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Intellectual disability, autosomal recessive 3(MRT3)

MedGen UID:
373870
•Concept ID:
C1838023
•
Mental or Behavioral Dysfunction
Synonyms: INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 3; MRT3
 
Gene (location): CC2D1A (19p13.12)
 
Monarch Initiative: MONDO:0012037
OMIM®: 608443

Definition

Any autosomal recessive non-syndromic intellectual disability in which the cause of the disease is a mutation in the CC2D1A gene. [from MONDO]

Clinical features

From HPO
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.
See: Feature record | Search on this feature
Short attention span
MedGen UID:
82652
•Concept ID:
C0262630
•
Finding
Reduced attention span characterized by distractibility and impulsivity.
See: Feature record | Search on this feature
Hyperactivity
MedGen UID:
98406
•Concept ID:
C0424295
•
Finding
Hyperactivity is a condition characterized by constant and unusually high levels of activity, even in situations where it is deemed inappropriate.
See: Feature record | Search on this feature
Delayed speech and language development
MedGen UID:
105318
•Concept ID:
C0454644
•
Finding
A degree of language development that is significantly below the norm for a child of a specified age.
See: Feature record | Search on this feature
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.
See: Feature record | Search on this feature
Incomprehensible speech
MedGen UID:
333001
•Concept ID:
C1838027
•
Finding
See: Feature record | Search on this feature
Progressive microcephaly
MedGen UID:
340542
•Concept ID:
C1850456
•
Anatomical Abnormality
Progressive microcephaly is diagnosed when the head circumference falls progressively behind age- and gender-dependent norms.
See: Feature record | Search on this feature
Hypomimic face
MedGen UID:
208827
•Concept ID:
C0813217
•
Finding
A reduced degree of motion of the muscles beneath the skin of the face, often associated with reduced facial crease formation.
See: Feature record | Search on this feature
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Professional guidelines

PubMed

Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder.
D'Onofrio G, Accogli A, Severino M, Caliskan H, Kokotović T, Blazekovic A, Jercic KG, Markovic S, Zigman T, Goran K, Barišić N, Duranovic V, Ban A, Borovecki F, Ramadža DP, Barić I, Fazeli W, Herkenrath P, Marini C, Vittorini R, Gowda V, Bouman A, Rocca C, Alkhawaja IA, Murtaza BN, Rehman MMU, Al Alam C, Nader G, Mancardi MM, Giacomini T, Srivastava S, Alvi JR, Tomoum H, Matricardi S, Iacomino M, Riva A, Scala M, Madia F, Pistorio A, Salpietro V, Minetti C, Rivière JB, Srour M, Efthymiou S, Maroofian R, Houlden H, Vernes SC, Zara F, Striano P, Nagy V
Hum Genet 2023 Jul;142(7):909-925. Epub 2023 May 14 doi: 10.1007/s00439-023-02552-2. PMID: 37183190Free PMC Article
Diagnosis and genotype-phenotype correlation in patients with PKD1/TSC2 contiguous gene deletion syndrome.
Shang S, Mei Y, Wang T, Zheng X, Chen K, Xiong S, Dong Y, Chang Y, Wu X, Kong X, Tan M, Wu L, Zhang Y, Xiao Y, Xie Y, Cai G, Chen X, Li Q
Clin Nephrol 2022 Jun;97(6):328-338. doi: 10.5414/CN110476. PMID: 35142283
Genotype-phenotype correlation in Phelan-McDermid syndrome: A comprehensive review of chromosome 22q13 deleted genes.
Ricciardello A, Tomaiuolo P, Persico AM
Am J Med Genet A 2021 Jul;185(7):2211-2233. Epub 2021 May 5 doi: 10.1002/ajmg.a.62222. PMID: 33949759Free PMC Article

Recent clinical studies

Etiology

Prevalence of propionic acidemia in China.
Zhang Y, Peng C, Wang L, Chen S, Wang J, Tian Z, Wang C, Chen X, Zhu S, Zhang GF, Wang Y
Orphanet J Rare Dis 2023 Sep 9;18(1):281. doi: 10.1186/s13023-023-02898-w. PMID: 37689673Free PMC Article
NGLY1 deficiency: Novel variants and literature review.
Kariminejad A, Shakiba M, Shams M, Namiranian P, Eghbali M, Talebi S, Makvand M, Jaeken J, Najmabadi H, Hennekam RC
Eur J Med Genet 2021 Mar;64(3):104146. Epub 2021 Jan 23 doi: 10.1016/j.ejmg.2021.104146. PMID: 33497766
Neurocognitive, adaptive, and psychosocial functioning in individuals with Robinow syndrome.
Schwartz DD, Fein RH, Carvalho CMB, Sutton VR, Mazzeu JF, Axelrad ME
Am J Med Genet A 2021 Dec;185(12):3576-3583. Epub 2020 Sep 21 doi: 10.1002/ajmg.a.61854. PMID: 32954672
Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism.
Ebrahimi-Fakhari D, Saffari A, Wahlster L, Lu J, Byrne S, Hoffmann GF, Jungbluth H, Sahin M
Brain 2016 Feb;139(Pt 2):317-37. Epub 2015 Dec 29 doi: 10.1093/brain/awv371. PMID: 26715604Free PMC Article
Psychiatric manifestations in cerebrotendinous xanthomatosis.
Fraidakis MJ
Transl Psychiatry 2013 Sep 3;3(9):e302. doi: 10.1038/tp.2013.76. PMID: 24002088Free PMC Article

Diagnosis

Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.
Kaiyrzhanov R, Ortigoza-Escobar JD, Stringer BW, Ganieva M, Gowda VK, Srinivasan VM, Macaya A, Laner A, Onbool E, Al-Shammari R, Al-Owain M, Deconinck N, Vilain C, Dontaine P, Self E, Akram R, Hussain G, Baig SM, Iqbal J, Salpietro V, Neshatdoust M, Kasiri M, Yesil G, Uygur T, Pysden K, Berry IR, Alves CA, Giacomotto J, Houlden H, Maroofian R
Mov Disord 2024 Jun;39(6):983-995. Epub 2024 Apr 6 doi: 10.1002/mds.29754. PMID: 38581205
Chanarin-Dorfman syndrome.
Kalyon S, Gökden Y, Demirel N, Erden B, Türkyılmaz A
Turk J Gastroenterol 2019 Jan;30(1):105-108. doi: 10.5152/tjg.2018.18014. PMID: 30457558Free PMC Article
Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.
Reuter MS, Tawamie H, Buchert R, Hosny Gebril O, Froukh T, Thiel C, Uebe S, Ekici AB, Krumbiegel M, Zweier C, Hoyer J, Eberlein K, Bauer J, Scheller U, Strom TM, Hoffjan S, Abdelraouf ER, Meguid NA, Abboud A, Al Khateeb MA, Fakher M, Hamdan S, Ismael A, Muhammad S, Abdallah E, Sticht H, Wieczorek D, Reis A, Abou Jamra R
JAMA Psychiatry 2017 Mar 1;74(3):293-299. doi: 10.1001/jamapsychiatry.2016.3798. PMID: 28097321
The eye and the skin in nonendocrine metabolic disorders.
Urrets-Zavalía JA, Espósito E, Garay I, Monti R, Ruiz-Lascano A, Correa L, Serra HM, Grzybowski A
Clin Dermatol 2016 Mar-Apr;34(2):166-82. Epub 2015 Dec 7 doi: 10.1016/j.clindermatol.2015.12.002. PMID: 26903184
Alpha-mannosidosis.
Malm D, Nilssen Ø
Orphanet J Rare Dis 2008 Jul 23;3:21. doi: 10.1186/1750-1172-3-21. PMID: 18651971Free PMC Article

Therapy

CDK5RAP2 primary microcephaly is associated with hypothalamic, retinal and cochlear developmental defects.
Nasser H, Vera L, Elmaleh-Bergès M, Steindl K, Letard P, Teissier N, Ernault A, Guimiot F, Afenjar A, Moutard ML, Héron D, Alembik Y, Momtchilova M, Milani P, Kubis N, Pouvreau N, Zollino M, Guilmin Crepon S, Kaguelidou F, Gressens P, Verloes A, Rauch A, El Ghouzzi V, Drunat S, Passemard S
J Med Genet 2020 Jun;57(6):389-399. Epub 2020 Feb 3 doi: 10.1136/jmedgenet-2019-106474. PMID: 32015000
Court orders on procreation.
Matevosyan NR
Arch Gynecol Obstet 2016 Jan;293(1):87-99. Epub 2015 Jun 11 doi: 10.1007/s00404-015-3770-6. PMID: 26063342
Clinical whole exome sequencing in child neurology practice.
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
Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations.
Roques G, Munzer M, Barthez MA, Beaufils S, Beaupain B, Flood T, Keren B, Bellanné-Chantelot C, Donadieu J
Pediatr Blood Cancer 2014 Jun;61(6):1041-8. Epub 2014 Jan 30 doi: 10.1002/pbc.24964. PMID: 24482108
Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in the Hmong population by newborn screening using tandem mass spectrometry.
Matern D, He M, Berry SA, Rinaldo P, Whitley CB, Madsen PP, van Calcar SC, Lussky RC, Andresen BS, Wolff JA, Vockley J
Pediatrics 2003 Jul;112(1 Pt 1):74-8. doi: 10.1542/peds.112.1.74. PMID: 12837870

Prognosis

Prevalence of propionic acidemia in China.
Zhang Y, Peng C, Wang L, Chen S, Wang J, Tian Z, Wang C, Chen X, Zhu S, Zhang GF, Wang Y
Orphanet J Rare Dis 2023 Sep 9;18(1):281. doi: 10.1186/s13023-023-02898-w. PMID: 37689673Free PMC Article
The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.
Saffari A, Lau T, Tajsharghi H, Karimiani EG, Kariminejad A, Efthymiou S, Zifarelli G, Sultan T, Toosi MB, Sedighzadeh S, Siu VM, Ortigoza-Escobar JD, AlShamsi AM, Ibrahim S, Al-Sannaa NA, Al-Hertani W, Sandra W, Tarnopolsky M, Alavi S, Li C, Day-Salvatore DL, Martínez-González MJ, Levandoski KM, Bedoukian E, Madan-Khetarpal S, Idleburg MJ, Menezes MJ, Siddharth A, Platzer K, Oppermann H, Smitka M, Collins F, Lek M, Shahrooei M, Ghavideldarestani M, Herman I, Rendu J, Faure J, Baker J, Bhambhani V, Calderwood L, Akhondian J, Imannezhad S, Mirzadeh HS, Hashemi N, Doosti M, Safi M, Ahangari N, Torbati PN, Abedini S, Salpietro V, Gulec EY, Eshaghian S, Ghazavi M, Pascher MT, Vogel M, Abicht A, Moutton S, Bruel AL, Rieubland C, Gallati S, Strom TM, Lochmüller H, Mohammadi MH, Alvi JR, Zackai EH, Keena BA, Skraban CM, Berger SI, Andrew EH, Rahimian E, Morrow MM, Wentzensen IM, Millan F, Henderson LB, Dafsari HS, Jungbluth H, Gomez-Ospina N, McRae A, Peter M, Veltra D, Marinakis NM, Sofocleous C, Ashrafzadeh F, Pehlivan D, Lemke JR, Melki J, Benezit A, Bauer P, Weis D, Lupski JR, Senderek J, Christodoulou J, Chung WK, Goodchild R, Offiah AC, Moreno-De-Luca A, Suri M, Ebrahimi-Fakhari D, Houlden H, Maroofian R
Brain 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039. PMID: 36757831Free PMC Article
Psychiatric manifestations in cerebrotendinous xanthomatosis.
Fraidakis MJ
Transl Psychiatry 2013 Sep 3;3(9):e302. doi: 10.1038/tp.2013.76. PMID: 24002088Free PMC Article
Diagnostic exome sequencing in persons with severe intellectual disability.
de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE
N Engl J Med 2012 Nov 15;367(20):1921-9. Epub 2012 Oct 3 doi: 10.1056/NEJMoa1206524. PMID: 23033978
Alpha-mannosidosis.
Malm D, Nilssen Ø
Orphanet J Rare Dis 2008 Jul 23;3:21. doi: 10.1186/1750-1172-3-21. PMID: 18651971Free PMC Article

Clinical prediction guides

Clinical and Molecular Spectrum of Autosomal Recessive CA8-Related Cerebellar Ataxia.
Kaiyrzhanov R, Ortigoza-Escobar JD, Stringer BW, Ganieva M, Gowda VK, Srinivasan VM, Macaya A, Laner A, Onbool E, Al-Shammari R, Al-Owain M, Deconinck N, Vilain C, Dontaine P, Self E, Akram R, Hussain G, Baig SM, Iqbal J, Salpietro V, Neshatdoust M, Kasiri M, Yesil G, Uygur T, Pysden K, Berry IR, Alves CA, Giacomotto J, Houlden H, Maroofian R
Mov Disord 2024 Jun;39(6):983-995. Epub 2024 Apr 6 doi: 10.1002/mds.29754. PMID: 38581205
Landscape of genetic infantile epileptic spasms syndrome-A multicenter cohort of 124 children from India.
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
The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.
Saffari A, Lau T, Tajsharghi H, Karimiani EG, Kariminejad A, Efthymiou S, Zifarelli G, Sultan T, Toosi MB, Sedighzadeh S, Siu VM, Ortigoza-Escobar JD, AlShamsi AM, Ibrahim S, Al-Sannaa NA, Al-Hertani W, Sandra W, Tarnopolsky M, Alavi S, Li C, Day-Salvatore DL, Martínez-González MJ, Levandoski KM, Bedoukian E, Madan-Khetarpal S, Idleburg MJ, Menezes MJ, Siddharth A, Platzer K, Oppermann H, Smitka M, Collins F, Lek M, Shahrooei M, Ghavideldarestani M, Herman I, Rendu J, Faure J, Baker J, Bhambhani V, Calderwood L, Akhondian J, Imannezhad S, Mirzadeh HS, Hashemi N, Doosti M, Safi M, Ahangari N, Torbati PN, Abedini S, Salpietro V, Gulec EY, Eshaghian S, Ghazavi M, Pascher MT, Vogel M, Abicht A, Moutton S, Bruel AL, Rieubland C, Gallati S, Strom TM, Lochmüller H, Mohammadi MH, Alvi JR, Zackai EH, Keena BA, Skraban CM, Berger SI, Andrew EH, Rahimian E, Morrow MM, Wentzensen IM, Millan F, Henderson LB, Dafsari HS, Jungbluth H, Gomez-Ospina N, McRae A, Peter M, Veltra D, Marinakis NM, Sofocleous C, Ashrafzadeh F, Pehlivan D, Lemke JR, Melki J, Benezit A, Bauer P, Weis D, Lupski JR, Senderek J, Christodoulou J, Chung WK, Goodchild R, Offiah AC, Moreno-De-Luca A, Suri M, Ebrahimi-Fakhari D, Houlden H, Maroofian R
Brain 2023 Aug 1;146(8):3273-3288. doi: 10.1093/brain/awad039. PMID: 36757831Free PMC Article
Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes.
Neri S, Maia N, Fortuna AM, Damasio J, Coale E, Willis M, Jorge P, Højte AF, Fenger CD, Møller RS, Bayat A
Eur J Med Genet 2022 Nov;65(11):104624. Epub 2022 Sep 18 doi: 10.1016/j.ejmg.2022.104624. PMID: 36130690
Diagnostic exome sequencing in persons with severe intellectual disability.
de Ligt J, Willemsen MH, van Bon BW, Kleefstra T, Yntema HG, Kroes T, Vulto-van Silfhout AT, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries BB, Brunner HG, Veltman JA, Vissers LE
N Engl J Med 2012 Nov 15;367(20):1921-9. Epub 2012 Oct 3 doi: 10.1056/NEJMoa1206524. PMID: 23033978

Recent systematic reviews

Clinical, Immunologic and Molecular Spectrum of Patients with Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome: A Systematic Review.
Kiaee F, Zaki-Dizaji M, Hafezi N, Almasi-Hashiani A, Hamedifar H, Sabzevari A, Shirkani A, Zian Z, Jadidi-Niaragh F, Aghamahdi F, Goudarzvand M, Yazdani R, Abolhassani H, Aghamohammadi A, Azizi G
Endocr Metab Immune Disord Drug Targets 2021;21(4):664-672. doi: 10.2174/1871530320666200613204426. PMID: 32533820

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