Evaluation of the Patients with the Diagnosis of Pontocerebellar Hypoplasia: A Multicenter National Study.

CLP1 Genotype Phenotype Pontocerebellar Hypoplasia

Journal

Cerebellum (London, England)

ISSN: 1473-4230

Titre abrégé: Cerebellum

Pays: United States

ID NLM: 101089443

Informations de publication

Date de publication:
15 Apr 2024

Historique:

accepted: 27 03 2024

medline: 16 4 2024

pubmed: 16 4 2024

entrez: 15 4 2024

Statut: aheadofprint

Résumé

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of neurodegenerative disorders characterized by hypoplasia and degeneration of the cerebellum and pons. We aimed to identify the clinical, laboratory, and imaging findings of the patients with diagnosed PCH with confirmed genetic analysis. We collected available clinical data, laboratory, and imaging findings in our retrospective multicenter national study of 64 patients with PCH in Turkey. The genetic analysis included the whole-exome sequencing (WES), targeted next-generation sequencing (NGS), or single gene analysis. Sixty-four patients with PCH were 28 female (43.8%) and 36 (56.3%) male. The patients revealed homozygous mutation in 89.1%, consanguinity in 79.7%, pregnancy at term in 85.2%, microcephaly in 91.3%, psychomotor retardation in 98.4%, abnormal neurological findings in 100%, seizure in 63.8%, normal biochemistry and metabolic investigations in 92.2%, and dysmorphic findings in 51.2%. The missense mutation was found to be the most common variant type in all patients with PCH. It was detected as CLP1 (n = 17) was the most common PCH related gene. The homozygous missense variant c.419G > A (p.Arg140His) was identified in all patients with CLP1. Moreover, all patients showed the same homozygous missense variant c.919G > T (p.A307S) in TSEN54 group (n = 6). In Turkey, CLP1 was identified as the most common causative gene with the identical variant c.419G > A; p.Arg140His. The current study supports that genotype data on PCH leads to phenotypic variability over a wide phenotypic spectrum.

Identifiants

DOI: 10.1007/s12311-024-01690-1 PMID: 38622473

pubmed: 38622473

doi: 10.1007/s12311-024-01690-1

pii: 10.1007/s12311-024-01690-1

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Informations de copyright

Références

van Dijk T, Baas F, Barth PG, Poll-The BT. What’s new in pontocerebellar hypoplasia? An update on genes and subtypes. Orphanet J Rare Dis. 2018;13(1):92.

pubmed: 29903031 pmcid: 6003036 doi: 10.1186/s13023-018-0826-2

Nuovo S, Micalizzi A, Romaniello R, Arrigoni F, Ginevrino M, Casella A, et al. Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study. J Med Genet. 2022;59(4):399–409.

pubmed: 34085948 doi: 10.1136/jmedgenet-2020-107497

Namavar Y, Barth PG, Kasher PR, van Ruissen F, Brockmann K, Bernert G, et al. Clinical, neuroradiological and genetic findings in pontocerebellar hypoplasia. Brain. 2011;134(Pt 1):143–56.

pubmed: 20952379 doi: 10.1093/brain/awq287

Brun R. Zur Kenntnis der Bildungsfehler des Kleinhirns. I. Über Aplasie und Hypoplasie des Neozerebellums. Schweiz Arch Neurol Psychiat. 1917;1:61–123.

Barth PG, Vrensen GF, Uylings HB, Oorthuys JW, Stam FC. Inherited syndrome of microcephaly, dyskinesia and pontocerebellar hypoplasia: a systemic atrophy with early onset. J Neurol Sci. 1990;97(1):25–42.

pubmed: 2370559 doi: 10.1016/0022-510X(90)90096-6

Barth PG. Pontocerebellar hypoplasias. An overview of a group of inherited neurodegenerative disorders with fetal onset. Brain Dev. 1993;15(6):411–22.

pubmed: 8147499 doi: 10.1016/0387-7604(93)90080-R

Rüsch CT, Bölsterli BK, Kottke R, Steinfeld R, Boltshauser E. Pontocerebellar hypoplasia: a pattern recognition approach. Cerebellum. 2020;19(4):569–82.

pubmed: 32410094 doi: 10.1007/s12311-020-01135-5

Accogli A, Addour-Boudrahem N, Srour M. Diagnostic approach to cerebellar hypoplasia. Cerebellum. 2021;20(4):631–58.

pubmed: 33534089 doi: 10.1007/s12311-020-01224-5

Mu W, Heller T, Barañano KW. Two siblings with a novel variant of EXOSC3 extended phenotypic spectrum of pontocerebellar hypoplasia 1B to an exceptionally mild form. BMJ Case Rep. 2021;14(1):e236732.

Turkdogan D, Turkyilmaz A, Sager G, Ozturk G, Unver O, Say M. Chromosomal microarray and exome sequencing in unexplained early infantile epileptic encephalopathies in a highly consanguineous population. Int J Neurosci. 2023;133(7):683–700.

pubmed: 34380004 doi: 10.1080/00207454.2021.1967349

Kaya Ozcora GD, Aktas D, Kumandas S. CLP1 associated pontocerebellar hypoplasia. Ann Med Res. 2020;28(3):614–7.

doi: 10.5455/annalsmedres.2020.03.183

Bilge S, Mert GG, Hergüner Ö, Özcanyüz D, Bozdoğan ST, Kaya Ö, et al. Clinical, radiological, and genetic variation in pontocerebellar hypoplasia disorder and our clinical experience. Ital J Pediatr. 2022;48(1):169.

pubmed: 36076253 pmcid: 9461104 doi: 10.1186/s13052-022-01349-9

Ghosh SG, Breuss MW, Schlachetzki Z, Chai G, Zaki MS, Abdel-Salam G, et al. Biallelic hypomorphic mutations in HEATR5B, encoding HEAT repeat-containing protein 5B, in a neurological syndrome with pontocerebellar hypoplasia. Eur J Hum Genet. 2021;29(6):957–64.

pubmed: 33824466 pmcid: 8187379 doi: 10.1038/s41431-021-00832-x

Ucuncu E, Rajamani K, Wilson MSC, Medina-Cano D, Altin N, David P, et al. MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia. Nat Commun. 2020;11(1):6087.

pubmed: 33257696 pmcid: 7705663 doi: 10.1038/s41467-020-19919-y

Sonmez FM, Gleeson JG, Celep F, Kul S. The very low density lipoprotein receptor-associated pontocerebellar hypoplasia and dysmorphic features in three Turkish patients. J Child Neurol. 2013;28(3):379–83.

pubmed: 22532556 doi: 10.1177/0883073812441065

Morisaki I, Shiraishi H, Fujinami H, Shimizu N, Hikida T, Arai Y, et al. Modeling a human CLP1 mutation in mouse identifies an accumulation of tyrosine pre-tRNA fragments causing pontocerebellar hypoplasia type 10. Biochem Biophys Res Commun. 2021;570:60–6.

pubmed: 34273619 doi: 10.1016/j.bbrc.2021.07.036

LaForce GR, Farr JS, Liu J, Akesson C, Gumus E, Pinkard O, et al. Suppression of premature transcription termination leads to reduced mRNA isoform diversity and neurodegeneration. Neuron. 2022;110(8):1340-57.e1347.

pubmed: 35139363 pmcid: 9035109 doi: 10.1016/j.neuron.2022.01.018

Sekulovski S, Trowitzsch S. What connects splicing of transfer RNA precursor molecules with pontocerebellar hypoplasia? BioEssays. 2023;45(2):e2200130.

pubmed: 36517085 doi: 10.1002/bies.202200130

Karaca E, Weitzer S, Pehlivan D, Shiraishi H, Gogakos T, Hanada T, et al. Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function. Cell. 2014;157(3):636–50.

pubmed: 24766809 pmcid: 4146440 doi: 10.1016/j.cell.2014.02.058

Schaffer AE, Eggens VR, Caglayan AO, Reuter MS, Scott E, Coufal NG, et al. CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration. Cell. 2014;157(3):651–63.

pubmed: 24766810 pmcid: 4128918 doi: 10.1016/j.cell.2014.03.049

Wafik M, Taylor J, Lester T, Gibbons RJ, Shears DJ. 2 new cases of pontocerebellar hypoplasia type 10 identified by whole exome sequencing in a Turkish family. Eur J Med Genet. 2018;61(5):273–9.

pubmed: 29307788 doi: 10.1016/j.ejmg.2018.01.002

Amin M, Vignal C, Hamed AAA, Mohammed IN, Elseed MA, Abubaker R, et al. Case Report: A New Family With Pontocerebellar Hypoplasia 10 From Sudan. Front Genet. 2022;13:883211.

pubmed: 35719383 pmcid: 9201487 doi: 10.3389/fgene.2022.883211

Müller JS, Burns DT, Griffin H, Wells GR, Zendah RA, Munro B, et al. RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels. Life Sci Alliance. 2020;3(8):e202000678.

Spyridakis AC, Cao Y, Litra F. Correction: A Rare Case of Pontocerebellar Hypoplasia Type 1B With Literature Review. Cureus. 2023;15(2):c100.

pubmed: 36788993 pmcid: 9912365

Radvanska E, Pos Z, Zatkova A, Hyblova M, Bauer F, Szemes T, et al. Molecularly confirmed pontocerebellar hypoplasia in a large family from Slovakia with four severely affected children. Bratisl Lek Listy. 2022;123(8):568–72.

pubmed: 35852507

Le Duc D, Horn S, Jamra RA, Schaper J, Wieczorek D, Redler S. Novel EXOSC3 pathogenic variant results in a mild course of neurologic disease with cerebellum involvement. Eur J Med Genet. 2020;63(2):103649.

pubmed: 30986545 doi: 10.1016/j.ejmg.2019.04.006

Rodríguez-García ME, Cotrina-Vinagre FJ, Bellusci M, Merino-López A, Chumilla-Calzada S, García-Silva MT, et al. New subtype of PCH1C caused by novel EXOSC8 variants in a 16-year-old Spanish patient. Neuromuscul Disord. 2021;31(8):773–82.

pubmed: 34210538 doi: 10.1016/j.nmd.2021.05.008

Gilboa T, Elefant N, Meiner V, Hacohen N. Delineating the phenotype and genetic basis of AMPD2-related pontocerebellar hypoplasia. Neurogenetics. 2023;24(1):61–6.

pubmed: 36445597 doi: 10.1007/s10048-022-00706-4

Kortüm F, Jamra RA, Alawi M, Berry SA, Borck G, Helbig KL, et al. Clinical and genetic spectrum of AMPD2-related pontocerebellar hypoplasia type 9. Eur J Hum Genet. 2018;26(5):695–708.

pubmed: 29463858 pmcid: 5945775 doi: 10.1038/s41431-018-0098-2

Scola E, Ganau M, Robinson R, Cleary M, De Cocker LJL, Mankad K, et al. Neuroradiological findings in three cases of pontocerebellar hypoplasia type 9 due to AMPD2 mutation: typical MRI appearances and pearls for differential diagnosis. Quant Imaging Med Surg. 2019;9(12):1966–72.

pubmed: 31929969 pmcid: 6942969 doi: 10.21037/qims.2019.08.12

Breuss MW, Sultan T, James KN, Rosti RO, Scott E, Musaev D, et al. Autosomal-Recessive Mutations in the tRNA Splicing Endonuclease Subunit TSEN15 Cause Pontocerebellar Hypoplasia and Progressive Microcephaly. Am J Hum Genet. 2016;99(1):228–35.

pubmed: 27392077 pmcid: 5005448 doi: 10.1016/j.ajhg.2016.05.023

Rudnik-Schöneborn S, Barth PG, Zerres K (2014) Pontocerebellar hypoplasia. Am J Med Genet C Semin Med Genet 166c(2):173–83

Maricich SM, Aqeeb KA, Moayedi Y, Mathes EL, Patel MS, Chitayat D, et al. Pontocerebellar hypoplasia: review of classification and genetics, and exclusion of several genes known to be important for cerebellar development. J Child Neurol. 2011;26(3):288–94.

pubmed: 21383226 doi: 10.1177/0883073810380047

Zhang Y, Yu Y, Zhao X, Xu Y, Chen L, Li N, et al. Novel RARS2 Variants: Updating the Diagnosis and Pathogenesis of Pontocerebellar Hypoplasia Type 6. Pediatr Neurol. 2022;131:30–41.

pubmed: 35468344 doi: 10.1016/j.pediatrneurol.2022.04.002

Namavar Y, Barth PG, Poll-The BT, Baas F. Classification, diagnosis and potential mechanisms in pontocerebellar hypoplasia. Orphanet J Rare Dis. 2011;6:50.

pubmed: 21749694 pmcid: 3159098 doi: 10.1186/1750-1172-6-50

Appelhof B, Wagner M, Hoefele J, Heinze A, Roser T, Koch-Hogrebe M, et al. Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1. Eur J Hum Genet. 2021;29(3):411–21.

pubmed: 33168985 doi: 10.1038/s41431-020-00749-x

Chen H, Li N, Xu Y, Li G, Song C, Yao RE, et al. Novel compound heterozygous variant of TOE1 results in a mild type of pontocerebellar hypoplasia type 7: an expansion of the clinical phenotype. Neurogenetics. 2022;23(1):11–7.

pubmed: 34716526 doi: 10.1007/s10048-021-00675-0

Wang C, Ge Y, Li R, He G, Lin Y. Novel compound heterozygous missense variants in TOE1 gene associated with pontocerebellar hypoplasia type 7. Gene. 2023;862:147250.

pubmed: 36738896 doi: 10.1016/j.gene.2023.147250

Laugwitz L, Buchert R, Groeschel S, Riess A, Grimmel M, Beck-Wödl S, et al. Pontocerebellar hypoplasia type 11: Does the genetic defect determine timing of cerebellar pathology? Eur J Med Genet. 2020;63(7):103938.

pubmed: 32360255 doi: 10.1016/j.ejmg.2020.103938

Huang W, Liu Z, Yang F, Zhou H, Yong X, Yang X, et al. Structural and functional studies of TBC1D23 C-terminal domain provide a link between endosomal trafficking and PCH. Proc Natl Acad Sci U S A. 2019;116(45):22598–608.

pubmed: 31624125 pmcid: 6842616 doi: 10.1073/pnas.1909316116

Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, Schaefer E, et al. Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development. Am J Hum Genet. 2017;101(3):428–40.

pubmed: 28823707 pmcid: 5590842 doi: 10.1016/j.ajhg.2017.07.010

Zhao R, Zhang L, Lu H (2022) Analysis of the Clinical Features and Imaging Findings of Pontocerebellar Hypoplasia Type 2D Caused by Mutations in SEPSECS Gene. Cerebellum

Ahmed MY, Chioza BA, Rajab A, Schmitz-Abe K, Al-Khayat A, Al-Turki S, et al. Loss of PCLO function underlies pontocerebellar hypoplasia type III. Neurology. 2015;84(17):1745–50.

pubmed: 25832664 pmcid: 4424132 doi: 10.1212/WNL.0000000000001523

Tissir F, Goffinet AM. Reelin and brain development. Nat Rev Neurosci. 2003;4(6):496–505.

pubmed: 12778121 doi: 10.1038/nrn1113

Hiesberger T, Trommsdorff M, Howell BW, Goffinet A, Mumby MC, Cooper JA, et al. Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of disabled-1 and modulates tau phosphorylation. Neuron. 1999;24(2):481–9.

pubmed: 10571241 doi: 10.1016/S0896-6273(00)80861-2

Kolb LE, Arlier Z, Yalcinkaya C, Ozturk AK, Moliterno JA, Erturk O, et al. Novel VLDLR microdeletion identified in two Turkish siblings with pachygyria and pontocerebellar atrophy. Neurogenetics. 2010;11(3):319–25.

pubmed: 20082205 doi: 10.1007/s10048-009-0232-y

Ali BR, Silhavy JL, Gleeson MJ, Gleeson JG, Al-Gazali L. A missense founder mutation in VLDLR is associated with Dysequilibrium Syndrome without quadrupedal locomotion. BMC Med Genet. 2012;13:80.

pubmed: 22973972 pmcid: 3495048 doi: 10.1186/1471-2350-13-80

Zysnarski CJ, Lahiri S, Javed FT, Martínez-Márquez JY, Trowbridge JW, Duncan MC. Adaptor protein complex-1 (AP-1) is recruited by the HEATR5 protein Laa1 and its co-factor Laa2 in yeast. J Biol Chem. 2019;294(4):1410–9.

pubmed: 30523155 doi: 10.1074/jbc.RA118.005253

Canagarajah BJ, Ren X, Bonifacino JS, Hurley JH. The clathrin adaptor complexes as a paradigm for membrane-associated allostery. Protein Sci. 2013;22(5):517–29.

pubmed: 23424177 pmcid: 3649254 doi: 10.1002/pro.2235

Hsueh YP. Calcium/calmodulin-dependent serine protein kinase and mental retardation. Ann Neurol. 2009;66(4):438–43.

pubmed: 19847910 doi: 10.1002/ana.21755

Moog U, Kutsche K, Kortüm F, Chilian B, Bierhals T, Apeshiotis N, et al. Phenotypic spectrum associated with CASK loss-of-function mutations. J Med Genet. 2011;48(11):741–51.

pubmed: 21954287 doi: 10.1136/jmedgenet-2011-100218

Xie G, Zhang Y, Yang W, Yang L, Wang R, Xu M, et al. Case report: A novel CASK mutation in a Chinese female child with microcephaly with pontine and cerebellar hypoplasia. Front Genet. 2022;13:856636.

pubmed: 36159992 pmcid: 9490368 doi: 10.3389/fgene.2022.856636