Description
PPP2R5D-related intellectual disability is a neurological disorder characterized by moderate to severe developmental delay and intellectual disability. Affected individuals have weak muscle tone (hypotonia); delayed development of motor skills, such as sitting, standing, and walking; and delayed speech development. Recurrent seizures (epilepsy) and autism spectrum disorder, which is characterized by impaired communications and social interaction, can also occur in affected individuals. Most people with PPP2R5D-related intellectual disability have an unusually large head size (macrocephaly), and some have other unusual facial features, including a prominent forehead (frontal bossing), widely spaced eyes (hypertelorism), and eyes that slant downward (downslanting palpebral fissures).
Frequency
PPP2R5D-related intellectual disability is a rare disorder. At least 20 individuals with this condition have been described in the medical literature.
Causes
Mutations in the PPP2R5D gene have been found to cause PPP2R5D-related intellectual disability. This gene provides instructions for making a protein called B56-delta (B56δ). The B56δ protein is one piece of an enzyme called protein phosphatase 2A (PP2A), which removes phosphate groups, consisting of clusters of oxygen and phosphorus atoms, from certain proteins. This process, called dephosphorylation, helps control whether the protein is turned on or off. PP2A enzymes containing the B56δ protein are found mainly in the brain, where they are thought to play roles in the normal development and function of nerve cells (neurons).
PPP2R5D gene mutations are thought to result in the production of an altered B56δ protein. Although the effects of these variations are unclear, researchers suspect that they change or impair the activity of the PP2A enzyme. Abnormal or reduced PP2A enzyme activity is thought to disrupt signaling pathways in neurons, impairing their normal development and functioning, which may underlie intellectual disability and other neurological features of PPP2R5D-related intellectual disability.
Inheritance
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
Most cases of this condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) in an affected individual’s parent or in early embryonic development. These cases occur in people with no history of the disorder in their family.
Other Names for This Condition
- Autosomal dominant mental retardation 35
Additional Information & Resources
Genetic Testing Information
Patient Support and Advocacy Resources
Clinical Trials
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
References
- Houge G, Haesen D, Vissers LE, Mehta S, Parker MJ, Wright M, Vogt J, McKee S, Tolmie JL, Cordeiro N, Kleefstra T, Willemsen MH, Reijnders MR, Berland S, Hayman E, Lahat E, Brilstra EH, van Gassen KL, Zonneveld-Huijssoon E, de Bie CI, Hoischen A, Eichler EE, Holdhus R, Steen VM, Doskeland SO, Hurles ME, FitzPatrick DR, Janssens V. B56delta-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J Clin Invest. 2015 Aug 3;125(8):3051-62. doi: 10.1172/JCI79860. Epub 2015 Jul 13. Citation on PubMed or Free article on PubMed Central
- Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J. 2001 Feb 1;353(Pt 3):417-39. doi: 10.1042/0264-6021:3530417. Citation on PubMed or Free article on PubMed Central
- Loveday C, Tatton-Brown K, Clarke M, Westwood I, Renwick A, Ramsay E, Nemeth A, Campbell J, Joss S, Gardner M, Zachariou A, Elliott A, Ruark E, van Montfort R; Childhood Overgrowth Collaboration; Rahman N. Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. Hum Mol Genet. 2015 Sep 1;24(17):4775-9. doi: 10.1093/hmg/ddv182. Epub 2015 May 13. Erratum In: Hum Mol Genet. 2019 May 1;28(9):1578. Citation on PubMed or Free article on PubMed Central
- Shang L, Henderson LB, Cho MT, Petrey DS, Fong CT, Haude KM, Shur N, Lundberg J, Hauser N, Carmichael J, Innis J, Schuette J, Wu YW, Asaikar S, Pearson M, Folk L, Retterer K, Monaghan KG, Chung WK. De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. Neurogenetics. 2016 Jan;17(1):43-9. doi: 10.1007/s10048-015-0466-9. Epub 2015 Nov 17. Citation on PubMed or Free article on PubMed Central
- Yu UY, Yoo BC, Ahn JH. Regulatory B Subunits of Protein Phosphatase 2A Are Involved in Site-specific Regulation of Tau Protein Phosphorylation. Korean J Physiol Pharmacol. 2014 Apr;18(2):155-61. doi: 10.4196/kjpp.2014.18.2.155. Epub 2014 Apr 3. Citation on PubMed or Free article on PubMed Central
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