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Pol III-related leukodystrophy

Reviewed June 2013

What is Pol III-related leukodystrophy?

Pol III-related leukodystrophy is a disorder that affects the nervous system and other parts of the body. Leukodystrophies are conditions that involve abnormalities of the nervous system's white matter, which consists of nerve fibers covered by a fatty substance called myelin. Myelin insulates nerve fibers and promotes the rapid transmission of nerve impulses.

Pol III-related leukodystrophy is a hypomyelinating disease, which means that the nervous system of affected individuals has a reduced ability to form myelin. Hypomyelination underlies most of the neurological problems associated with Pol III-related leukodystrophy. A small number of people with this disorder also have a loss of nerve cells in a part of the brain involved in coordinating movements (cerebellar atrophy) and underdevelopment (hypoplasia) of tissue that connects the left and right halves of the brain (the corpus callosum). These brain abnormalities likely contribute to the neurological problems in affected individuals.

People with Pol III-related leukodystrophy usually have intellectual disability ranging from mild to severe, which gradually worsens over time. Some affected individuals have normal intelligence in early childhood but develop mild intellectual disability during the course of the disease.

Difficulty coordinating movements (ataxia), which begins in childhood and slowly worsens over time, is a characteristic feature of Pol III-related leukodystrophy. Affected children typically have delayed development of motor skills such as walking. Their gait is unstable, and they usually walk with their feet wide apart for balance. Affected individuals may eventually need to use a walker or wheelchair. Involuntary rhythmic shaking (tremor) of the arms and hands may occur in this disorder. In some cases the tremor occurs mainly during movement (intentional tremor); other affected individuals experience the tremor both during movement and at rest.

Development of the teeth (dentition) is often abnormal in Pol III-related leukodystrophy, resulting in the absence of some teeth (known as hypodontia or oligodontia). Some affected infants are born with a few teeth (natal teeth), which fall out during the first weeks of life. The primary (deciduous) teeth appear later than usual, beginning at about age 2. In Pol III-related leukodystrophy, the teeth may not appear in the usual sequence, in which front teeth (incisors) appear before back teeth (molars). Instead, molars often appear first, with incisors appearing later or not at all. Permanent teeth are also delayed, and may not appear until adolescence. The teeth may also be unusually shaped.

Some individuals with Pol III-related leukodystrophy have excessive salivation and difficulty chewing or swallowing (dysphagia), which can lead to choking. They may also have speech impairment (dysarthria). People with Pol III-related leukodystrophy often have abnormalities in eye movement, such as progressive vertical gaze palsy, which is restricted up-and-down eye movement that worsens over time. Nearsightedness is common in affected individuals, and clouding of the lens of the eyes (cataracts) has also been reported. Deterioration (atrophy) of the nerves that carry information from the eyes to the brain (the optic nerves) and seizures may also occur in this disorder.

Hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development, may occur in Pol III-related leukodystrophy. Affected individuals have delayed development of the typical signs of puberty, such as the growth of body hair.

People with Pol III-related leukodystrophy may have different combinations of its signs and symptoms. These varied combinations of clinical features were originally described as separate disorders. Affected individuals may be diagnosed with ataxia, delayed dentition, and hypomyelination (ADDH); hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); tremor-ataxia with central hypomyelination (TACH); leukodystrophy with oligodontia (LO); or hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Because these disorders were later found to have the same genetic cause, researchers now group them as variations of the single condition Pol III-related leukodystrophy.

How common is Pol III-related leukodystrophy?

Pol III-related leukodystrophy is a rare disorder; its prevalence is unknown. Only about 40 cases have been described in the medical literature. However, researchers believe that a significant percentage of people with an unspecified hypomyelinating leukodystrophy could have Pol III-related leukodystrophy.

What genes are related to Pol III-related leukodystrophy?

Pol III-related leukodystrophy is caused by mutations in the POLR3A or POLR3B gene. These genes provide instructions for making the two largest parts (subunits) of an enzyme called RNA polymerase III. This enzyme is involved in the production (synthesis) of ribonucleic acid (RNA), a chemical cousin of DNA. The RNA polymerase III enzyme attaches (binds) to DNA and synthesizes RNA in accordance with the instructions carried by the DNA, a process called transcription. RNA polymerase III helps synthesize several forms of RNA, including ribosomal RNA (rRNA) and transfer RNA (tRNA). Molecules of rRNA and tRNA assemble protein building blocks (amino acids) into working proteins; this process is essential for the normal functioning and survival of cells.

Researchers suggest that mutations in the POLR3A or POLR3B gene may impair the ability of subunits of the RNA polymerase III enzyme to assemble properly or result in an RNA polymerase III with impaired ability to bind to DNA. Reduced function of the RNA polymerase III molecule likely affects development and function of many parts of the body, including the nervous system and the teeth, but the relationship between POLR3A and POLR3B gene mutations and the specific signs and symptoms of Pol III-related leukodystrophy is unknown.

Related Gene(s)

Changes in these genes are associated with Pol III-related leukodystrophy.

  • POLR3A
  • POLR3B

How do people inherit Pol III-related leukodystrophy?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of Pol III-related leukodystrophy?

These resources address the diagnosis or management of Pol III-related leukodystrophy and may include treatment providers.

  • Eastman Dental Hospital: Hypodontia Clinic (http://www.uclh.nhs.uk/OurServices/ServiceA-Z/EDH/RESDEN/EDHHC/Pages/Home.aspx)
  • Gene Review: Pol III-Related Leukodystrophies (http://www.ncbi.nlm.nih.gov/books/NBK99167/)
  • Genetic Testing Registry: Pol III-related leukodystrophy (http://www.ncbi.nlm.nih.gov/gtr/conditions/CN168056)
  • Johns Hopkins Medicine: Treating Ataxia (http://www.hopkinsmedicine.org/neurology_neurosurgery/specialty_areas/movement_disorders/ataxia/conditions/ataxia_treatment.html)
  • National Ataxia Foundation: Diagnosis of Ataxia (http://www.ataxia.org/learn/ataxia-diagnosis.aspx)
  • UCSF Benioff Children's Hospital: Hypodontia (http://www.ucsfbenioffchildrens.org/conditions/hypodontia/)
  • University of Chicago Ataxia Center (http://ataxia.uchicago.edu/)

You might also find information on the diagnosis or management of Pol III-related leukodystrophy in Educational resources (http://ghr.nlm.nih.gov/condition/pol-iii-related-leukodystrophy/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/pol-iii-related-leukodystrophy/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Pol III-related leukodystrophy?

You may find the following resources about Pol III-related leukodystrophy helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for Pol III-related leukodystrophy?

  • ADDH
  • ataxia, delayed dentition, and hypomyelination
  • dentoleukoencephalopathy
  • HCAHC
  • HLD7
  • HLD8
  • hypomyelination, hypodontia, hypogonadotropic hypogonadism
  • hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum
  • leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism
  • leukodystrophy, hypomyelinating, 8, with or without oligodontia and/or hypogonadotropic hypogonadism
  • leukodystrophy with oligodontia
  • leukoencephalopathy-ataxia-hypodontia-hypomyelination
  • LO
  • odontoleukodystrophy
  • Pol III disorder
  • Pol III-related hypomyelinating leukodystrophies
  • 4H syndrome
  • TACH
  • tremor-ataxia with central hypomyelination

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Pol III-related leukodystrophy?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Pol III-related leukodystrophy?

acids ; ataxia ; atrophy ; autosomal ; autosomal recessive ; cell ; corpus callosum ; DNA ; dysarthria ; dysphagia ; enzyme ; gait ; gene ; hypodontia ; hypogonadism ; hypogonadotropic ; hypoplasia ; involuntary ; leukodystrophy ; leukoencephalopathy ; molecule ; motor ; nearsightedness ; nervous system ; neurological ; oligodontia ; palsy ; prevalence ; protein ; puberty ; recessive ; ribonucleic acid ; ribosomal RNA ; RNA ; RNA polymerase ; syndrome ; synthesis ; tissue ; transcription ; transfer RNA ; tremor ; tRNA ; white matter

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Bernard G, Chouery E, Putorti ML, Tétreault M, Takanohashi A, Carosso G, Clément I, Boespflug-Tanguy O, Rodriguez D, Delague V, Abou Ghoch J, Jalkh N, Dorboz I, Fribourg S, Teichmann M, Megarbane A, Schiffmann R, Vanderver A, Brais B. Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am J Hum Genet. 2011 Sep 9;89(3):415-23. doi: 10.1016/j.ajhg.2011.07.014. Erratum in: Am J Hum Genet. 2012 Nov 2;91(5):972. (http://www.ncbi.nlm.nih.gov/pubmed/21855841?dopt=Abstract)
  • Bernard G, Thiffault I, Tetreault M, Putorti ML, Bouchard I, Sylvain M, Melançon S, Laframboise R, Langevin P, Bouchard JP, Vanasse M, Vanderver A, Sébire G, Brais B. Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3-10q23.31. Neurogenetics. 2010 Oct;11(4):457-64. doi: 10.1007/s10048-010-0251-8. Epub 2010 Jul 17. (http://www.ncbi.nlm.nih.gov/pubmed/20640464?dopt=Abstract)
  • Chouery E, Delague V, Jalkh N, Salem N, Kfoury J, Rodriguez D, Chabrol B, Boespflug-Tanguy O, Lévy N, Serre JL, Mégarbané A. A whole-genome scan in a large family with leukodystrophy and oligodontia reveals linkage to 10q22. Neurogenetics. 2011 Feb;12(1):73-8. doi: 10.1007/s10048-010-0256-3. Epub 2010 Aug 19. (http://www.ncbi.nlm.nih.gov/pubmed/20721593?dopt=Abstract)
  • Daoud H, Tétreault M, Gibson W, Guerrero K, Cohen A, Gburek-Augustat J, Synofzik M, Brais B, Stevens CA, Sanchez-Carpintero R, Goizet C, Naidu S, Vanderver A, Bernard G. 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 Mar;50(3):194-7. doi: 10.1136/jmedgenet-2012-101357. Epub 2013 Jan 25. (http://www.ncbi.nlm.nih.gov/pubmed/23355746?dopt=Abstract)
  • Orcesi S, Tonduti D, Uggetti C, Larizza D, Fazzi E, Balottin U. New case of 4H syndrome and a review of the literature. Pediatr Neurol. 2010 May;42(5):359-64. doi: 10.1016/j.pediatrneurol.2010.01.015. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20399393?dopt=Abstract)
  • Osterman B, Sylvain M, Chouinard S, Bernard G. Tremor-ataxia with central hypomyelination (TACH): dystonia as a new clinical feature. Mov Disord. 2012 Dec;27(14):1829-30. doi: 10.1002/mds.25270. Epub 2012 Dec 3. (http://www.ncbi.nlm.nih.gov/pubmed/23208740?dopt=Abstract)
  • Outteryck O, Devos D, Jissendi P, Boespflug-Tanguy O, Hopes L, Renard D, Ferri J, Vermersch P, Labauge P. 4H syndrome: a rare cause of leukodystrophy. J Neurol. 2010 Oct;257(10):1759-61. doi: 10.1007/s00415-010-5598-0. Epub 2010 May 30. (http://www.ncbi.nlm.nih.gov/pubmed/20512583?dopt=Abstract)
  • Potic A, Brais B, Choquet K, Schiffmann R, Bernard G. 4H syndrome with late-onset growth hormone deficiency caused by POLR3A mutations. Arch Neurol. 2012 Jul;69(7):920-3. (http://www.ncbi.nlm.nih.gov/pubmed/22451160?dopt=Abstract)
  • Sasaki M, Takanashi J, Tada H, Sakuma H, Furushima W, Sato N. Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum. Brain Dev. 2009 Sep;31(8):582-7. doi: 10.1016/j.braindev.2008.09.003. Epub 2008 Oct 11. (http://www.ncbi.nlm.nih.gov/pubmed/18851904?dopt=Abstract)
  • Sato I, Onuma A, Goto N, Sakai F, Fujiwara I, Uematsu M, Osaka H, Okahashi S, Nonaka I, Tanaka S, Haginoya K. A case with central and peripheral hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) plus cataract. J Neurol Sci. 2011 Jan 15;300(1-2):179-81. doi: 10.1016/j.jns.2010.09.009. Epub 2010 Sep 29. (http://www.ncbi.nlm.nih.gov/pubmed/20884016?dopt=Abstract)
  • Terao Y, Saitsu H, Segawa M, Kondo Y, Sakamoto K, Matsumoto N, Tsuji S, Nomura Y. Diffuse central hypomyelination presenting as 4H syndrome caused by compound heterozygous mutations in POLR3A encoding the catalytic subunit of polymerase III. J Neurol Sci. 2012 Sep 15;320(1-2):102-5. doi: 10.1016/j.jns.2012.07.005. Epub 2012 Jul 21. (http://www.ncbi.nlm.nih.gov/pubmed/22819058?dopt=Abstract)
  • Tétreault M, Choquet K, Orcesi S, Tonduti D, Balottin U, Teichmann M, Fribourg S, Schiffmann R, Brais B, Vanderver A, Bernard G. Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am J Hum Genet. 2011 Nov 11;89(5):652-5. doi: 10.1016/j.ajhg.2011.10.006. Epub 2011 Oct 27. (http://www.ncbi.nlm.nih.gov/pubmed/22036172?dopt=Abstract)
  • Vanderver A, Tonduti D, Bernard G, Lai J, Rossi C, Carosso G, Quezado M, Wong K, Schiffmann R. More than hypomyelination in Pol-III disorder. J Neuropathol Exp Neurol. 2013 Jan;72(1):67-75. doi: 10.1097/NEN.0b013e31827c99d2. (http://www.ncbi.nlm.nih.gov/pubmed/23242285?dopt=Abstract)
  • Wolff A, Koch MJ, Benzinger S, van Waes H, Wolf NI, Boltshauser E, Luder HU. Rare dental peculiarities associated with the hypomyelinating leukoencephalopathy 4H syndrome/ADDH. Pediatr Dent. 2010 Sep-Oct;32(5):386-92. (http://www.ncbi.nlm.nih.gov/pubmed/21070704?dopt=Abstract)
  • Wolf NI, Harting I, Innes AM, Patzer S, Zeitler P, Schneider A, Wolff A, Baier K, Zschocke J, Ebinger F, Boltshauser E, Rating D. Ataxia, delayed dentition and hypomyelination: a novel leukoencephalopathy. Neuropediatrics. 2007 Apr;38(2):64-70. (http://www.ncbi.nlm.nih.gov/pubmed/17712733?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: June 2013
Published: April 17, 2014