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Pol III-related leukodystrophy

MedGen UID:
1803536
Concept ID:
C5679947
Disease or Syndrome
Synonym: Pol III-Related Leukodystrophies
SNOMED CT: 4H leukodystrophy (1208933000); POLR-related leukodystrophy (1208933000)
 
Related genes: POLR3B, POLR3A
 
Orphanet: ORPHA289494

Disease characteristics

Excerpted from the GeneReview: POLR3-Related Leukodystrophy
POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome. [from GeneReviews]
Authors:
Geneviève Bernard  |  Adeline Vanderver   view full author information

Recent clinical studies

Etiology

Ji H, Li D, Wu Y, Zhang Q, Gu Q, Xie H, Ji T, Wang H, Zhao L, Zhao H, Yang Y, Feng H, Xiong H, Ji J, Yang Z, Kou L, Li M, Bao X, Chang X, Zhang Y, Li L, Li H, Niu Z, Wu X, Xiao J, Jiang Y, Wang J
PLoS One 2018;13(2):e0188869. Epub 2018 Feb 16 doi: 10.1371/journal.pone.0188869. PMID: 29451896Free PMC Article
Battini R, Bertelloni S, Astrea G, Casarano M, Travaglini L, Baroncelli G, Pasquariello R, Bertini E, Cioni G
BMC Med Genet 2015 Jul 25;16:53. doi: 10.1186/s12881-015-0203-0. PMID: 26204956Free PMC Article

Diagnosis

Muirhead KJ, Clause AR, Schlachetzki Z, Dubbs H, Perry DL, Hagelstrom RT, Taft RJ, Vanderver A
Cold Spring Harb Mol Case Stud 2021 Dec;7(6) Epub 2021 Dec 9 doi: 10.1101/mcs.a006143. PMID: 34737199Free PMC Article
Merheb E, Cui MH, DuBois JC, Branch CA, Gulinello M, Shafit-Zagardo B, Moir RD, Willis IM
Proc Natl Acad Sci U S A 2021 Oct 5;118(40) doi: 10.1073/pnas.2024378118. PMID: 34583988Free PMC Article
Ji H, Li D, Wu Y, Zhang Q, Gu Q, Xie H, Ji T, Wang H, Zhao L, Zhao H, Yang Y, Feng H, Xiong H, Ji J, Yang Z, Kou L, Li M, Bao X, Chang X, Zhang Y, Li L, Li H, Niu Z, Wu X, Xiao J, Jiang Y, Wang J
PLoS One 2018;13(2):e0188869. Epub 2018 Feb 16 doi: 10.1371/journal.pone.0188869. PMID: 29451896Free PMC Article
Battini R, Bertelloni S, Astrea G, Casarano M, Travaglini L, Baroncelli G, Pasquariello R, Bertini E, Cioni G
BMC Med Genet 2015 Jul 25;16:53. doi: 10.1186/s12881-015-0203-0. PMID: 26204956Free PMC Article
Potic A, Popovic V, Ostojic J, Pekic S, Kozic D, Guerrero K, Schiffmann R, Bernard G
BMC Neurol 2015 Mar 4;15:22. doi: 10.1186/s12883-015-0283-7. PMID: 25868523Free PMC Article

Prognosis

Hiraide T, Nakashima M, Ikeda T, Tanaka D, Osaka H, Saitsu H
J Hum Genet 2020 Oct;65(10):921-925. Epub 2020 Jun 1 doi: 10.1038/s10038-020-0786-y. PMID: 32483275
Verberne EA, Dalen Meurs L, Wolf NI, van Haelst MM
Am J Med Genet A 2020 Jul;182(7):1776-1779. Epub 2020 Apr 22 doi: 10.1002/ajmg.a.61600. PMID: 32319736Free PMC Article
Battini R, Bertelloni S, Astrea G, Casarano M, Travaglini L, Baroncelli G, Pasquariello R, Bertini E, Cioni G
BMC Med Genet 2015 Jul 25;16:53. doi: 10.1186/s12881-015-0203-0. PMID: 26204956Free PMC Article

Clinical prediction guides

Hiraide T, Nakashima M, Ikeda T, Tanaka D, Osaka H, Saitsu H
J Hum Genet 2020 Oct;65(10):921-925. Epub 2020 Jun 1 doi: 10.1038/s10038-020-0786-y. PMID: 32483275
Battini R, Bertelloni S, Astrea G, Casarano M, Travaglini L, Baroncelli G, Pasquariello R, Bertini E, Cioni G
BMC Med Genet 2015 Jul 25;16:53. doi: 10.1186/s12881-015-0203-0. PMID: 26204956Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    Curated

    • AAP, 2021
      Leukodystrophies in Children: Diagnosis, Care, and Treatment, Pediatrics (2021) 148 (3): e2021053126.

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