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Syndromic X-linked intellectual disability 94(MRXSW)

MedGen UID:
437111
Concept ID:
C2678051
Disease or Syndrome
Synonyms: MENTAL RETARDATION, X-LINKED, SYNDROMIC 29; MRXSW; X-Linked Mental Retardation 94
 
Gene (location): GRIA3 (Xq25)
 
Monarch Initiative: MONDO:0010402
OMIM®: 300699

Definition

A syndromic X-linked intellectual disability characterized by moderate intellectual disability with variable occurrence of asthenic body habitus, dysmorphic features, autistic features, macrocephaly, seizures, myoclonic jerks, and hyporeflexia that has material basis in mutation in the GRIA3 gene on chromosome Xq25. [from MONDO]

Clinical features

From HPO
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Slender build
MedGen UID:
376828
Concept ID:
C1850573
Finding
Asthenic habitus refers to a slender build with long limbs, an angular profile, and prominent muscles or bones.
Aggressive behavior
MedGen UID:
1375
Concept ID:
C0001807
Individual Behavior
Behavior or an act aimed at harming a person, animal, or physical property (e.g., acts of physical violence; shouting, swearing, and using harsh language; slashing someone's tires).
Autism
MedGen UID:
13966
Concept ID:
C0004352
Mental or Behavioral Dysfunction
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006). Levy et al. (2009) provided a general review of autism and autism spectrum disorder, including epidemiology, characteristics of the disorder, diagnosis, neurobiologic hypotheses for the etiology, genetics, and treatment options. Genetic Heterogeneity of Autism Autism is considered to be a complex multifactorial disorder involving many genes. Accordingly, several loci have been identified, some or all of which may contribute to the phenotype. Included in this entry is AUTS1, which has been mapped to chromosome 7q22. Other susceptibility loci include AUTS3 (608049), which maps to chromosome 13q14; AUTS4 (608636), which maps to chromosome 15q11; AUTS6 (609378), which maps to chromosome 17q11; AUTS7 (610676), which maps to chromosome 17q21; AUTS8 (607373), which maps to chromosome 3q25-q27; AUTS9 (611015), which maps to chromosome 7q31; AUTS10 (611016), which maps to chromosome 7q36; AUTS11 (610836), which maps to chromosome 1q41; AUTS12 (610838), which maps to chromosome 21p13-q11; AUTS13 (610908), which maps to chromosome 12q14; AUTS14A (611913), which has been found in patients with a deletion of a region of 16p11.2; AUTS14B (614671), which has been found in patients with a duplication of a region of 16p11.2; AUTS15 (612100), associated with mutation in the CNTNAP2 gene (604569) on chromosome 7q35-q36; AUTS16 (613410), associated with mutation in the SLC9A9 gene (608396) on chromosome 3q24; AUTS17 (613436), associated with mutation in the SHANK2 gene (603290) on chromosome 11q13; AUTS18 (615032), associated with mutation in the CHD8 gene (610528) on chromosome 14q11; AUTS19 (615091), associated with mutation in the EIF4E gene (133440) on chromosome 4q23; and AUTS20 (618830), associated with mutation in the NLGN1 gene (600568) on chromosome 3q26. (NOTE: the symbol 'AUTS2' has been used to refer to a gene on chromosome 7q11 (KIAA0442; 607270) and therefore is not used as a part of this autism locus series.) There are several X-linked forms of autism susceptibility: AUTSX1 (300425), associated with mutations in the NLGN3 gene (300336); AUTSX2 (300495), associated with mutations in NLGN4 (300427); AUTSX3 (300496), associated with mutations in MECP2 (300005); AUTSX4 (300830), associated with variation in the region on chromosome Xp22.11 containing the PTCHD1 gene (300828); AUTSX5 (300847), associated with mutations in the RPL10 gene (312173); and AUTSX6 (300872), associated with mutation in the TMLHE gene (300777). A locus on chromosome 2q (606053) associated with a phenotype including intellectual disability and speech deficits was formerly designated AUTS5. Folstein and Rosen-Sheidley (2001) reviewed the genetics of autism.
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 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.
Self-injurious behavior
MedGen UID:
88371
Concept ID:
C0085271
Individual Behavior
Self-aggression.
Hyperreflexia
MedGen UID:
57738
Concept ID:
C0151889
Finding
Hyperreflexia is the presence of hyperactive stretch reflexes of the muscles.
Limb tremor
MedGen UID:
115980
Concept ID:
C0235081
Sign or Symptom
Hyporeflexia
MedGen UID:
195967
Concept ID:
C0700078
Finding
Reduction of neurologic reflexes such as the knee-jerk reaction.
Focal tonic seizure
MedGen UID:
199867
Concept ID:
C0752324
Disease or Syndrome
A type of focal motor seizure characterized by sustained increase in muscle contraction, lasting a few seconds to minutes.
Autistic behavior
MedGen UID:
163547
Concept ID:
C0856975
Mental or Behavioral Dysfunction
Persistent deficits in social interaction and communication and interaction as well as a markedly restricted repertoire of activity and interest as well as repetitive patterns of behavior.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Interictal epileptiform activity
MedGen UID:
869073
Concept ID:
C4023491
Finding
Epileptiform activity refers to distinctive EEG waves or complexes distinguished from background activity found in in a proportion of human subjects with epilepsy, but which can also be found in subjects without seizures. Interictal epileptiform activity refers to such activity that occurs in the absence of a clinical or subclinical seizure.
Frontal cortical atrophy
MedGen UID:
870517
Concept ID:
C4024965
Anatomical Abnormality
Atrophy of the frontal cortex.
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.
Brachycephaly
MedGen UID:
113165
Concept ID:
C0221356
Congenital Abnormality
An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.
Distal muscle weakness
MedGen UID:
140883
Concept ID:
C0427065
Finding
Reduced strength of the musculature of the distal extremities.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Prominent supraorbital ridges
MedGen UID:
333982
Concept ID:
C1842060
Finding
Greater than average forward and/or lateral protrusion of the supraorbital portion of the frontal bones.
Deeply set eye
MedGen UID:
473112
Concept ID:
C0423224
Finding
An eye that is more deeply recessed into the plane of the face than is typical.

Recent clinical studies

Etiology

Charzewska A, Maiwald R, Kahrizi K, Oehl-Jaschkowitz B, Dufke A, Lemke JR, Enders H, Najmabadi H, Tzschach A, Hachmann W, Jensen C, Bienek M, Poznański J, Nawara M, Chilarska T, Obersztyn E, Hoffman-Zacharska D, Gos M, Bal J, Kalscheuer VM
Clin Genet 2018 Nov;94(5):450-456. Epub 2018 Aug 9 doi: 10.1111/cge.13412. PMID: 30006928
Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, Thiruvahindrapuram B, Xu X, Ziman R, Wang Z, Vorstman JA, Thompson A, Regan R, Pilorge M, Pellecchia G, Pagnamenta AT, Oliveira B, Marshall CR, Magalhaes TR, Lowe JK, Howe JL, Griswold AJ, Gilbert J, Duketis E, Dombroski BA, De Jonge MV, Cuccaro M, Crawford EL, Correia CT, Conroy J, Conceição IC, Chiocchetti AG, Casey JP, Cai G, Cabrol C, Bolshakova N, Bacchelli E, Anney R, Gallinger S, Cotterchio M, Casey G, Zwaigenbaum L, Wittemeyer K, Wing K, Wallace S, van Engeland H, Tryfon A, Thomson S, Soorya L, Rogé B, Roberts W, Poustka F, Mouga S, Minshew N, McInnes LA, McGrew SG, Lord C, Leboyer M, Le Couteur AS, Kolevzon A, Jiménez González P, Jacob S, Holt R, Guter S, Green J, Green A, Gillberg C, Fernandez BA, Duque F, Delorme R, Dawson G, Chaste P, Café C, Brennan S, Bourgeron T, Bolton PF, Bölte S, Bernier R, Baird G, Bailey AJ, Anagnostou E, Almeida J, Wijsman EM, Vieland VJ, Vicente AM, Schellenberg GD, Pericak-Vance M, Paterson AD, Parr JR, Oliveira G, Nurnberger JI, Monaco AP, Maestrini E, Klauck SM, Hakonarson H, Haines JL, Geschwind DH, Freitag CM, Folstein SE, Ennis S, Coon H, Battaglia A, Szatmari P, Sutcliffe JS, Hallmayer J, Gill M, Cook EH, Buxbaum JD, Devlin B, Gallagher L, Betancur C, Scherer SW
Am J Hum Genet 2014 May 1;94(5):677-94. Epub 2014 Apr 24 doi: 10.1016/j.ajhg.2014.03.018. PMID: 24768552Free PMC Article
Møller LB, Lenartowicz M, Zabot MT, Josiane A, Burglen L, Bennett C, Riconda D, Fisher R, Janssens S, Mohammed S, Ausems M, Tümer Z, Horn N, Jensen TG
Orphanet J Rare Dis 2012 Jan 22;7:6. doi: 10.1186/1750-1172-7-6. PMID: 22264391Free PMC Article
Hammer S, Dorrani N, Dragich J, Kudo S, Schanen C
Ment Retard Dev Disabil Res Rev 2002;8(2):94-8. doi: 10.1002/mrdd.10023. PMID: 12112734
Chudley AE, Knoll J, Gerrard JW, Shepel L, McGahey E, Anderson J
Am J Med Genet 1983 Apr;14(4):699-712. doi: 10.1002/ajmg.1320140412. PMID: 6846402

Diagnosis

Nagarajan B, Gowda VK, Yoganathan S, Sharawat IK, Srivastava K, Vora N, Badheka R, Danda S, Kalane U, Kaur A, Madaan P, Mehta S, Negi S, Panda PK, Rajadhyaksha S, Saini AG, Saini L, Shah S, Srinivasan VM, Suthar R, Thomas M, Vyas S, Sankhyan N, Sahu JK
Epilepsia Open 2023 Dec;8(4):1383-1404. Epub 2023 Aug 25 doi: 10.1002/epi4.12811. PMID: 37583270Free PMC Article
Lumaka A, Race V, Peeters H, Corveleyn A, Coban-Akdemir Z, Jhangiani SN, Song X, Mubungu G, Posey J, Lupski JR, Vermeesch JR, Lukusa P, Devriendt K
Am J Med Genet A 2018 Sep;176(9):1897-1909. Epub 2018 Aug 8 doi: 10.1002/ajmg.a.40382. PMID: 30088852Free PMC Article
Hackmann K, Rump A, Haas SA, Lemke JR, Fryns JP, Tzschach A, Wieczorek D, Albrecht B, Kuechler A, Ripperger T, Kobelt A, Oexle K, Tinschert S, Schrock E, Kalscheuer VM, Di Donato N
Am J Med Genet A 2016 Jan;170A(1):94-102. Epub 2015 Sep 11 doi: 10.1002/ajmg.a.37378. PMID: 26358559
Hammer S, Dorrani N, Dragich J, Kudo S, Schanen C
Ment Retard Dev Disabil Res Rev 2002;8(2):94-8. doi: 10.1002/mrdd.10023. PMID: 12112734
Chudley AE, Knoll J, Gerrard JW, Shepel L, McGahey E, Anderson J
Am J Med Genet 1983 Apr;14(4):699-712. doi: 10.1002/ajmg.1320140412. PMID: 6846402

Therapy

Møller LB, Lenartowicz M, Zabot MT, Josiane A, Burglen L, Bennett C, Riconda D, Fisher R, Janssens S, Mohammed S, Ausems M, Tümer Z, Horn N, Jensen TG
Orphanet J Rare Dis 2012 Jan 22;7:6. doi: 10.1186/1750-1172-7-6. PMID: 22264391Free PMC Article

Prognosis

Zhong L, Gao X, Wang Y, Qiu W, Han L, Gu X, Zhang H
Clin Genet 2023 Jun;103(6):655-662. Epub 2023 Mar 22 doi: 10.1111/cge.14329. PMID: 36945845
Charzewska A, Maiwald R, Kahrizi K, Oehl-Jaschkowitz B, Dufke A, Lemke JR, Enders H, Najmabadi H, Tzschach A, Hachmann W, Jensen C, Bienek M, Poznański J, Nawara M, Chilarska T, Obersztyn E, Hoffman-Zacharska D, Gos M, Bal J, Kalscheuer VM
Clin Genet 2018 Nov;94(5):450-456. Epub 2018 Aug 9 doi: 10.1111/cge.13412. PMID: 30006928
Butler MG, Manzardo AM
J Assist Reprod Genet 2015 Jun;32(6):909-15. Epub 2015 May 1 doi: 10.1007/s10815-015-0484-4. PMID: 25925349Free PMC Article
Møller LB, Lenartowicz M, Zabot MT, Josiane A, Burglen L, Bennett C, Riconda D, Fisher R, Janssens S, Mohammed S, Ausems M, Tümer Z, Horn N, Jensen TG
Orphanet J Rare Dis 2012 Jan 22;7:6. doi: 10.1186/1750-1172-7-6. PMID: 22264391Free PMC Article
Wong VC, Li SY
J Child Neurol 2007 Dec;22(12):1397-400. doi: 10.1177/0883073807307091. PMID: 18174559

Clinical prediction guides

Nagarajan B, Gowda VK, Yoganathan S, Sharawat IK, Srivastava K, Vora N, Badheka R, Danda S, Kalane U, Kaur A, Madaan P, Mehta S, Negi S, Panda PK, Rajadhyaksha S, Saini AG, Saini L, Shah S, Srinivasan VM, Suthar R, Thomas M, Vyas S, Sankhyan N, Sahu JK
Epilepsia Open 2023 Dec;8(4):1383-1404. Epub 2023 Aug 25 doi: 10.1002/epi4.12811. PMID: 37583270Free PMC Article
Zhong L, Gao X, Wang Y, Qiu W, Han L, Gu X, Zhang H
Clin Genet 2023 Jun;103(6):655-662. Epub 2023 Mar 22 doi: 10.1111/cge.14329. PMID: 36945845
Charzewska A, Maiwald R, Kahrizi K, Oehl-Jaschkowitz B, Dufke A, Lemke JR, Enders H, Najmabadi H, Tzschach A, Hachmann W, Jensen C, Bienek M, Poznański J, Nawara M, Chilarska T, Obersztyn E, Hoffman-Zacharska D, Gos M, Bal J, Kalscheuer VM
Clin Genet 2018 Nov;94(5):450-456. Epub 2018 Aug 9 doi: 10.1111/cge.13412. PMID: 30006928
Møller LB, Lenartowicz M, Zabot MT, Josiane A, Burglen L, Bennett C, Riconda D, Fisher R, Janssens S, Mohammed S, Ausems M, Tümer Z, Horn N, Jensen TG
Orphanet J Rare Dis 2012 Jan 22;7:6. doi: 10.1186/1750-1172-7-6. PMID: 22264391Free PMC Article
Geiger K, Muendlein A, Stark N, Saely CH, Wabitsch M, Fraunberger P, Drexel H
Horm Metab Res 2011 Jun;43(6):380-5. Epub 2011 Mar 29 doi: 10.1055/s-0031-1273767. PMID: 21448846Free PMC Article

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