More on 4H Leukodystrophy

There are plenty more papers related to 4H Leukodystrophy below to explore at your own pace. They are categorized so you can find what you’re most interested in.

>Video Presentations

2021 ELA Conference

2019 Glia Conference: Session V – Pol III-related Leukodystrophy (4H)

RNA Polymerase III Structures, Mechanisms & Potential for Intervention


>Patient Descriptions

Pelletier, Félixe et al. “Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C” The Journal of clinical endocrinology and metabolism vol. 106,2 (2021): e660-e674. doi:10.1210/clinem/dgaa700

La Piana, Roberta et al. “Diffuse hypomyelination is not obligate for POLR3-related disorders” Neurology vol. 86,17 (2016): 1622-6. doi:10.1212/WNL.0000000000002612

Saitsu, Hirotomo et al. “Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy.” American journal of human genetics vol. 89,5 (2011): 644-51. doi:10.1016/j.ajhg.2011.10.003



Lata, Elisabeth et al. “RNA Polymerase III Subunit Mutations in Genetic Diseases.” Frontiers in molecular biosciences vol. 8 696438. 30 Jul. 2021, doi:10.3389/fmolb.2021.696438

Yeganeh, Meghdad, and Nouria Hernandez. “RNA polymerase III transcription as a disease factor.” Genes & development vol. 34,13-14 (2020): 865-882. doi:10.1101/gad.333989.119

Ramsay, Ewan Phillip et al. “Structure of human RNA polymerase III.” Nature communications vol. 11,1 6409. 17 Dec. 2020, doi:10.1038/s41467-020-20262-5


>Reference papers

Bernard, Geneviève, and Adeline Vanderver. “POLR3-Related Leukodystrophy.” GeneReviews®,  edited by Margaret P Adam et. al., University of Washington, Seattle, 2 August 2012.



Bernard, Geneviève et al. “Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy.” American journal of human genetics vol. 89,3 (2011): 415-23. doi:10.1016/j.ajhg.2011.07.014

>Case/Family Report

Yang, Yi-Ming et al. “A 42-year-old woman with 4H leukodystrophy caused by a homozygous mutation in POLR3A gene.” Chinese medical journal vol. 132,15 (2019): 1879-1880. doi:10.1097/CM9.0000000000000328

Furukawa, Soma et al. “Case Report: Severe Osteoporosis and Preventive Therapy in RNA Polymerase III-Related Leukodystrophy.” Frontiers in neurology vol. 12 622355. 26 Feb. 2021, doi:10.3389/fneur.2021.622355

Wu, Shuiyan et al. “Novel mutations of the POLR3A gene caused POLR3-related leukodystrophy in a Chinese family: a case report.” BMC pediatrics vol. 19,1 289. 22 Aug. 2019, doi:10.1186/s12887-019-1656-7

Tewari, Vishal V et al. “A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report.” BMC pediatrics vol. 18,1 126. 4 Apr. 2018, doi:10.1186/s12887-018-1108-9

Vanderver, Adeline et al. “More than hypomyelination in Pol-III disorder.” Journal of neuropathology and experimental neurology vol. 72,1 (2013): 67-75. doi:10.1097/NEN.0b013e31827c99d2

Shimojima, Keiko et al. “Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination.” Brain & development vol. 36,4 (2014): 315-21. doi:10.1016/j.braindev.2013.04.011

Terao, Yasuo et al. “Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A encoding the catalytic subunit of polymerase III.” Journal of the neurological sciences vol. 320,1-2 (2012): 102-5. doi:10.1016/j.jns.2012.07.005

Potic, Ana et al. “4H syndrome with late-onset growth hormone deficiency caused by POLR3A mutations.” Archives of neurology vol. 69,7 (2012): 920-3. doi:10.1001/archneurol.2011.1963rec

Zanette, Vanessa et al. “Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations.” Neurology. Genetics vol. 6,6 e521. 7 Oct. 2020, doi:10.1212/NXG.0000000000000521

Campopiano, Rosa et al. “A novel POLR3A genotype leads to leukodystrophy type-7 in two siblings with unusually late age of onset.” BMC neurology vol. 20,1 258. 29 Jun. 2020, doi:10.1186/s12883-020-01835-9

Zanette, Vanessa et al. “Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations” Neurology. Genetics vol. 6,6 e521. 7 Oct. 2020, doi:10.1212/NXG.0000000000000521

Jauhari, Prashant et al. “An Indian boy with a novel leukodystrophy: 4H syndrome.” Journal of child neurology vol. 29,1 (2014): 135-8. doi:10.1177/0883073812470737

Neocleous, Vassos et al. “GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature.” Frontiers in endocrinology vol. 11 626. 28 Aug. 2020, doi:10.3389/fendo.2020.00626

Uygun, Özge et al. “Adult-onset 4H leukodystrophy: a case presentation and review of the literature.” Acta neurologica Belgica vol. 120,6 (2020): 01297-3

Potic, Ana et al. “Neurogenic bladder and neuroendocrine abnormalities in Pol III-related leukodystrophy.” BMC neurology vol. 15 22. 4 Mar. 2015, doi:10.1186/s12883-015-0283-7



Choquet, Karine et al. “Leukodystrophy-associated POLR3A mutations down-regulate the RNA polymerase III transcript and important regulatory RNA BC200.” The Journal of biological chemistry vol. 294,18 (2019): 7445-7459. doi:10.1074/jbc.RA118.006271


Choquet, Karine et al. “Absence of neurological abnormalities in mice homozygous for the Polr3a G672E hypomyelinating leukodystrophy mutation.” Molecular brain vol. 10,1 13. 13 Apr. 2017, doi:10.1186/s13041-017-0294-y

Moir, Robyn D et al. “Functional characterization of Polr3a hypomyelinating leukodystrophy mutations in the S. cerevisiae homolog, RPC160” Gene vol. 768 (2021): 145259. doi:10.1016/j.gene.2020.145259


>Other Associations

>>Association with Wiedemann-Rautenstrauch syndrome

Majethia, Purvi, and Katta Mohan Girisha. “Wiedemann-Rautenstrauch syndrome in an Indian patient with biallelic pathogenic variants in POLR3A.” American journal of medical genetics. Part A vol. 185,5 (2021): 1602-1605. doi:10.1002/ajmg.a.62115

Wambach, Jennifer A et al. “Bi-allelic POLR3A Loss-of-Function Variants Cause Autosomal-Recessive Wiedemann-Rautenstrauch Syndrome.” American journal of human genetics vol. 103,6 (2018): 968-975. doi:10.1016/j.ajhg.2018.10.010

Paolacci, Stefano et al. “Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome” Journal of medical genetics vol. 55,12 (2018): 837-846. doi:10.1136/jmedgenet-2018-105528

 Temel, Sehime Gulsun et al. “Unique combination and in silico modeling of biallelic POLR3A variants as a cause of Wiedemann-Rautenstrauch syndrome.” European journal of human genetics : EJHG vol. 28,12 (2020): 1675-1680. doi:10.1038/s41431-020-0673-1

 >>Association with Spastic Ataxia

Di Donato, Ilaria et al. “POLR3A variants in hereditary spastic paraparesis and ataxia: clinical, genetic, and neuroradiological findings in a cohort of Italian patients.” Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 10.1007/s10072-021-05462-1. 23 Jul. 2021, doi:10.1007/s10072-021-05462-1

Fellner, Avi et al. “Two intronic cis-acting variants in both alleles of the POLR3A gene cause progressive spastic ataxia with hypodontia.” Clinical genetics vol. 99,5 (2021): 713-718. doi:10.1111/cge.13929

Ruggiero, Lucia et al. “Multimodal evaluation of an Italian family with a hereditary spastic paraplegia and POLR3A mutations” Annals of clinical and translational neurology vol. 7,11 (2020): 2326-2331. doi:10.1002/acn3.51221

Morales-Rosado, Joel A et al. “Interpretation challenges of novel dual-class missense and splice-impacting variant in POLR3A-related late-onset hereditary spastic ataxia.” Molecular genetics & genomic medicine vol. 8,9 (2020): e1341. doi:10.1002/mgg3.1341

Rydning, Siri L et al. “Biallelic POLR3A variants confirmed as a frequent cause of hereditary ataxia and spastic paraparesis.” Brain : a journal of neurology vol. 142,4 (2019): e12. doi:10.1093/brain/awz041

Minnerop, Martina et al. “Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.” Brain : a journal of neurology vol. 140,6 (2017): 1561-1578. doi:10.1093/brain/awx095

Gauquelin, Laurence et al. “POLR3A variants in hereditary spastic paraplegia and ataxia.” Brain : a journal of neurology vol. 141,1 (2018): e1. doi:10.1093/brain/awx290

Infante, Jon et al. “POLR3A-related spastic ataxia: new mutations and a look into the phenotype.” Journal of neurology vol. 267,2 (2020): 324-330. doi:10.1007/s00415-019-09574-9

>>Striatal Involvement

Harting, Inga et al. “POLR3A variants with striatal involvement and extrapyramidal movement disorder.” Neurogenetics vol. 21,2 (2020): 121-133. doi:10.1007/s10048-019-00602-4

Azmanov, Dimitar N et al. “Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement.” Human molecular genetics vol. 25,19 (2016): 4302-4314. doi:10.1093/hmg/ddw263

Hiraide, Takuya et al. “POLR3A variants in striatal involvement without diffuse hypomyelination.” Brain & development vol. 42,4 (2020): 363-368. doi:10.1016/j.braindev.2019.12.012



Tétreault, Martine et al. “Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy.” American journal of human genetics vol. 89,5 (2011): 652-5. doi:10.1016/j.ajhg.2011.10.006

Kulhánek, Jan et al. “POLR3B-associated leukodystrophy: clinical, neuroimaging and molecular-genetic analyses in four patients: clinical heterogeneity and novel mutations in POLR3B gene.” Neurologia i neurochirurgia polska vol. 53,5 (2019): 369-376. doi:10.5603/PJNNS.a2019.0042

Richards, Mary R et al. “Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies.” Journal of medical genetics vol. 54,1 (2017): 19-25. doi:10.1136/jmedgenet-2016-104064

Djordjevic, Djurdja et al. “De novo variants in POLR3B cause ataxia, spasticity, and demyelinating neuropathy.” American journal of human genetics vol. 108,1 (2021): 186-193. doi:10.1016/j.ajhg.2020.12.002


>Case/Family Report

Dinov, Darina et al. “Child Neurology: Hypotonia and Delayed Teeth Eruption in a 2-Year-Old Female.” Neurology, 10.1212/WNL.0000000000012445. 29 Jun. 2021, doi:10.1212/WNL.0000000000012445

DeGasperis, Stephanie M et al. “4H leukodystrophy: Mild clinical phenotype and comorbidity with multiple sclerosis.” Neurology. Genetics vol. 6,2 e409. 11 Mar. 2020, doi:10.1212/NXG.0000000000000409

Verberne, Eline A et al. “4H leukodystrophy caused by a homozygous POLR3B mutation: Further delineation of the phenotype.” American journal of medical genetics. Part A vol. 182,7 (2020): 1776-1779. doi:10.1002/ajmg.a.61600

Thomas, Aby, and Anna Kalathil Thomas. “POLR3-related Leukodystrophy.” Journal of clinical imaging science vol. 9 45. 24 Oct. 2019, doi:10.25259/JCIS_116_2019

Currie, Amanda D, and Swati A Karmarkar. “Ataxia With Hypodontia: A Unique Leukodystrophy.” Pediatric neurology vol. 80 (2018): 94-95. doi:10.1016/j.pediatrneurol.2017.06.013

Jurkiewicz, E et al. “Recessive Mutations in POLR3B Encoding RNA Polymerase III Subunit Causing Diffuse Hypomyelination in Patients with 4H Leukodystrophy with Polymicrogyria and Cataracts.” Clinical neuroradiology vol. 27,2 (2017): 213-220. doi:10.1007/s00062-015-0472-1

Gutierrez, Mariana et al. “Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy.” Orphanet journal of rare diseases vol. 10 69. 5 Jun. 2015, doi:10.1186/s13023-015-0279-9

Billington, Emma et al. “Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature.” Case reports in endocrinology vol. 2015 (2015): 314594. doi:10.1155/2015/314594

Battini, Roberta et al. “Longitudinal follow up of a boy affected by Pol III-related leukodystrophy: a detailed phenotype description.” BMC medical genetics vol. 16 53. 25 Jul. 2015, doi:10.1186/s12881-015-0203-0


Choquet, Karine et al. “The leukodystrophy mutation Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis.” Molecular brain vol. 12,1 59. 20 Jun. 2019, doi:10.1186/s13041-019-0479-7

Kieckhaefer, Julia et al. “The RNA polymerase III subunit Polr3b is required for the maintenance of small intestinal crypts in mice.” Cellular and molecular gastroenterology and hepatology vol. 2,6 (2016): 783-795. doi:10.1016/j.jcmgh.2016.08.003

>Other associations

Wu, Shao-Wen et al. “Whole-exome sequencing reveals POLR3B variants associated with progeria-related Wiedemann-Rautenstrauch syndrome.” Italian journal of pediatrics vol. 47,1 160. 21 Jul. 2021, doi:10.1186/s13052-021-01112-6



Gauquelin, Laurence et al. “Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants.” Neurology. Genetics vol. 5,6 e369. 30 Oct. 2019, doi:10.1212/NXG.0000000000000369

 >Case/Family Report

Kashiki, Hitoshi et al. “POLR1C variants dysregulate splicing and cause hypomyelinating leukodystrophy.” Neurology. Genetics vol. 6,6 e524. 13 Oct. 2020, doi:10.1212/NXG.0000000000000524

Kraoua, Ichraf et al. “Novel POLR1C mutation in RNA polymerase III-related leukodystrophy with severe myoclonus and dystonia.” Molecular genetics & genomic medicine vol. 7,9 (2019): e914. doi:10.1002/mgg3.914



Thiffault, Isabelle et al. “Recessive mutations in POLR1C cause a leukodystrophy by impairing      biogenesis of RNA polymerase III” Nature communications vol. 6 7623. 7 Jul. 2015,                        doi:10.1038/ncomms8623



Dorboz, Imen et al. “Mutation in POLR3K causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation.” Neurology. Genetics vol. 4,6 e289. 3 Dec. 2018, doi:10.1212/NXG.0000000000000289



Terhal, Paulien A et al. “Biallelic variants in POLR3GL cause endosteal hyperostosis and oligodontia.” European journal of human genetics : EJHG vol. 28,1 (2020): 31-39. doi:10.1038/s41431-019-0427-0

Hypomyelinating leukodystrophies

Wolf, Nicole I et al. “Hypomyelinating leukodystrophies – unravelling myelin biology” Nature reviews. Neurology vol. 17,2 (2021): 88-103. doi:10.1038/s41582-020-00432-1

Yan, Huifang et al. “Genetic analysis of 20 patients with hypomyelinating leukodystrophy by trio-based whole-exome sequencing.” Journal of human genetics vol. 66,8 (2021): 761-768. doi:10.1038/s10038-020-00896-5

Di Bella, Daniela et al. “Hypomyelinating leukodystrophies in adults: Clinical and genetic features.” European journal of neurology vol. 28,3 (2021): 934-944. doi:10.1111/ene.14646

Ji, Haoran et al. “Hypomyelinating disorders in China: The clinical and genetic heterogeneity in 119 patients.” PloS one vol. 13,2 e0188869. 16 Feb. 2018, doi:10.1371/journal.pone.0188869

Cayami, Ferdy K et al. “POLR3A and POLR3B Mutations in Unclassified Hypomyelination.” Neuropediatrics vol. 46,3 (2015): 221-8. doi:10.1055/s-0035-1550148

Daoud, Hussein et al. “Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism.” Journal of medical genetics vol. 50,3 (2013): 194-7. doi:10.1136/jmedgenet-2012-101357


2020 ULF Leukodystrophies 101 Presentation with Dr. Paul Watkins

Bonkowsky, J L et al. “The burden of inherited leukodystrophies in children.” Neurology vol. 75,8 (2010): 718-25. doi:10.1212/WNL.0b013e3181eee46b

Barczykowski, Amy L et al. “Death rates in the U.S. due to Leukodystrophies with pediatric forms.” American journal of medical genetics. Part A vol. 185,8 (2021): 2361-2373. doi:10.1002/ajmg.a.62248

van der Knaap, Marjo S, and Marianna Bugiani. “Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms.” Acta neuropathologica vol. 134,3 (2017): 351-382. doi:10.1007/s00401-017-1739-1

Dermer, E et al. “Stress in Parents of Children With Genetically Determined Leukoencephalopathies: A Pilot Study.” Journal of child neurology vol. 35,13 (2020): 901-907. doi:10.1177/0883073820938645

Vanderver, Adeline et al. “Whole exome sequencing in patients with white matter abnormalities.” Annals of neurology vol. 79,6 (2016): 1031-1037. doi:10.1002/ana.24650

Helman, Guy et al. “Genome sequencing in persistently unsolved white matter disorders.” Annals of clinical and translational neurology vol. 7,1 (2020): 144-152. doi:10.1002/acn3.50957