PPP2R5D-Related Neurodevelopmental Disorder or Developmental and Epileptic Encephalopathy?: A Novel Phenotypic Description and Review of Published Cases

Abstract

Background Protein phosphatase 2 regulatory subunit B′ delta (PPP2R5D)-related neurodevelopmental disorder is caused by pathogenic variations in the PPP2R5D gene, product of which is involved in dephosphorylation. This is a rare disorder with description limited to case reports. Its phenotypic spectrum has expanded over the last decade.

Methods We report a child with a developmental and epileptic encephalopathy phenotype with a pathogenic PPP2R5D variant. This phenotype has not been previously reported. We also reviewed the previously published reports of patients with this disorder.

Results Including the index child, 28 cases (15 girls) were identified from nine relevant research items for analysis. All patients had developmental delay. History of seizures was observed in seven patients while macrocephaly was seen in nearly 80% of patients. Nonneurological manifestations were observed in 13 patients with the most common one being ophthalmological manifestations. The most common genetic variation was c.G592A (p.E198K). The common phenotypic associations of this variation were developmental delay, macrocephaly (11/15), and epilepsy (6/15).

Conclusion PPP2R5D gene variations should be suspected in children with developmental delay, autistic features, macrocephaly with or without epilepsy in the absence of any clear etiology. Dysmorphic features might provide a diagnostic clue. DEE phenotype may also be the presenting feature and might be an underreported entity.

Keywords

PPP2R5D - epilepsy - DEE - neurodevelopmental disorder

Authors' Contribution

P.M. and A.K. contributed by patient management, literature search, qualitative synthesis, and writing of the manuscript.

S.V. contributed by interpretation of neuroradiological images and critical review of manuscript.

A.R.S. contributed by literature search, qualitative synthesis, and critical review of manuscript.

P.P., and J.K.S. contributed by patient management and critical review of the manuscript.

L.S. contributed by patient management, writing, and critical review of manuscript.

All authors approved the final version of manuscript to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Declarations of Interest

None.

^* Contributed equally and share first authorship.

Publikationsverlauf

Eingereicht: 02. November 2020

Angenommen: 04. Januar 2021

Artikel online veröffentlicht:
26. August 2021

• References

• 1 Zablotsky B, Black LI, Maenner MJ. et al. Prevalence and trends of developmental disabilities among children in the United States: 2009-2017. Pediatrics 2019; 144 (04) e20190811
• 2 Scheffer IE, Berkovic S, Capovilla G. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58 (04) 512-521
• 3 Scheffer IE, Liao J. Deciphering the concepts behind “Epileptic encephalopathy” and “Developmental and epileptic encephalopathy.”. Eur J Paediatr Neurol 2020; 24: 11-14
• 4 Happ HC, Carvill GLA. A 2020 view on the genetics of developmental and epileptic encephalopathies. Epilepsy Curr 2020; 20 (02) 90-96
• 5 Borlot F, Abushama A, Morrison-Levy N. et al. KCNT1-related epilepsy: an international multicenter cohort of 27 pediatric cases. Epilepsia 2020; 61 (04) 679-692
• 6 Flore LA, Milunsky JM. Updates in the genetic evaluation of the child with global developmental delay or intellectual disability. Semin Pediatr Neurol 2012; 19 (04) 173-180
• 7 Kim YE, Baek ST. Neurodevelopmental aspects of RASopathies. Mol Cells 2019; 42 (06) 441-447
• 8 Yeung KS, Tso WWY, Ip JJK. et al. Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism. Mol Autism 2017; 8: 66
• 9 Mirzaa G, Foss K, Nattakom M, Chung WK. PPP2R5D-Related Neurodevelopmental Disorder. In: Adam MP, Ardinger HH, Pagon RA. et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993-2020
• 10 Shang L, Henderson LB, Cho MT. et al. De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism. Neurogenetics 2016; 17 (01) 43-49
• 11 Houge G, Haesen D, Vissers LELM. et al. B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability. J Clin Invest 2015; 125 (08) 3051-3062
• 12 Matkovic H, Janecic MS, Frkovic SH. Mutations in the PPP2R5D gene in a patient with macrocephaly and developmental delay-Jordan's syndrome. Abstracts from the 52nd European Society of Human Genetics Conference: Posters |. Eur J Hum Genet 2020; 27: 1852
• 13 Rodrigues O, Sa J, Ramos F, Saraiva J. PPP2R5D-related neurodevelopmental disorder - a case report- Proceedings of the 23rd Annual Meeting of the Portuguese Society of Human Genetics. Medicine (Baltimore) 2020; 99: e19291
• 14 Lording A, Bird-Lieberman G, Kharbanda M, Gawne-Cain M, Singh J. Expanding the radiological features in PPP2R5D mutation. Poster presentations. Dev Med Child Neurol 2019; 61 (S1): 23
• 15 Kattentidt A, de Faber JTHN, Pfundt R, Kersseboom R. Intellectual disability due to a PPP2R5D-mutation; what do we know about natural history and adult phenotype? Abstracts from the 51st European Society of Human Genetics (ESHG) Conference: Posters. Eur J Hum Genet 2019; 27: 237
• 16 Maia Almeida P, Sa J, Ramos F, Saraiva JM. How new technologies can improve the old clinical awareness. Abstracts from the 51st European Society of Human Genetics (ESHG) Conference: Posters. Eur J Hum Genet 2019; 27: 1848
• 17 Loveday C, Tatton-Brown K, Clarke M. et al; Childhood Overgrowth Collaboration. Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth. Hum Mol Genet 2015; 24 (17) 4775-4779
• 18 Jordan's Guardian Angels. Accessed October 20, 2020 at: https://jordansguardianangels.org
• 19 Biswas D, Cary W, Nolta JA. PPP2R5D-related intellectual disability and neurodevelopmental delay: a review of the current understanding of the genetics and biochemical basis of the disorder. Int J Mol Sci 2020; 21 (04) 1286
• 20 Ahn J-H, McAvoy T, Rakhilin SV, Nishi A, Greengard P, Nairn AC. Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit. Proc Natl Acad Sci U S A 2007; 104 (08) 2979-2984
• 21 Yu UY, Yoo BC, Ahn J-H. Regulatory B subunits of protein phosphatase 2a are involved in site-specific regulation of tau protein phosphorylation. Korean J Physiol Pharmacol 2014; 18 (02) 155-161
• 22 Eichhorn PJA, Creyghton MP, Bernards R. Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta 2009; 1795 (01) 1-15
• 23 Lambrecht C, Libbrecht L, Sagaert X. et al. Loss of protein phosphatase 2A regulatory subunit B56δ promotes spontaneous tumorigenesis in vivo. Oncogene 2018; 37 (04) 544-552
• 24 Kiely M, Kiely PA. PP2A: the wolf in sheep's clothing?. Cancers (Basel) 2015; 7 (02) 648-669
• 25 Coste de Bagneaux P, von Elsner L, Bierhals T. et al. A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions. PLoS Genet 2020; 16 (03) e1008625
• 26 Tadmouri A, Kiyonaka S, Barbado M. et al. Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy. EMBO J 2012; 31 (18) 3730-3744
• 27 Ronjat M, Kiyonaka S, Barbado M, De Waard M, Mori Y. Nuclear life of the voltage-gated Cacnb4 subunit and its role in gene transcription regulation. Channels (Austin) 2013; 7 (02) 119-125
• 28 Escayg A, De Waard M, Lee DD. et al. Coding and noncoding variation of the human calcium-channel beta4-subunit gene CACNB4 in patients with idiopathic generalized epilepsy and episodic ataxia. Am J Hum Genet 2000; 66 (05) 1531-1539
• 29 Wang L, Zhou K, Fu Z. et al. Brain development and Akt signaling: the crossroads of signaling pathway and neurodevelopmental diseases. J Mol Neurosci 2017; 61 (03) 379-384
• 30 Kim CY, Wirth T, Hubsch C. et al. Early-onset Parkinsonism is a manifestation of the PPP2R5D p.E200K mutation. Ann Neurol 2020; 88 (05) 1028-1033
• 31 Madaan P, Saini L, Sankhyan N. et al. Tuberous sclerosis and cutaneous stigmata: ever-expanding spectrum. Arch Dis Child 2020; 105 (08) 797