buée L, Destée A, Grolez G, Delmaire C, Dujardin K, Dellacherie D, Brice A, Stevanin G, Strubi-Vuillaume I, Dürr A, Sablonnière B
Brain 2014 Oct;137(Pt 10):2657-63. Epub 2014 Jul 28 doi: 10.1093/brain/awu202. PMID: 25070513
Blair MA, Abou-Khalil B, Crunk A, Haines JL, Hedera P
Epilepsia 2011 May;52(5):993-9. Epub 2011 Apr 11 doi: 10.1111/j.1528-1167.2011.03059.x. PMID: 21480884
Kumar H, Prabhu N, Cameron A
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009 Sep;108(3):e72-9. doi: 10.1016/j.tripleo.2009.04.035. PMID: 19716495
Finch R, Moore HG, Lindor N, Jalal SM, Markowitz A, Suresh J, Offit K, Guillem JG
Dis Colon Rectum 2005 Nov;48(11):2148-52. doi: 10.1007/s10350-005-0177-7. PMID: 16228830
Raedle J, Friedl W, Engels H, Koenig R, Trojan J, Zeuzem S
Am J Gastroenterol 2001 Oct;96(10):3016-20. doi: 10.1111/j.1572-0241.2001.04674.x. PMID: 11693343

Diagnosis

Schlögel MJ, Mendola A, Fastré E, Vasudevan P, Devriendt K, de Ravel TJ, Van Esch H, Casteels I, Arroyo Carrera I, Cristofoli F, Fieggen K, Jones K, Lipson M, Balikova I, Singer A, Soller M, Mercedes Villanueva M, Revencu N, Boon LM, Brouillard P, Vikkula M
Orphanet J Rare Dis 2015 May 2;10:52. doi: 10.1186/s13023-015-0271-4. PMID: 25934493Free PMC Article
Bartholdi D, Stray-Pedersen A, Azzarello-Burri S, Kibaek M, Kirchhoff M, Oneda B, Rødningen O, Schmitt-Mechelke T, Rauch A, Kjaergaard S
Am J Med Genet A 2014 May;164A(5):1277-83. Epub 2014 Mar 24 doi: 10.1002/ajmg.a.36439. PMID: 24664804
Shimada S, Okamoto N, Nomura S, Fukui M, Shimakawa S, Sangu N, Shimojima K, Osawa M, Yamamoto T
Am J Med Genet A 2013 Aug;161A(8):2078-83. Epub 2013 Jul 4 doi: 10.1002/ajmg.a.36027. PMID: 23825006
Blair MA, Abou-Khalil B, Crunk A, Haines JL, Hedera P
Epilepsia 2011 May;52(5):993-9. Epub 2011 Apr 11 doi: 10.1111/j.1528-1167.2011.03059.x. PMID: 21480884
Zweier C, Peippo MM, Hoyer J, Sousa S, Bottani A, Clayton-Smith J, Reardon W, Saraiva J, Cabral A, Gohring I, Devriendt K, de Ravel T, Bijlsma EK, Hennekam RC, Orrico A, Cohen M, Dreweke A, Reis A, Nurnberg P, Rauch A
Am J Hum Genet 2007 May;80(5):994-1001. Epub 2007 Mar 23 doi: 10.1086/515583. PMID: 17436255Free PMC Article

Therapy

Srivastava S, Cohen JS, Vernon H, Barañano K, McClellan R, Jamal L, Naidu S, Fatemi A
Ann Neurol 2014 Oct;76(4):473-83. Epub 2014 Aug 30 doi: 10.1002/ana.24251. PMID: 25131622
Miyajima T, Kumada T, Saito K, Fujii T
Brain Dev 2013 Feb;35(2):155-7. Epub 2012 Aug 9 doi: 10.1016/j.braindev.2012.07.012. PMID: 22883468
Gras D, Jonard L, Roze E, Chantot-Bastaraud S, Koht J, Motte J, Rodriguez D, Louha M, Caubel I, Kemlin I, Lion-François L, Goizet C, Guillot L, Moutard ML, Epaud R, Héron B, Charles P, Tallot M, Camuzat A, Durr A, Polak M, Devos D, Sanlaville D, Vuillaume I, Billette de Villemeur T, Vidailhet M, Doummar D
J Neurol Neurosurg Psychiatry 2012 Oct;83(10):956-62. Epub 2012 Jul 24 doi: 10.1136/jnnp-2012-302505. PMID: 22832740
Hiraki T, Mimura H, Gobara H, Fujiwara H, Iguchi T, Sakurai J, Norikane S, Kato K, Kanazawa S
J Vasc Interv Radiol 2009 Jun;20(6):819-23. doi: 10.1016/j.jvir.2009.02.019. PMID: 19465308
Jones AC, Daniells CE, Snell RG, Tachataki M, Idziaszczyk SA, Krawczak M, Sampson JR, Cheadle JP
Hum Mol Genet 1997 Nov;6(12):2155-61. PMID: 9328481

Prognosis

Kleyner R, Malcolmson J, Tegay D, Ward K, Maughan A, Maughan G, Nelson L, Wang K, Robison R, Lyon GJ
Cold Spring Harb Mol Case Stud 2016 Nov;2(6):a001131. doi: 10.1101/mcs.a001131. PMID: 27900361Free PMC Article
Al-Maawali A, Barry BJ, Rajab A, El-Quessny M, Seman A, Coury SN, Barkovich AJ, Yang E, Walsh CA, Mochida GH, Stoler JM
Am J Med Genet A 2016 Feb;170A(2):435-40. Epub 2015 Oct 13 doi: 10.1002/ajmg.a.37422. PMID: 26463574Free PMC Article
Carreño M, Garcia-Alvarez D, Maestro I, Fernández S, Donaire A, Boget T, Rumià J, Pintor L, Setoain X
Epileptic Disord 2010 Jun;12(2):155-8. Epub 2010 May 18 doi: 10.1684/epd.2010.0307. PMID: 20478764
Kumar H, Prabhu N, Cameron A
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009 Sep;108(3):e72-9. doi: 10.1016/j.tripleo.2009.04.035. PMID: 19716495
Coutinho P, Barros J, Zemmouri R, Guimarães J, Alves C, Chorão R, Lourenço E, Ribeiro P, Loureiro JL, Santos JV, Hamri A, Paternotte C, Hazan J, Silva MC, Prud'homme JF, Grid D
Arch Neurol 1999 Aug;56(8):943-9. PMID: 10448799

Clinical prediction guides

Zhang B, Willing M, Grange DK, Shinawi M, Manwaring L, Vineyard M, Kulkarni S, Cottrell CE
Am J Med Genet A 2016 Mar;170(3):583-93. Epub 2015 Nov 24 doi: 10.1002/ajmg.a.37445. PMID: 26601658
Bartholdi D, Stray-Pedersen A, Azzarello-Burri S, Kibaek M, Kirchhoff M, Oneda B, Rødningen O, Schmitt-Mechelke T, Rauch A, Kjaergaard S
Am J Med Genet A 2014 May;164A(5):1277-83. Epub 2014 Mar 24 doi: 10.1002/ajmg.a.36439. PMID: 24664804
Shimada S, Okamoto N, Nomura S, Fukui M, Shimakawa S, Sangu N, Shimojima K, Osawa M, Yamamoto T
Am J Med Genet A 2013 Aug;161A(8):2078-83. Epub 2013 Jul 4 doi: 10.1002/ajmg.a.36027. PMID: 23825006
Blair MA, Abou-Khalil B, Crunk A, Haines JL, Hedera P
Epilepsia 2011 May;52(5):993-9. Epub 2011 Apr 11 doi: 10.1111/j.1528-1167.2011.03059.x. PMID: 21480884
Holinski-Feder E, Reyniers E, Uhrig S, Golla A, Wauters J, Kroisel P, Bossuyt P, Rost I, Jedele K, Zierler H, Schwab S, Wildenauer D, Speicher MR, Willems PJ, Meitinger T, Kooy RF
Am J Hum Genet 2000 Jan;66(1):16-25. doi: 10.1086/302703. PMID: 10631133Free PMC Article

Recent systematic reviews

Loddenkemper T, Grote K, Evers S, Oelerich M, Stögbauer F
J Neurol 2002 May;249(5):584-95. doi: 10.1007/s004150200068. PMID: 12021949

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