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

Priyanka Madaan; Amrit Kaur; Lokesh Saini; Pradip Paria; Sameer Vyas; Amit R. Sharma; Jitendra K. Sahu

doi:10.1055/s-0041-1733984

Neuropediatrics, Inhaltsverzeichnis

Neuropediatrics 2022; 53(01): 020-025
DOI: 10.1055/s-0041-1733984

Original Article

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

Autor*innen

Priyanka Madaan^*

¹Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Amrit Kaur^*

²Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Lokesh Saini

¹Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

⁵Department of Pediatrics, All India Institute of Medical Sciences, Jodhpur, India
Pradip Paria

¹Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Sameer Vyas

³Department of Radiodiagnosis and Imaging (Section of Neuroimaging and Interventional Radiology), Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Amit R. Sharma

⁴Department of Neurology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
Jitendra K. Sahu

¹Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

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

Volltext

Referenzen

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