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Pol III-Related Leukodystrophies

, MD, MSc, FRCPc and , MD.

Author Information
, MD, MSc, FRCPc
Department of Pediatrics, Neurology and Neurosurgery
Division of Pediatric Neurology
Montreal Children’s Hospital
McGill University Health Center
Montreal, Quebec, Canada
, MD
Department of Neurology and Center for Genetic Medicine Research
Children's National Medical Center
Washington, DC

Initial Posting: .

Summary

Disease characteristics. The Pol III-related leukodystrophies, hypomyelinating leukodystrophies with some shared features on brain MRI, are characterized by varying combinations of the three major clinical findings:

  • Motor dysfunction (progressive gait abnormalities due to spasticity, cerebellar ataxia, and/or tremor)
  • Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth)
  • Hypogonadotropic hypogonadism.

The five overlapping clinical phenotypes (described as distinct entities before their molecular basis was known) include:

  • Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome);
  • Ataxia, delayed dentition, and hypomyelination (ADDH);
  • Tremor-ataxia with central hypomyelination (TACH);
  • Leukodystrophy with oligodontia (LO); and
  • Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC).

Age of onset ranges from infancy to adolescence.

Diagnosis/testing. Pol III-related leukodystrophies are diagnosed by the combination of classic clinical findings, brain MRI features of hypomyelinating leukodystrophy, and the presence of biallelic mutations in either POLR3A or POLR3B. A hypomyelinating leukodystrophy is identified when two MRIs obtained at least six months apart after age one year reveal no significant improvement in myelination.

Management. Treatment of manifestations: Care by a multidisciplinary team including a pediatric neurologist, medical geneticist, physiotherapist, occupational therapist, neuropsychologist, dentist, endocrinologist, and primary care physician is recommended. Ambulation difficulties, swallowing difficulties, and seizures should be monitored by a neurologist and physiatrist. Management of spasticity can include removal of noxious stimuli, physical therapy and stretching exercises, oral baclofen, botulinum toxin injections, neurolysis, orthopedic procedures, and, less commonly, placement of an intrathecal baclofen pump. Treatment of hypersalivation can include oro-motor and behavioral therapy, glycopyrrolate, anticholinergic medications and/or botulinum toxin injections, and surgical relocation of the parotid ducts or submandibular ducts with or without sublingual gland excision. Dental manifestations should be managed when necessary by a dentist/orthodontist. Hypogonadotropic hypogonadism and other pituitary hormone deficiencies should be managed in consultation with an endocrinologist.

Genetic counseling. Pol III-related leukodystrophies are inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both disease-causing mutations in the family are known.

GeneReview Scope

Pol III-Related Leukodystrophies: Included Disorders
  • Hypomyelination, hypodontia, and hypogonadotropic hypogonadism syndrome (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)

Diagnosis

Pol III-related leukodystrophies are diagnosed by the combination of classic clinical and MRI features and the presence of biallelic mutations in either POLR3A or POLR3B.

The major/shared clinical features (that vary between the Pol III-related leukodystrophies) are:

  • Motor dysfunction: progressive gait abnormalities due to spasticity, cerebellar ataxia, and/or tremor
  • Abnormal dentition (e.g., hypodontia, oligodontia, delayed teeth eruption) [Wolff et al 2010]
  • Hypogonadotropic hypogonadism

Note: Although this triad is highly suggestive of the diagnosis, not all features are present in individuals who have biallelic POLR3A or POLR3B mutations.

Brain MRI reveals a hypomyelinating leukodystrophy pattern characterized by:

  • T2 mild hyperintensity of the white matter
  • T1 hyperintensity, isointensity, or mild hypointensity of the white matter when compared with grey matter structures [Schiffmann & van der Knaap 2009];
  • T2 hypointense signal (normal or almost normal white matter signal) of the hilus of the dentate nuclei, anterolateral nuclei of the thalami, globi pallidi, pyramidal tracts in the posterior limb of the internal capsule, and optic radiations [Steenweg et al 2010].

See Figure 1.

Figure 1

Figure

Figure 1. MRI of the brain of an individual with molecularly confirmed 4H syndrome

A. Sagittal T1-weighted image (midline) showing cerebellar atrophy (arrowhead) as well as a thin corpus callosum (arrow).
B. Axial T2-weighted (more...)

Molecular Genetic Testing

Genes. POLR3A and POLR3B are the only two genes in which biallelic mutations are known to cause Pol III-related leukodystrophies [Bernard et al 2011, Saitsu et al 2011, Tétreault et al 2011, Potic et al 2012].

Table 1. Summary of Molecular Genetic Testing Used in Pol III-Related Leukodystrophies

Gene 1Proportion of Pol III-Related Leukodystrophies Attributed to Mutations in This Gene 2Test MethodMutations Detected 3
POLR3A81%Sequence analysis 4Sequence variants 5, 6
POLR3B19%Sequence analysis 4Sequence variants 5, 6

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Bernard et al [2011], Saitsu et al [2011], Tétreault et al [2011], Potic et al [2012]

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Missense, nonsense, and splice-site mutations, deletions, and insertions in POLR3A or POLR3B were identified by Sanger sequencing of the exons and intron-exon boundaries. Bernard et al [2011], Saitsu et al [2011], Tétreault et al [2011], Potic et al [2012].

6. To date, no exonic or whole-gene deletions or duplications have been identified.

Testing Strategy

To confirm/establish the diagnosis in a proband when clinical and MRI features are consistent with the diagnosis:

1.

Perform molecular genetic testing of POLR3A.

2.

If only one or no mutations are identified, perform molecular genetic testing of POLR3B.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family. Note: Although the phenotype is similar among family members, the severity and age of onset can vary.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

The Pol III-related leukodystrophies, which are hypomyelinating leukodystrophies that share some features on brain MRI, have varying combinations of three major clinical findings: motor dysfunction, abnormal dentition, and hypogonadotropic hypogonadism.

The five clinical phenotypes that comprise the Pol III-related leukodystrophies (described as distinct entities before their molecular basis was known) appear to be overlapping disorders on a continuum:

Motor dysfunction includes progressive gait abnormalities due to spasticity, cerebellar ataxia, and/or tremor. Abnormalities range from mild (as in 4H syndrome, HCAHC [Sasaki et al 2009], and LO) to severe with early loss of ambulation as in TACH and some individuals with 4H syndrome, possibly as a result of more severe cerebellar and pyramidal findings [Bernard et al 2010, Bernard et al 2011]. Children with earlier-onset symptoms may have more significant ataxia and tremor, and may fail to gain independent ambulation or lose it earlier in childhood. In other affected individuals the onset of motor symptoms (spasticity, ataxia and extrapyramidal dysfunction) may be in adolescence or young adulthood, with loss of ambulation in early adulthood.

Dental abnormalities include delayed dentition, hypodontia, oligodontia, and eruption of abnormally placed or shaped teeth, among others [Wolff et al 2010]. Dental abnormalities may be subtle and have not been seen in all phenotypes (e.g., HCAHC).

Hypogonadotropic hypogonadism (HH) is an inconstant feature: it has not been reported in LO and HCAHC. When reported, HH typically presents with delayed puberty or absence of early pubertal changes. Early childhood manifestations of HH seen in isolated hypogonadotropic hypogonadism have not been reported in Pol III-related leukodystrophies.

Age of onset, which varies in the Pol-III related leukodystrophies, may correlate with phenotype, with more severe disease associated with earlier onset.

  • TACH. Onset is between ages one and five years.
  • 4H syndrome. Clinically milder; onset is between infancy and adolescence.
  • LO. Initially described in a large consanguineous Syrian family [Atrouni et al 2003] and subsequently in two other families [Bernard et al 2011]; onset is from age two to 13 years.

Additional features seen in a subset of the phenotypes include the following [Wolf et al 2005, Timmons et al 2006, Vázquez-López et al 2008, Bekiesinska-Figatowska et al 2010, Orcesi et al 2010, Wolff et al 2010, Sato et al 2011, Potic et al 2012]:

  • Intellectual disability and/or slow cognitive regression
  • Extrapyramidal findings (e.g., dystonia of variable severity and ranging from focal to generalized); seen as the disease progresses in some individuals with 4H syndrome and TACH [Authors, personal observation]
  • Hypersalivation and dysphagia. Reported in 4H syndrome and ADDH. The oldest reported person with 4H syndrome died of accidental choking after age 35 years.
  • Abnormal extraocular movements
    • Progressive vertical gaze restriction has been reported in 4H syndrome, TACH, HCAHC and ADDH.
    • Gaze-evoked nystagmus as well as abnormal ocular pursuits and saccades have been described in TACH, HCAHC and 4H syndrome.
  • Optic atrophy; described in four individuals with TACH
  • Seizures; reported in two individuals with 4H syndrome [Bernard et al 2011], one individual with HCAHC, and one individual with TACH
  • Peripheral neuropathy
    • Some persons with 4H syndrome have an asymptomatic peripheral neuropathy that typically is associated with normal nerve conduction studies [Timmons et al 2006]. Typical findings on electronic microscopy of a nerve biopsy include clefts lined with granular debris, expanded abaxonal space, outpocketing with vacuolar disruption, and loss of normal myelin periodicity.
    • Normal findings on nerve biopsy were observed in two persons with TACH [Bernard et al 2010, Bernard et al 2011] and one individual with LO.
    • Nerve biopsy was not performed in HCAHC [Saitsu et al 2011].
  • Growth hormone deficiency; reported in one person with 4H syndrome [Potic et al 2012]
  • Cataracts; reported in one person with 4H syndrome [Sato et al 2011]

Neurophysiologic investigations. All affected individuals undergoing EMG and nerve conduction studies had normal results.

Genotype-Phenotype Correlations

To date, no study of genotype-phenotype correlations has been performed.

POLR3A

  • Individuals with TACH have unique homozygous POLR3A mutations.
  • Individuals with 4H syndrome, HCAHC, and LO may have biallelic POLR3A mutations with no specific genotype-phenotype correlations thus far identified [Bernard et al 2011].

POLR3B.

Differential Diagnosis

The differential diagnosis of Pol III-related leukodystrophies includes other hypomyelinating leukodystrophies. Note: A hypomyelinating leukodystrophy is identified when two MRIs obtained at least six months apart after age one year reveal no significant improvement in myelination.

See Leukodystrophy, Hypomyelinating: OMIM Phenotypic Series, a table of similar phenotypes that are genetically diverse.

PLP1-related disorders, caused by mutation of PLP1, have a variable age of onset; severity ranges from a neonatal presentation with nystagmus, axial hypotonia evolving into spastic quadraparesis, and ataxia (Pelizaeus-Merzbacher disease) to a later-onset presentation with spastic paraparesis (SPG2). Brain MRI in the earlier-onset forms reveals severe hypomyelination, whereas brain MRI in individuals with later-onset forms (spastic paraparesis) reveals no (or more discrete) abnormalities. Inheritance is X-linked.

Pelizaeus-Merzbacher-like disease (hypomyelinating leukodystrophy-2; HLD-2), caused by biallelic mutation of GJC2 (also known as GJA12), has a variable age of onset and severity. Those with early-infantile onset have more severe disease; those with later onset have spastic paraparesis designated as SPG44. Brain MRI findings are similar to those seen in PMD: diffuse hypomyelination as well as some involvement of the brain stem, in particular the pons. Inheritance is autosomal recessive.

Classic Cockayne syndrome (CS type I), caused by biallelic mutations in ERCC6 and ERCC8, typically presents in early childhood. The main clinical features are postnatal growth failure, acquired progressive microcephaly, and developmental delay and regression with or without other neurologic features (e.g., spasticity, ataxia, tremor, seizures, and behavioral abnormalities). Other variably present features include photosensitivity (seen in two thirds of cases), demyelinating peripheral neuropathy, ocular findings including pigmentary retinopathy and cataracts, sensorineural hearing loss, and dental abnormalities. Brain MRI demonstrates hypomyelination or delayed myelination, cerebral atrophy, and brain calcifications. Inheritance is autosomal recessive.

Trichothiodystrophy, part of the same family of disorders of DNA nucleotide excision repair defects as Cockayne syndrome, is a group of autosomal recessive disorders caused by mutations in ERCC3, GTF2H5, and ERCC2 [Takayama et al 1997, Giglia-Mari et al 2004, Kraemer et al 2007]. The clinical features are variable and include varying combinations of the following: brittle hair (sulfur-deficient hair with a “tiger tail” appearance of alternating dark and light banding on light microscopy); skin hypersensitivity to sun exposure; ichthyosis; infertility; and neurologic manifestations that may include intellectual disability, microcephaly, and ataxia. MRI of the brain reveals cerebral hypomyelination without prominent cerebral atrophy and calcifications of the basal ganglia.

Free sialic acid storage disorders (including Salla disease, intermediate severe Salla disease, and infantile free sialic storage disease (ISSD]) are caused by biallelic mutation of SLC17A5. Severity is variable; ISSD, the most severe of the disorders, is characterized by early-onset multisystemic disease including nonimmune hydrops fetalis, hepatosplenomegaly, failure to thrive, facial coarsening, and progressive neurologic deterioration leading to early death. Salla disease, the mildest form, is typically characterized by normal development in the first six months of life, after which hypotonia and truncal ataxia become apparent. Progression over time includes developmental delay, growth retardation, severe spasticity and ataxia, and progressive facial coarsening. Intermediate severe Salla disease is in the middle on the severity spectrum. Brain MRI demonstrates a hypomyelinating leukodystrophy of the cerebrum and cerebellum with or without cerebellar atrophy [Lancaster et al 2005, Linnankivi et al 2006, Benini et al 2012]. Inheritance is autosomal recessive.

Hypomyelination with congenital cataracts (HCC; hypomyelinating leukodystrophy-5 [HLD5]) is caused by mutations in HCC (also known as FAM126A and previously known as DRCTNNB1A). Onset is typically in infancy with congenital cataracts (variably present) and psychomotor regression. Peripheral neuropathy is present in most individuals. Brain MRI reveals diffuse hypomyelination. Some areas of T2 hyperintensities corresponding to T1 hypointensities may be present. The cerebellar hemispheres may show mild high T2 signal resulting in a blurry grey-white matter junction. Inheritance is autosomal recessive.

Hypomyelination with atrophy of the basal ganglia and cerebellum (HABC, hypomyelinating leukodystrophy-6 [HLD6]) is characterized by early-onset motor regression and/or delay. The characteristic brain MRI finding that help differentiate HABC from the other hypomyelinating leukodystrophies is progressive atrophy of the basal ganglia (specifically the putamen) and cerebellum [van der Knaap et al 2002, van der Knaap et al 2007]. Inheritance is thought to be autosomal dominant (caused by de novo mutations) or autosomal recessive. The gene in which mutations are causative has not been identified.

18q minus syndrome, caused a deletion of the distal part of the long arm of chromosome 18 that includes 18q23, is differentiated from the other hypomyelinating leukodystrophies by the presence of a multisystem findings including: dysmorphisms, endocrine abnormalities, cardiac malformations, immunodeficiency, and musculoskeletal deformities [Kline et al 1993]. Neurologic manifestations include developmental delay, intellectual disability, microcephaly, behavioral abnormalities, seizures, pyramidal and extrapyramidal signs, hypotonia, impaired coordination, and nystagmus [Linnankivi et al 2006, Miller et al 1990]. The two main white matter abnormalities on brain MRI are hypomyelination and multifocal T2 and FLAIR hyperintensities. Structural brain abnormalities can include: heterotopias, ex vacuo ventriculomegaly, cerebellar hypoplasia, and porencephalic cysts. The white matter abnormalities are thought to be secondary to haploinsufficiency of MBP (encoding myelin basic protein) at 18q23, an important protein of the central nervous system white matter.

Fucosidosis is caused by biallelic mutations in FUCA1. Fucosidosis type 1 is differentiated clinically from the other hypomyelinating leukodystrophies by the presence of coarse facial features, hepatosplenomegaly, and cardiomegaly. Fucosidosis type 2 is typically differentiated by the presence of mild coarsening, growth retardation, and angiokeratoma corporis diffusum [Durand et al 1969, Kousseff et al 1976]. Brain MRI reveals a distinctive hypomyelinating pattern and, with time, atrophy involving both the cerebrum and cerebellum, with hypointensities of the globi pallidi, substantia nigra, and thalami. Inheritance is autosomal recessive.

Hypomyelination of the early myelinating structures (HEMS) is a recently described hypomyelinating leukodystrophy characterized by infantile-onset nystagmus, gait ataxia, and dysarthria with or without spasticity [Steenweg et al 2012]. Brain MRI shows a characteristic pattern with mild T2 hyperintensities of the frontoparietal periventricular white matter, optic radiations, medulla oblongata, caudal pons, subcortical cerebellar white matter, hilus of the dentate nucleus, and peridentate white matter. A typical pattern of alternating hyper-hypo-hyperintense stripes on T2-weighted imaging can be seen in the posterior limb of the internal capsule. Inheritance is thought to be X linked; the gene in which mutations are causative has not been identified.

Peripheral neuropathy, central hypomyelination, Waardenburg, Hirschsprung (PCWH) is caused by mutations in SOX10 [Inoue et al 1999, Inoue et al 2002]. Clinical features include: peripheral demyelinating neuropathy (leading to sensory deficits and loss of stretch reflexes); hypomyelinating leukodystrophy (leading to early-onset hypotonia, developmental delay, and nystagmus which evolve over time into spasticity and cerebellar ataxia); Waardenburg syndrome (manifest as pigmentary abnormalities including heterochromia iridis and sensorineral hearing loss); and Hirschsprung disease. Inheritance is autosomal dominant.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with a Pol III-related leukodystrophy, the following are recommended:

  • Pediatric neurology consultation
  • Swallowing assessment
  • Physiotherapy evaluation
  • Occupational therapy evaluation
  • Neuropsychology evaluation
  • Brain MRI, if not performed at the time of diagnosis
  • Dentistry consultation
  • Endocrine consultation
  • Medical genetics consultation

Treatment of Manifestations

Care by a multidisciplinary team including a pediatric neurologist, medical geneticist, physiotherapist, occupational therapist, neuropsychologist, dentist, endocrinologist, and primary care physician is recommended.

Manifestations such as ambulation difficulties, dysphagia, and seizures are managed in a routine manner.

Spasticity management includes removal of noxious stimuli, rehabilitation (e.g., physical therapy, stretching), oral medications (e.g., baclofen), neurolysis, botulinum toxin injections, orthopedic procedures, and less commonly, placement of an intrathecal baclofen pump.

Hypersalivation is managed with the multidisciplinary team and an otolaryngologist and social worker. Treatment is individualized. Therapies to consider include rehabilitation (e.g., oro-motor therapy, behavioral therapy); medical therapy (e.g., glycopyrrolate, anticholinergic medications, botulinum toxin injections); and surgery (e.g., relocation of the parotid ducts and relocation of the submandibular ducts with or without sublingual gland excision).

Swallowing and hence nutrition can be issues and some individuals require gastrostomy.

Difficulties with school are likely to progress slowly because cognitive involvement is much less severe than motor involvement. In contrast, activities of daily living are likely to become problematic early on in the disease course as motor difficulties make patients progressively more dependent on assistance from others.

Dental manifestations should be managed, when necessary by a dentist/orthodontist.

Hormone replacement therapy may be indicated.

Surveillance

No surveillance guidelines have been developed to date. The following are recommended:

  • Regular evaluations, every three to six months, and more frequently if necessary, to manage the manifestations of the leukodystrophy (spasticity, hypersalivation)
  • Follow-up evaluations to manage the endocrine abnormalities

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Pol III-related leukodystrophies are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

    Note: The phenotype is similar among family members; however, the severity can vary.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. To date, no individual with a Pol III-related leukodystrophy has been known to reproduce.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Australian Leukodystrophy Support Group, Inc.
    Nerve Centre
    54 Railway Road
    Blackburn Victoria 3130
    Australia
    Phone: 1800-141-400 (toll free); +61 3 98452831
    Fax: +61 3 95834379
    Email: mail@alds.org.au
  • European Leukodystrophy Association (ELA)
    2, rue Mi-les-Vignes
    B.P. 61024
    Laxou Cedex 54521
    France
    Phone: 03833093 34
    Fax: 03833000 68
    Email: ela@ela-asso.com
  • United Leukodystrophy Foundation (ULF)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    Email: office@ulf.org
  • Myelin Disorders Bioregistry Project
    Email: myelindisorders@cnmc.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Pol III-Related Leukodystrophies: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Pol III-Related Leukodystrophies (View All in OMIM)

607694LEUKODYSTROPHY, HYPOMYELINATING, 7, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM; HLD7
614258POLYMERASE III, RNA, SUBUNIT A; POLR3A
614366POLYMERASE III, RNA, SUBUNIT B; POLR3B
614381LEUKODYSTROPHY, HYPOMYELINATING, 8, WITH OR WITHOUT OLIGODONTIA AND/OR HYPOGONADOTROPIC HYPOGONADISM; HLD8

Molecular Genetic Pathogenesis

Three types of polymerases (Pol I, II, and III) are responsible for the transcription of DNA into RNA [Werner et al 2009, Cramer et al 2008]. Pol I, II, and III have a distinct repertoire of DNA targets. POLR3A and POLR3B are the two largest subunits of Pol III and form the catalytic core of the polymerase III.

  • Pol I transcribes pre-rsRNAs, which are modified into most of the ribosomal rsRNAs constituting the 18S, 5.8S, and 28S ribosomal subunits.
  • Pol II transcribes all protein-coding genes and multiple non-coding genes, including the majority of microRNAs (miRNAs).
  • Pol III has a diverse repertoire of nuclear targets and also transcribes exogenous DNA in the cytoplasm.
    • In the nucleus it transcribes all tRNAs (transfer RNAs), the RNA 7SL (which is necessary for the insertion of proteins into membranes), RNAs 7SK, Alu, and B2 elements (which are responsible for the regulation of the transcription of Pol II).
    • Pol III may play a role in the transcription of some miRNAs, but not to the same extent as Pol II [Dieci et al 2007].
    • Pol III is responsible for the transcription of the ribosomal subunit 5S gene, which is involved in cytoplasmic and mitochondrial translation [Szymański et al 2003].
    • Pol III transcribes vault RNAs which become the vault organelles (responsible for the transport of the mRNAs from the nucleus to the cytoplasm).

POLR3A

Gene structure. POLR3A comprises 31 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Pathogenic variants include missense, nonsense, and splice-site mutations, deletions, and insertions [Bernard et al 2011, Saitsu et al 2011, Potic et al 2012]. See Table 2 (pdf).

No affected individual has been found to have two null mutations, which may be explained by the role of POLR3A as a housekeeping gene, suggesting that some residual Pol III function is essential for embryonic/fetal survival.

Normal gene product. POLR3A encodes the DNA-directed RNA polymerase III subunit A (POLR3A) which comprises 1390 amino acids. POLR3A, the largest of the 17 subunits of polymerase III (Pol III), forms (together with POLR3B) the catalytic core of the polymerase.

Abnormal gene product. The mapping of the mutations to protein domains of POLR3A suggests that they can interfere with DNA binding directly, modify the catalytic cleft structure, change POLR3A/POLR3B interaction, and perturb interactions between POLR3A and other Pol III subunits [Bernard et al 2011].

It is hypothesized that mutations in POLR3A lead to suboptimal assembly of the Pol III complex and to a lesser extent the Pol III macromolecule. Indeed, western blot studies on fibroblasts and brain tissue from a POLR3A mutation-positive individual with 4H syndrome showed a statistically significant decrease in POLR3A levels, with a more significant reduction in the cerebral white matter compared to the cortex [Bernard et al 2011].

POLR3B

Gene structure. POLR3B comprises 28 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Pathogenic variants include missense, nonsense, and splice-site mutations, and deletions [Saitsu et al 2011, Tétreault et al 2011]. See Table 3 (pdf).

No affected individual has been found to have two null mutations, which may be explained by the role of POLR3B as a housekeeping gene, suggesting that some residual Pol III function is essential for embryonic/fetal survival.

Normal gene product. POLR3B encodes the DNA-directed RNA polymerase III subunit B (POLR3B) which comprises 1133 amino acids. POLR3B, the second largest of the 17 subunits of polymerase III (Pol III), forms (together with POLR3A) the catalytic core of the polymerase.

Abnormal gene product. The mapping of the mutations to protein domains of POLR3B suggests that they can interfere with DNA binding directly, modify the catalytic cleft structure, change POLR3A/POLR3B interaction, and perturb interactions between POLR3B and other Pol III subunits [Tétreault et al 2011].

References

Literature Cited

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Suggested Reading

  1. Hu P, Wu S, Sun Y, Yuan CC, Kobayashi R, Myers MP, Hernandez N. Characterization of human RNA polymerase III identifies orthologues for Saccharomyces cerevisiae RNA polymerase III subunits. Mol Cell Biol. 2002;22:8044–55. [PMC free article: PMC134740] [PubMed: 12391170]

Chapter Notes

Acknowledgments

Dr. Bernard wishes to thank the “Fondation sur les Leucodystrophies,” the “Fondation Go,” the European Leukodystrophy Association, and the Montreal Children’s Hospital and Montreal University Health Center Research Institutes for financing her research projects on leukodystrophies. She also wishes to thank the Montreal Children’s Hospital Foundation, the MSSA (Medical Staff Service Association), the MCHAN (Montreal Children’s Hospital Associates in Neurology) and FRSQ (Fonds de Recherche en Santé du Québec) for her clinician-scientist salary awards. She also wishes to thank Dr. Bernard Brais for his mentorship throughout this project. Dr. Vanderver wishes to thank the Intramural Research Program of the National Human Genome Research Institute and the Myelin Disorders Bioregistry Project. Drs. Bernard and Vanderver wish to thank all patients and their families as well as all the collaborators who were involved in the Pol III-related leukodystrophy project.

Revision History

  • 2 August 2012 (me) Review posted live
  • 1 March 2012 (av) Original submission
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