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Rare neurodevelopmental disorder
Medical condition
Jordan's syndrome Other names PPP2R5D -related intellectual disability, mental retardation, autosomal dominant 35(MRD35)Specialty Psychiatry , pediatrics , occupational medicine , neurology , ophthalmology Symptoms Mild to severe global developmental delay , seizure , macrocephaly , hypotonia , autism , dysmorphic facial features Duration Lifelong Causes Heterozygous PPP2R5D mutation Diagnostic method Molecular genetic testing Differential diagnosis Cowden syndrome , Sotos syndrome , Smith-Kingsmore syndrome, M-CM , MPPH , 9q34 deletion syndrome , 16p11.2 deletion syndromeManagement Occupational therapy , physical therapy , speech therapy , applied behavior analysis Frequency 23 (2019)[1]
Jordan's syndrome (JS ) or PPP2R5D -related intellectual disability is a rare autosomal dominant neurodevelopmental disorder caused by de novo mutations in the PPP2R5D gene.[2] It is characterized by hypotonia , intellectual disability , and macrocephaly .[3] Children with JS may also have epilepsy or meet criteria for diagnosis with autism spectrum disorder .[4]
Signs and symptoms [ edit ]
Symptoms of Jordan's syndrome (JS ) are not formally defined but typically appear in early childhood and can range from mild to severe global developmental delay and intellectual disability , usually including speech delay and impairment.[5] [1] Patients with JS may meet some or all criteria for diagnosis with autism spectrum disorder due to many shared developmental symptoms.[4] Initial clinical findings may include macrocephaly , hypotonia , epilepsy , ophthalmologic abnormalities, and dysmorphic facial features. Magnetic resonance imaging may further reveal megalencephaly or defects of the ventricles or white matter . Individuals with JS may also have skeletal, cardiac, endocrine, or genital abnormalities.[1] Certain JS mutations can also cause early-onset parkinsonism between ages 20 and 40.[6]
Genetics [ edit ]
All cases of JS are caused by de novo missense point mutations in PPP2R5D , which encodes a subunit of the enzyme PP2A . At least eight pathogenic mutations have been identified: E197K, E198K, E200K, E420K, P201R, W207R, Q211P, and P53S.[7]
Patients are exclusively diagnosed with JS upon discovery of a pathogenic variant of PPP2R5D via genetic testing .[3] [4] As of 2019, at least 23 individuals with JS have been reported.[1]
Mechanisms [ edit ]
The molecular mechanisms underlying JS are unknown. Broadly, PP2A dysfunction is known to be associated with other pathologies such as Alzheimer's disease , Parkinson's disease , and cancer .[7] Studies of specific JS-causing variants such as E420K have implicated PI3K/AKT/mTOR pathway dysregulation in JS pathogenesis.[5]
Diagnosis [ edit ]
Jordan's syndrome is diagnosed through molecular genetic testing, most commonly exome sequencing.[2]
Research [ edit ]
PPP2R5D -related intellectual disability was named "Jordan's syndrome" after Jordan Lang, who was diagnosed by whole exome sequencing in 2014.[8] Lang's parents founded the charitable organization Jordan's Guardian Angels to connect families of individuals with JS. The foundation also funds PPP2R5D research, spanning diverse model systems from alpacas and fruit flies [9] to patient-derived induced pluripotent stem cells .[10] Ten primary investigators are affiliated with the foundation:[11]
References [ edit ]
^ a b c d Mirzaa G, Foss K, Nattakom M, Chung WK (24 January 2019). "PPP2R5D-Related Neurodevelopmental Disorder". In Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Mirzaa G (eds.). GeneReviews® . Seattle, WA: University of Washington. PMID 30676711 .
^ a b "PPP2R5D-related intellectual disability" . MedlinePlus . 1 February 2021. Retrieved 2021-10-01 .
^ a b Yan, Lulu; Shen, Ru; Cao, Zongfu; Han, Chunxiao; Zhang, Yuxin; Liu, Yingwen; Yang, Xiangchun; Xie, Min; Li, Haibo (2021-02-12). "A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype" . BioMed Research International . 2021 : 1–7. doi :10.1155/2021/6661860 . PMC 7895568 . PMID 33628804 .
^ a b c Shang, Linshan; Henderson, Lindsay B.; Cho, Megan T.; Petrey, Donald S.; Fong, Chin-To; Haude, Katrina M.; Shur, Natasha; Lundberg, Julie; Hauser, Natalie; Carmichael, Jason; Innis, Jeffrey (2016-01-01). "De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism" . Neurogenetics . 17 (1 ): 43–49. doi :10.1007/s10048-015-0466-9 . ISSN 1364-6753 . PMC 4765493 . PMID 26576547 .
^ a b Papke, Cinta M.; Smolen, Kali A.; Swingle, Mark R.; Cressey, Lauren; Heng, Richard A.; Toporsian, Mourad; Deng, Liyong; Hagen, Jacob; Shen, Yufeng; Chung, Wendy K.; Kettenbach, Arminja N. (January 2021). "A disorder-related variant (E420K) of a PP2A-regulatory subunit (PPP2R5D) causes constitutively active AKT-mTOR signaling and uncoordinated cell growth" . Journal of Biological Chemistry . 296 : 100313. doi :10.1016/j.jbc.2021.100313 . ISSN 0021-9258 . PMC 7952134 . PMID 33482199 .
^ Kim CY, Wirth T, Hubsch C, Németh AH, Okur V, Anheim M, et al. (2020). "Early-Onset Parkinsonism Is a Manifestation of the PPP2R5D p.E200K Mutation" . Ann Neurol . 88 (5 ): 1028–1033. doi :10.1002/ana.25863 . PMC 9052555 . PMID 32743835 . S2CID 220943402 .
^ a b Biswas, Dayita; Cary, Whitney; Nolta, Jan A. (January 2020). "PPP2R5D-Related Intellectual Disability and Neurodevelopmental Delay: A Review of the Current Understanding of the Genetics and Biochemical Basis of the Disorder" . International Journal of Molecular Sciences . 21 (4 ): 1286. doi :10.3390/ijms21041286 . PMC 7072873 . PMID 32074998 .
^ "The History of Jordan's Syndrome" . Jordan's Guardian Angels . Retrieved 2021-10-01 .
^ a b Turney, Spencer (13 August 2019). "Meet the alpacas that are helping researchers who study autism, Alzheimer's and cancer" . Vanderbilt University . Retrieved 2021-10-01 .
^ a b c "On a mission: $12 million state appropriation earmarked for Jordan's syndrome" . 25 July 2018. Retrieved 2021-10-01 .
^ "Our Research Team" . Jordan's Guardian Angels . Retrieved 2021-10-01 .
R e t r i e v e d f r o m " https://en.wikipedia.org/w/index.php?title=Jordan%27s_syndrome&oldid=1205635160 "
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