Tremor Ataxia With Central Hypomyelation Phenotype Related to a Recurrent POLR3A Mutation in Six Unrelated Tunisian Families

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2024 Oct 22

PMID 39436788

Authors

Ichraf Kraoua

Maha Jamoussi

Cyrine Drissi

Lilia Kraoua

Severine Drunat

Hanene Benrhouma

Thouraya Ben Younes

Sonia Nagi

Sonia Abdelhak

Odile Boespflug Tanguy

Ilhem Ben Youssef-Turki

Mediha Trabelsi

Imen Dorboz

Affiliations

Soon will be listed here.

Abstract

Background: POLIII-related leukodystrophies are a group of recently recognized hereditary white matter diseases with a similar clinical and radiological phenotype. No Tunisian studies have been published about POLIII-related leukodystrophy due to POLR3A variants. The aim of this study was to contribute to the clinical, radiological, and genetic characterization of POLR3A-related leukodystrophy in a Tunisian cohort.

Methods: We report six cases of genetically confirmed POLR3A-related leukodystrophy belonging to six unrelated Tunisian families, along with a review of previously published pediatric cases.

Results: All patients were born to consanguineous marriages and originated from the North or the Center of Tunisia. Age at onset varied between 15 months and 6 years. The clinical phenotype was similar in all patients with cerebellar ataxia, tremor, and nystagmus being the key features. Brain imaging showed diffuse hypomyelination in all patients with progressive cerebellar atrophy in three patients. Molecular analysis identified the same bi-allelic NM_007055.4:c.2011T>C; p.(Trp671Arg) variant in the POLR3A gene in all patients.

Conclusion: We hypothesize a founder effect for the identified variant given its recurrence in six unrelated individuals with a similar clinical phenotype. Given the apparent genetic homogeneity of Tunisian POLR3A patients, the recurrent variant should be directly targeted. This should facilitate diagnosis in index patients, and genetic counseling.

References

Daoud H, Tetreault M, Gibson W, Guerrero K, Cohen A, Gburek-Augustat J . Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism. J Med Genet. 2013; 50(3):194-7. DOI: 10.1136/jmedgenet-2012-101357. View

Infante J, Serrano-Cardenas K, Corral-Juan M, Farre X, Sanchez I, de Lucas E . POLR3A-related spastic ataxia: new mutations and a look into the phenotype. J Neurol. 2019; 267(2):324-330. DOI: 10.1007/s00415-019-09574-9. View

Jellouli N, Hadj Salem I, Ellouz E, Louhichi N, Tlili A, Kammoun F . Molecular confirmation of founder mutation c.-167A>G in Tunisian patients with PMLD disease. Gene. 2012; 513(2):233-8. DOI: 10.1016/j.gene.2012.10.070. View

Thomas A, Thomas A . POLR3-related Leukodystrophy. J Clin Imaging Sci. 2019; 9:45. PMC: 6826334. DOI: 10.25259/JCIS_116_2019. View

Wu S, Bai Z, Dong X, Yang D, Chen H, Hua J . Novel mutations of the POLR3A gene caused POLR3-related leukodystrophy in a Chinese family: a case report. BMC Pediatr. 2019; 19(1):289. PMC: 6704677. DOI: 10.1186/s12887-019-1656-7. View

La Piana R, Cayami F, Tran L, Guerrero K, Van Spaendonk R, Ounap K . Diffuse hypomyelination is not obligate for POLR3-related disorders. Neurology. 2016; 86(17):1622-6. PMC: 4844237. DOI: 10.1212/WNL.0000000000002612. View

Romdhane L, Kefi R, Azaiez H, Ben Halim N, Dellagi K, Abdelhak S . Founder mutations in Tunisia: implications for diagnosis in North Africa and Middle East. Orphanet J Rare Dis. 2012; 7:52. PMC: 3495028. DOI: 10.1186/1750-1172-7-52. View

Bernard G, Chouery E, Putorti M, Tetreault M, Takanohashi A, Carosso G . Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011; 89(3):415-23. PMC: 3169829. DOI: 10.1016/j.ajhg.2011.07.014. View

Bernard G, Thiffault I, Tetreault M, Putorti M, Bouchard I, Sylvain M . Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31. Neurogenetics. 2010; 11(4):457-64. PMC: 4147760. DOI: 10.1007/s10048-010-0251-8. View

10.

Kraoua I, Bouyacoub Y, Drissi C, Chargui M, Rebai I, Chebil A . Hypomyelination and Congenital Cataract: Clinical, Imaging, and Genetic Findings in Three Tunisian Families and Literature Review. Neuropediatrics. 2021; 52(4):302-309. DOI: 10.1055/s-0041-1728654. View

11.

Tewari V, Mehta R, Sreedhar C, Tewari K, Mohammad A, Gupta N . A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report. BMC Pediatr. 2018; 18(1):126. PMC: 5883641. DOI: 10.1186/s12887-018-1108-9. View

12.

Hiraide T, Kubota K, Kono Y, Watanabe S, Matsubayashi T, Nakashima M . POLR3A variants in striatal involvement without diffuse hypomyelination. Brain Dev. 2020; 42(4):363-368. DOI: 10.1016/j.braindev.2019.12.012. View

13.

Dorboz I, Dumay-Odelot H, Boussaid K, Bouyacoub Y, Barreau P, Samaan S . Mutation in causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation. Neurol Genet. 2018; 4(6):e289. PMC: 6283457. DOI: 10.1212/NXG.0000000000000289. View

14.

Harting I, Al-Saady M, Krageloh-Mann I, Bley A, Hempel M, Bierhals T . POLR3A variants with striatal involvement and extrapyramidal movement disorder. Neurogenetics. 2020; 21(2):121-133. PMC: 7064625. DOI: 10.1007/s10048-019-00602-4. View

15.

Nikkhah A, Rezakhani S . Developmental regression and movement disorder as a phenotypic variant of POLR3A Mutation-Case report. Clin Case Rep. 2022; 10(11):e6556. PMC: 9664542. DOI: 10.1002/ccr3.6556. View

16.

Macintosh J, Perrier S, Pinard M, Tran L, Guerrero K, Prasad C . Biallelic pathogenic variants in alter tRNA transcription and cause a hypomyelinating leukodystrophy: A case report. Front Neurol. 2023; 14:1254140. PMC: 10616956. DOI: 10.3389/fneur.2023.1254140. View

17.

Pelletier F, Perrier S, Cayami F, Mirchi A, Saikali S, Tran L . Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C. J Clin Endocrinol Metab. 2020; 106(2):e660-e674. PMC: 7823228. DOI: 10.1210/clinem/dgaa700. View

18.

Shimojima K, Shimada S, Tamasaki A, Akaboshi S, Komoike Y, Saito A . Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination. Brain Dev. 2013; 36(4):315-21. DOI: 10.1016/j.braindev.2013.04.011. View

19.

Vanderver A, Tonduti D, Bernard G, Lai J, Rossi C, Carosso G . More than hypomyelination in Pol-III disorder. J Neuropathol Exp Neurol. 2012; 72(1):67-75. PMC: 3797528. DOI: 10.1097/NEN.0b013e31827c99d2. View

20.

Saitsu H, Osaka H, Sasaki M, Takanashi J, Hamada K, Yamashita A . Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. Am J Hum Genet. 2011; 89(5):644-51. PMC: 3213392. DOI: 10.1016/j.ajhg.2011.10.003. View