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Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.

Neurology. 2014 Nov 18;83(21):1898-905. doi: 10.1212/WNL.0000000000001002. Epub 2014 Oct 22.

Abstract
Objective: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B.

Methods: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases.

Results: The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis.

Conclusions: 4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features.

Wolf NI, Vanderver A, van Spaendonk RM, Schiffmann R, Brais B, Bugiani M, Sistermans E, Catsman-Berrevoets C, Kros JM, Pinto PS, Pohl D, Tirupathi S, Strømme P, de Grauw T, Fribourg S, Demos M, Pizzino A, Naidu S, Guerrero K, van der Knaap MS, Bernard G; 4H Research Group.

FULL ARTICLE

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.

Abstract
Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterized by abnormal white matter visible by brain imaging. It is estimated that at least 30% to 40% of individuals remain without a precise diagnosis despite extensive investigations. We mapped tremor-ataxia with central hypomyelination (TACH) to 10q22.3-23.1 in French-Canadian families and sequenced candidate genes within this interval. Two missense and one insertion mutations in five individuals with TACH were uncovered in POLR3A, which codes for the largest subunit of RNA polymerase III (Pol III). Because these families were mapped to the same locus as leukodystrophy with oligodontia (LO) and presented clinical and radiological overlap with individuals with hypomyelination, hypodontia and hypogonadotropic hypogonadism (4H) syndrome, we sequenced this gene in nine individuals with 4H and eight with LO. In total, 14 recessive mutations were found in 19 individuals with TACH, 4H, or LO, establishing that these leukodystrophies are allelic. No individual was found to carry two nonsense mutations. Immunoblots on 4H fibroblasts and on the autopsied brain of an individual diagnosed with 4H documented a significant decrease in POLR3A levels, and there was a more significant decrease in the cerebral white matter compared to that in the cortex. Pol III has a wide set of target RNA transcripts, including all nuclear-coded tRNA. We hypothesize that the decrease in POLR3A leads to dysregulation of the expression of certain Pol III targets and thereby perturbs cytoplasmic protein synthesis. This type of broad alteration in protein synthesis is predicted to occur in other leukoencephalopathies such as hypomyelinating leukodystrophy-3, caused by mutations in aminoacyl-tRNA synthetase complex-interacting multifunctional protein 1 (AIMP1).

Bernard GChouery EPutorti MLTétreault MTakanohashi ACarosso GClément IBoespflug-Tanguy ORodriguez DDelague VAbou Ghoch JJalkh NDorboz IFribourg STeichmann MMegarbane ASchiffmann RVanderver ABrais B.

FULL ARTICLE

Novel mutations of the POLR3A gene caused POLR3-related leukodystrophy in a Chinese family: a case report.

BMC Pediatr. 2019 Aug 22;19(1):289. doi: 10.1186/s12887-019-1656-7.

Abstract 

Background: POLR3-related leukodystrophy is an autosomal recessive neurodegenerative disorder characterized by onset time ranging from the neonatal period to late childhood, progressive motor decline that manifests as spasticity, ataxia, tremor, and cerebellar symptoms, as well as mild cognitive regression and hypodontia. POLR3-related leukodystrophy belongs to the family of RNA polymerase III-related leukodystrophy, which are caused by biallelic mutations in the POLR3A, POLR3B, POLRC1, or POLR3K genes.

Case Presentation: In this study, we report a female child with POLR3-related leukodystrophy manifesting as cognitive decline, moderate dysarthria, motor decline, cerebellar syndrome, short stature, dysphagia, hypodontia, and mild delayed myelination by brain imaging. Interestingly, polytrichia and bronchodysplasia were first observed in a POLR3-related leukodystrophy patient. Medical exome sequencing with high coverage depth was employed to identify potential genetic variants in the patient. Novel compound heterozygous mutations of the POLR3A gene, c.1771-6C > G and c.2611del (p.M871Cfs*8), were detected. One of them is an uncommon splice site mutation, and this is the first report of this mutation in a Chinese family. The father was determined to be a heterozygous carrier of the c.2611del (p.M871Cfs*8) mutation and the mother a heterozygous carrier of the c.1771-6C > G mutation.

Conclusion: The patient’s newly emerged clinical features and mutations provide useful information for further exploration of genotype-phenotype correlations of POLR3-related leukodystrophy.

Wu S, Bai Z, Dong X, Yang D, Chen H, Hua J, Zhou L, Lv H.

FULL ARTICLE

The leukodystrophy mutation Polr3b R103H causes homozygote mouse embryonic lethality and impairs RNA polymerase III biogenesis.

Mol Brain. 2019 Jun 20;12(1):59. doi: 10.1186/s13041-019-0479-7.

Abstract

Recessive mutations in the ubiquitously expressed POLR3A and POLR3B genes are the most common cause of POLR3-relatedhypomyelinating leukodystrophy (POLR3-HLD), a rare childhood-onset disorder characterized by deficient cerebral myelin formation and cerebellar atrophy. POLR3A and POLR3B encode the two catalytic subunits of RNA Polymerase III (Pol III), which synthesizes numerous small non-coding RNAs. We recently reported that mice homozygous for the Polr3a mutation c.2015G > A (p.Gly672Glu) have no neurological abnormalities and thus do not recapitulate the human POLR3-HLD phenotype. To determine if other POLR3-HLD mutations can cause a leukodystrophy phenotype in mouse, we characterized mice carrying the Polr3b mutation c.308G > A (p.Arg103His). Surprisingly, homozygosity for this mutation was embryonically lethal with only wild-type and heterozygous animals detected at embryonic day 9.5. Using proteomics in a human cell line, we found that the POLR3B R103H mutation severely impairs assembly of the Pol III complex. We next generated Polr3aG672E/G672E/Polr3b+/R103Hdouble mutant mice but observed that this additional mutation was insufficient to elicit a neurological or transcriptional phenotype. Taken together with our previous study on Polr3a G672E mice, our results indicate that missense mutations in Polr3a and Polr3b can variably impair mouse development and Pol III function. Developing a proper model of POLR3-HLD is crucial to gain insights into the pathophysiological mechanisms involved in this devastating neurodegenerative disease.

Choquet K, Pinard M, Yang S, Moir RD, Poitras C, Dicaire MJ, Sgarioto N, Larivière R, Kleinman CL, Willis IM, Gauthier MS, Coulombe B, Brais B.

FULL ARTICLE

Dystonia in RNA Polymerase III-Related Leukodystrophy.

Mov Disord Clin Pract. 2019 Jan 9;6(2):155-159. doi: 10.1002/mdc3.12715. eCollection 2019 Feb.

Abstract

Objectives: To identify the prevalence of dystonia in a RNA Polymerase III (POLR3)-related leukodystrophy patient cohort and to further characterize their dystonic features.

Background: POLR3-related leukodystrophy is a hypomyelinating leukodystrophy characterized by neurological and non-neurological features. Dystonia remains a challenging and under-recognized feature.

Methods: A retrospective chart review was performed in a cohort of 20 patients for whom videos of a standardized neurological examination were available. Patients were recruited at the Montreal Children’s Hospital of the McGill University Health Center and the Myelin Disorders Bioregistry Project. Families were consented at the initial assessment and the following data was recorded: age and symptoms at clinical presentation, investigations, causal gene and mutation(s), type and severity of dystonia, and treatment response when needed. Standardized examination videos were reviewed by three independent reviewers and scored using the Global Dystonia Scale.

Results: 10 males and 10 females were included in this study; 12/20 had POLR3A mutations, while 8/20 had POLR3B mutations; 19/20 patients had documented dystonia, with 3/19 requiring therapy. There was a good response in two patients to a single agent, and a poor response in one patient to three agents; the majority had mild-to-moderate multifocal dystonia without a functional impact.

Conclusions: Dystonia is a common, yet underdiagnosed, slowly progressive manifestation of POLR3-related leukodystrophy, and in most cases has limited-to-no functional impact. When treatment is needed, good response to typically used medication may occur. Further studies are needed to assess evolution of dystonia over time, patients’ functional outcome, and response to therapy (when needed).

Al Yazidi G, Tran LT, Guerrero K, Vanderver A, Schiffmann R, Wolf NI, Chouinard S, Bernard G.

FULL ARTICLE

POLR3-Related Leukodystrophy.

Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. SourceGeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Abstract

Clinical Characteristics: 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.

Diagnosis/Testing: POLR3-related leukodystrophy is diagnosed by the combination of classic clinical findings, typical brain MRI features, and the presence of biallelic pathogenic variants in POLR3A, POLR3B, or POLR1C.

Management: Treatment of manifestations: Individualized care by a multidisciplinary team including a pediatric neurologist, clinical geneticist, physiotherapist, occupational therapist, speech and language pathologist, neuropsychologist, rehabilitation physician, dentist, endocrinologist, ophthalmologist, ear-nose-and-throat specialist, and primary care physician is recommended. Special caution needs to be taken when managing dysphagia in this disorder as it is known to vary widely, even in a single day. Swallowing difficulties will progress over time and dystonia should be monitored and treated to prevent complications and improve the quality of life.

Genetic Counseling: POLR3-related leukodystrophy is 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 pathogenic variants in the family are known.

Bernard G, Vanderver A.

FULL ARTICLE

Diffuse hypomyelination is not obligate for POLR3-related disorders.

Neurology. 2016 Apr 26;86(17):1622-6. doi: 10.1212/WNL.0000000000002612. Epub 2016 Mar 30.

Abstract

Objective: To report atypical MRI patterns associated with POLR3A and POLR3B mutations.

Methods: This was a multicenter retrospective study to collect neuroradiologic, clinical, and molecular data of patients with mutations in POLR3A and POLR3B without the classic MRI phenotype, i.e., diffuse hypomyelination associated with relative T2 hypointensity of the ventrolateral thalamus, globus pallidus, optic radiation, corticospinal tract at the level of the internal capsule, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum.

Results: Eight patients were identified: 6 carried mutations in POLR3A and 2 in POLR3B. We identified 2 novel MRI patterns: 4 participants presented a selective involvement of the corticospinal tracts, specifically at the level of the posterior limbs of the internal capsules; 4 patients presented moderate to severe cerebellar atrophy. Incomplete hypomyelination was observed in 5 participants.

Conclusion: Diffuse hypomyelination is not an obligatory feature of POLR3-related disorders. Two distinct patterns, selective involvement of the corticospinal tracts and cerebellar atrophy, are added to the MRI presentation of POLR3-related disorders.

La Piana R, Cayami FK, Tran LT, Guerrero K, van Spaendonk R, Õunap K, Pajusalu S, Haack T, Wassmer E, Timmann D, Mierzewska H, Poll-Thé BT, Patel C, Cox H, Atik T, Onay H, Ozkınay F, Vanderver A, van der Knaap MS, Wolf NI, Bernard G.

FULL ARTICLE

Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III.

Nat Commun. 2015 Jul 7;6:7623. doi: 10.1038/ncomms8623.

Abstract

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes’ availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.

Thiffault I, Wolf NI, Forget D, Guerrero K, Tran LT, Choquet K, Lavallée-Adam M, Poitras C, Brais B, Yoon G, Sztriha L, Webster RI, Timmann D, van de Warrenburg BP, Seeger J, Zimmermann A, Máté A, Goizet C, Fung E, van der Knaap MS, Fribourg S, Vanderver A, Simons C, Taft RJ, Yates JR 3rd, Coulombe B, Bernard G.

FULL ARTICLE

Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy.

Orphanet J Rare Dis. 2015 Jun 5;10:69. doi: 10.1186/s13023-015-0279-9.

Abstract

POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non-neurological features. In a small proportion of patients, no mutation in either gene or only one mutation is found. Analysis of the POLR3B cDNA revealed a large deletion of exons 21-22 in one case and of exons 26-27 in another case. These are the first reports of long deletions causing POLR3-related leukodystrophy, suggesting that deletions and duplications in POLR3A or POLR3B should be investigated in patients with a compatible phenotype, especially if one pathogenic variant has been identified.

Gutierrez M, Thiffault I, Guerrero K, Martos-Moreno GÁ, Tran LT, Benko W, van der Knaap MS, van Spaendonk RM, Wolf NI, Bernard G.

FULL ARTICLE

A 42-year-old woman with 4H leukodystrophy caused by a homozygous mutation in POLR3A gene.

Chin Med J (Engl). 2019 Aug 5;132(15):1879-1880. doi: 10.1097/CM9.0000000000000328.

No abstract available

Yi-Ming Yang, Zhong-Min Zhao, Yan-Li Jia, Yang-Juan Jia, Ning Han, and Jian-Hua Wang.

FULL ARTICLE

A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report.

BMC Pediatr. 2018 Apr 4;18(1):126. doi: 10.1186/s12887-018-1108-9.

Abstract

Background: 4H syndrome is a congenital hypomyelinating leukodystrophy characterized by hypodontia, hypomyelination and hypogonadotropic hypogonadism belonging to the Pol III-related leukodystrophies which arise due to mutations in the POLR3A or POLR3B gene. The clinical presentation is of neurodevelopmental delay or regression with ataxia, dystonia, nystagmus, delayed deciduous dentition and abnormal order of eruption of teeth. MRI brain shows a characteristic hypomyelination pattern. Several mutations have been described in the implicated genes but there are no reports on mutations seen in patients from India.

Case Presentation: We report a 1½ year old girl, only child of a non-consanguinous couple who presented with delayed developmental milestones and delayed dentition. On physical examination she had downward slanting palpebral fissures, low set ears, smooth philtrum, hypodontia, prominent body hair and clitoromegaly. There was prominent horizontal nystagmus, hypertonia of both upper and lower limbs, exaggerated deep tendon jerks and flexor planter response. She had not attained complete head control and required support to sit. She showed absent waves on brainstem evoked response audiometry and her fundus examination showed bilateral optic atrophy with prolongation of P100 latencies on visual evoked potentials. MRI Brain showed hyperintensity of entire white matter with involvement of the internal and external capsule, frontal deep white matter and corpus callosum. Her karyotype was 46 XX and her endocrinal profile was unremarkable. Clinical exome sequencing identified an unreported mutation in the POLR3A gene. The same mutation was identified by Sanger sequencing in heterozygous state in both parents. The child is being managed with physiotherapy and developmental therapy. She has been provided with hearing aids and started on speech therapy. Parents were provided anticipatory guidance and genetic counselling about autosomal recessive nature of inheritance, risk of recurrence and need for follow-up.

Conclusion: 4H syndrome is a rare congenital hypomyelinating leukodystrophy inherited as an autosomal recessive disorder due to mutations in the POLR3A and POLR3B gene. Delay or regression of milestones, abnormalities in dentition and endocrinal perturbations are its hallmark. A novel mutation in the POLR3A gene resulting in amino acid substitution of arginine for glutamine at codon 808 (p.R808Q) was detected in exon 18 in our case.

Tewari VV, Mehta R, Sreedhar CM, Tewari K, Mohammad A, Gupta N, Gulati S, Kabra M.

FULL ARTICLE

Dystonia in RNA Polymerase III-Related Leukodystrophy.

Mov Disord Clin Pract. 2019 Jan 9;6(2):155-159. doi: 10.1002/mdc3.12715. eCollection 2019 Feb.

Abstract

Objectives: To identify the prevalence of dystonia in a RNA Polymerase III (POLR3)-related leukodystrophy patient cohort and to further characterize their dystonic features.

Background: POLR3-related leukodystrophy is a hypomyelinating leukodystrophy characterized by neurological and non-neurological features. Dystonia remains a challenging and under-recognized feature.

Methods: A retrospective chart review was performed in a cohort of 20 patients for whom videos of a standardized neurological examination were available. Patients were recruited at the Montreal Children’s Hospital of the McGill University Health Center and the Myelin Disorders Bioregistry Project. Families were consented at the initial assessment and the following data was recorded: age and symptoms at clinical presentation, investigations, causal gene and mutation(s), type and severity of dystonia, and treatment response when needed. Standardized examination videos were reviewed by three independent reviewers and scored using the Global Dystonia Scale.

Results: 10 males and 10 females were included in this study; 12/20 had POLR3A mutations, while 8/20 had POLR3B mutations; 19/20 patients had documented dystonia, with 3/19 requiring therapy. There was a good response in two patients to a single agent, and a poor response in one patient to three agents; the majority had mild-to-moderate multifocal dystonia without a functional impact.

Conclusions: Dystonia is a common, yet underdiagnosed, slowly progressive manifestation of POLR3-related leukodystrophy, and in most cases has limited-to-no functional impact. When treatment is needed, good response to typically used medication may occur. Further studies are needed to assess evolution of dystonia over time, patients’ functional outcome, and response to therapy (when needed).

Al Yazidi G, Tran LT, Guerrero K, Vanderver A, Schiffmann R, Wolf NI, Chouinard S, Bernard G.

FULL ARTICLE

4H Leukodystrophy: Lessons from 3T Imaging.

Neuropediatrics. 2018 Apr;49(2):112-117. doi: 10.1055/s-0037-1608780. Epub 2017 Nov 27.

Abstract

4H leukodystrophy is characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. With its variability in clinical symptoms, application of pattern recognition to identify specific magnetic resonance imaging (MRI) features proved useful for the diagnosis. We collected 3T MR imaging data of 12 patients with mutations in POLR3A (n = 8), POLR3B (n = 3), and POLR1C (n = 1), all obtained at the same scanner. We assessed these images and compared them with previously obtained 1.5T images in 8 patients. Novel MRI findings were myelin islets, closed eye sign, and a cyst-like lesion in the splenium. Myelin islets were variable numbers of small T1 hyperintense and T2 hypointense dots, mostly in the frontal and parietal white matter, and present in all patients. This interpretation was supported with perivascular staining of myelin protein in the hypomyelinated white matter of a deceased 4H patient. All patients had better myelination of the medial lemniscus with a relatively hypointense signal of this structure on axial T2-weighted (T2W) images (“closed eye sign”). Five patients had a small cyst-like lesion in the splenium. In 10 patients with sagittal T2W images, we also found spinal cord hypomyelination. In conclusion, imaging at 3T identified additional features in 4H leukodystrophy, aiding the MRI diagnosis of this entity.

Cayami FK, Bugiani M, Pouwels PJW, Bernard G, van der Knaap MS, Wolf NI.

Available Online at Thieme-Connect (Link presently not available)

4H Leukodystrophy: A Brain Magnetic Resonance Imaging Scoring System.

Neuropediatrics. 2017 Jun;48(3):152-160. doi: 10.1055/s-0037-1599141. Epub 2017 Mar 1.

Abstract

4H (hypomyelination, hypodontia and hypogonadotropic hypogonadism) leukodystrophy (4H) is an autosomal recessive hypomyelinating white matter (WM) disorder with neurologic, dental, and endocrine abnormalities. The aim of this study was to develop and validate a magnetic resonance imaging (MRI) scoring system for 4H. A scoring system (0-54) was developed to quantify hypomyelination and atrophy of different brain regions. Pons diameter and bicaudate ratio were included as measures of cerebral and brainstem atrophy, and reference values were determined using controls. Five independent raters completed the scoring system in 40 brain MRI scans collected from 36 patients with genetically proven 4H. Interrater reliability (IRR) and correlations between MRI scores, age, gross motor function, gender, and mutated gene were assessed. IRR for total MRI severity was found to be excellent (intraclass correlation coefficient: 0.87; 95% confidence interval: 0.80-0.92) but varied between different items with some (e.g., myelination of the cerebellar WM) showing poor IRR. Atrophy increased with age in contrast to hypomyelination scores. MRI scores (global, hypomyelination, and atrophy scores) significantly correlated with clinical handicap (p < 0.01 for all three items) and differed between the different genotypes. Our 4H MRI scoring system reliably quantifies hypomyelination and atrophy in patients with 4H, and MRI scores reflect clinical disease severity.

Vrij-van den Bos S, Hol JA, La Piana R, Harting I, Vanderver A, Barkhof F, Cayami F, van Wieringen WN, Pouwels PJW, van der Knaap MS, Bernard G, Wolf NI.

Available Online at Thieme-Connect (Link presently not available)

Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies.

J Med Genet. 2017 Jan;54(1):19-25. doi: 10.1136/jmedgenet-2016-104064. Epub 2016 Aug 10.

Abstract

Background: A constellation of neurodegenerative disorders exists (Gordon Holmes syndrome, 4H leucodystrophy, Boucher-Neuhauser syndrome) in which patients suffer from both neurological disease (typically manifested by ataxia) and reproductive failure (idiopathic hypogonadotropic hypogonadism (IHH)). POLR3B, which encodes the second largest subunit of RNA polymerase III (pol III), and POLR3A, which forms the pol III catalytic centre, are associated with 4H leucodystrophy.

Methods: Whole exome sequencing was performed on a large cohort of subjects with IHH (n=565). Detailed neuroendocrine studies were performed in some individuals within this cohort.

Results: Four individuals (two of them siblings) were identified with two rare nucleotide variants in POLR3B. On initial evaluation, all subjects were free of neurological disease. One patient underwent treatment with exogenous pulsatile gonadotropin-releasing hormone for 8 weeks which failed to result in normalisation of his sex steroid milieu due to pituitary resistance.

Conclusions: These findings suggest that the spectrum of phenotypes resulting from POLR3B mutations is wider than previously believed and that POLR3B can be associated exclusively with disorders characterised by abnormal gonadotropin secretion.

Richards MR, Plummer L, Chan YM, Lippincott MF, Quinton R, Kumanov P, Seminara SB.

FULL ARTICLE

Recessive Mutations in POLR3B Encoding RNA Polymerase III Subunit Causing Diffuse Hypomyelination in Patients with 4H Leukodystrophy with Polymicrogyria and Cataracts.

Clin Neuroradiol. 2017 Jun;27(2):213-220. doi: 10.1007/s00062-015-0472-1. Epub 2015 Oct 19.

Abstract

The diagnosis of 4H leukodystrophy (hypomyelination, hypogonadotropic hypogonadism, and hypodontia) is based on clinical findings and magnetic resonance imaging (MRI). Recently, mutations of the genes encoding Pol III (RNA polymerase III) subunit A (POLR3A) and subunit B (POL3B) have been identified as the genetic causes of hypomyelination. We describe two Polish female siblings aged 5 and 10 years with compound heterozygous mutations in POLR3B. They both presented with similar clinical symptoms and MRI findings presenting as 4H leukodystrophy, and the association of polymicrogyria and cataract. According to our observation in young children with the absence of hypogonadotropic hypogonadism, brain MRI pattern is very essential in proper early diagnosis of 4H leukodystrophy. All clinical and radiological results are of course helpful, however genetic conformation is always necessary.

Jurkiewicz E, Dunin-Wąsowicz D, Gieruszczak-Białek D, Malczyk K, Guerrero K, Gutierrez M, Tran L, Bernard G.

FULL ARTICLE

Longitudinal follow up of a boy affected by Pol III-related leukodystrophy: a detailed phenotype description.

BMC Med Genet. 2015 Jul 25;16:53. doi: 10.1186/s12881-015-0203-0.

Abstract

Background: The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is a newly recognized leukodystrophy. The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of two genes (POLR3A and POLR3B) responsible for the syndrome demonstrates that these three main characteristics can be variably combined among “Pol-III (polymerase III)-related leukodystrophies.”

Case Presentation: We report on the clinical, neuroradiological and endocrinological follow-up of a male affected by 4H syndrome with confirmed POLR3B mutations (c.1568 T > A/p.V523E variant in exon 15 and the novel c.1988C > T/p.T663I mutation in exon 19). Spastic-ataxic gait with worsening of motor performance, progressive moderate intellectual disability and language difficulties were the main neurological findings observed. The first six years of substantial stability of the clinical and imaging features were followed by additional six years that showed a progressive worsening of motor, language and learning disabilities in relation to a progression of the cerebellar involvement. Hypogonadotropic hypogonadism and growth hormone deficiency followed by central hypocortisolism became part of the patient’s phenotype. Thyroid function resulted unaffected during follow up.

Conclusions: A novel mutation in POLR3B in a patient with an analogue phenotype than those previously described but with more extensive endocrinological features, including hypogonadotropic hypogonadism, growth hormone deficiency and hypocortisolism, was described. These findings permit to better define the clinical spectrum of the disease, to direct specific genetic tests and to tailor clinical management.

Battini R, Bertelloni S, Astrea G, Casarano M, Travaglini L, Baroncelli G, Pasquariello R, Bertini E, Cioni G.

FULL ARTICLE

Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature.

Case Rep Endocrinol. 2015;2015:314594. doi: 10.1155/2015/314594. Epub 2015 May 31.

Abstract

Introduction: 4H leukodystrophy is an autosomal recessive RNA polymerase III-related leukodystrophy, characterized by hypomyelination, with or without hypodontia (or other dental abnormalities) and hypogonadotropic hypogonadism.

Case Presentation: We describe a 28-year-old female who presented with primary amenorrhea at the age of 19. She had a history of very mild neurological and dental abnormalities. She was found to have hypogonadotropic hypogonadism, and magnetic resonance imaging of the brain showed hypomyelination. The diagnosis of 4H leukodystrophy was made. She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III. She wished to become pregnant and failed to respond to pulsatile GnRH but achieved normal follicular growth and ovulation with subcutaneous gonadotropin therapy.

Discussion: Patients with 4H leukodystrophy may initially present with hypogonadotropic hypogonadism, particularly if neurological and dental manifestations are subtle. Making the diagnosis has important implications for prognosis and management. Progressive neurologic deterioration is expected, and progressive endocrine dysfunction may occur. Patients with 4H leukodystrophy should be counseled about disease progression and about this disease’s autosomal recessive inheritance pattern. In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective.

Billington E, Bernard G, Gibson W, Corenblum B.

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POLR3A and POLR3B Mutations in Unclassified Hypomyelination.

Neuropediatrics. 2015 Jun;46(3):221-8. doi: 10.1055/s-0035-1550148. Epub 2015 May 8.

Abstract

Objective: This study aims to ascertain frequency of mutations in POLR3A or POLR3B, which are associated with 4H leukodystrophy, in a cohort of patients with unclassified hypomyelination.

Methods and Results: In a cohort of 22 patients with the magnetic resonance imaging (MRI) diagnosis of unclassified hypomyelination and without typical clinical signs, we evaluated clinical and MRI features. Developmental delay or intellectual disability, ataxia, and spasticity were frequent symptoms. POLR3A and POLR3B were sequenced. A compound heterozygote mutation in POLR3B was found in only one patient. Additional investigations allowed a definitive diagnosis in 10 patients.

Conclusion: Mutations in POLR3A or POLR3B are rare in patients with unclassified hypomyelination, and alternative diagnoses should be considered first.

Cayami FK, La Piana R, van Spaendonk RM, Nickel M, Bley A, Guerrero K, Tran LT, van der Knaap MS, Bernard G, Wolf NI.

Available Online at Thieme-Connect (Link presently not available)

Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy.

Orphanet J Rare Dis. 2015 Jun 5;10:69. doi: 10.1186/s13023-015-0279-9.

Abstract

POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non-neurological features. In a small proportion of patients, no mutation in either gene or only one mutation is found. Analysis of the POLR3B cDNA revealed a large deletion of exons 21-22 in one case and of exons 26-27 in another case. These are the first reports of long deletions causing POLR3-related leukodystrophy, suggesting that deletions and duplications in POLR3A or POLR3B should be investigated in patients with a compatible phenotype, especially if one pathogenic variant has been identified.

Gutierrez M, Thiffault I, Guerrero K, Martos-Moreno GÁ, Tran LT, Benko W, van der Knaap MS, van Spaendonk RM, Wolf NI, Bernard G.

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Neurogenic bladder and neuroendocrine abnormalities in Pol III-related leukodystrophy.

BMC Neurol. 2015 Mar 4;15:22. doi: 10.1186/s12883-015-0283-7.

Abstract

Background: Pol III-related leukodystrophies, including 4H leukodystrophy, are recently recognized disorders that comprise hypomyelination and various neurologic and non-neurologic clinical manifestations. We report the unique neurologic presentation of the micturition dysfunction in Pol III-related leukodystrophy and describe the novel endocrine abnormalities in this entity.

Case Presentation: A 32-year-old Caucasian female exhibited chronic urinary incontinence that commenced at the age of 7 years and remained the unexplained symptom more than two decades before the onset of progressive neurologic decline. A transient growth failure and absent sexual development with hypoprolactinemia appeared in the meanwhile. Neurologic, endocrine, neuroradiologic, and genetic evaluation performed only in the patient’s thirties, confirmed the diagnosis of 4H leukodystrophy as the only cause of the micturition disturbance.

Conclusion: The report shows for the first time that an unexplained chronic bladder dysfunction should be evaluated also as a possible 4H leukodystrophy, thus alerting to the unexpected neurologic and endocrine features in 4H leukodystrophy.

Potic A, Popovic V, Ostojic J, Pekic S, Kozic D, Guerrero K, Schiffmann R, Bernard G.

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Teaching neuroimages: hypomyelinating leukodystrophy with hypodontia due to POLR3B: look into a leukodystrophy’s mouth.

Neurology. 2013 Nov 5;81(19):e145. doi: 10.1212/01.wnl.0000435300.64776.7e.

Abstract

An 18-year-old German woman presented with progressive cerebellar ataxia since early childhood, delayed cognitive development, and hypogonadotropic hypogonadism. MRI demonstrated diffuse cerebral hypomyelination, cerebellar atrophy, and thin corpus callosum; X-ray revealed persistent milk teeth and hypoplastic crowns and roots (figure), indicative of 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism). POLR3B sequencing(1) revealed 2 compound heterozygous mutations (C527R [C.1579T>C] and the common ancestral V523E [C.1568T>A](2)).

Synofzik M, Bernard G, Lindig T, Gburek-Augustat J.

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Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination.

Brain Dev. 2014 Apr;36(4):315-21. doi: 10.1016/j.braindev.2013.04.011. Epub 2013 May 18.

Abstract

Objective: Congenital white matter disorders are a heterogeneous group of hypomyelination disorders affecting the white matter of the brain. Recently, mutations in the genes encoding the subunits of RNA polymerase III (Pol III), POLR3A and POLR3B, have been identified as new genetic causes for hypomyelinating disorders.

Method: Whole-exome sequencing was applied to identify responsible gene mutations in a 29-year-old female patient showing hypomyelination of unknown cause. To investigate the pathological mechanism underlying the hypomyelination in this patient, the expression level of 7SL RNA, a transcriptional target of Pol III, was analyzed in cultured skin fibroblasts derived from the patient with POLR3A mutations.

Results: Novel compound heterozygous mutations of POLR3A were identified in the patient, who started to show cerebellar signs at 3 years, lost ambulation at 7 years, and became bedridden at 18 years. Brain magnetic resonance imaging showed severe volume loss in the brainstem, the cerebellum, and the white matter associated with hypomyelination. In addition to hypodontia and hypogonadism, she showed many pituitary hormone-related deficiencies. The expression level of 7SL RNA in cultured skin fibroblasts derived from this patient showed no significant abnormality.

Conclusion: The many pituitary hormone-related deficiencies identified in this patient may be an essential finding for the Pol III-related leukodystrophies spectrum. Further investigation is needed for a better understanding of the disease mechanism.

Shimojima K, Shimada S, Tamasaki A, Akaboshi S, Komoike Y, Saito A, Furukawa T, Yamamoto T.

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An Indian boy with a novel leukodystrophy: 4H syndrome.

J Child Neurol. 2014 Jan;29(1):135-8. doi: 10.1177/0883073812470737. Epub 2013 Jan 9.

Abstract

4H syndrome is a rare and distinct leukodystrophy characterized by hypomyelination, hypogonadotropic hypogonadism, and hypodontia. Detecting signs of pubertal growth failure and abnormal dentition offer the clues to the diagnosis. We present an Indian boy with this novel syndrome with previously unreported feature of bilateral undescended testes. We also provide a brief overview of all published cases.

Jauhari P, Sahu JK, Singhi P, Dayal D, Khandelwal N.

FULL ARTICLE

More than hypomyelination in Pol-III disorder.

J Neuropathol Exp Neurol. 2013 Jan;72(1):67-75. doi: 10.1097/NEN.0b013e31827c99d2.

Abstract

The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is a newly recognized leukodystrophy. The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of 2 genes responsible for the syndrome demonstrates that these 3 main characteristics can be variably combined among “Pol-III (polymerase III)-related leukodystrophies.” The pathophysiology of this group of diseases is still to be elucidated, and there are no neuropathologic descriptions of brain tissue. We report the clinical, neuroradiologic, and neuropathologic findings of a patient affected by 4H syndrome with confirmed POLR3A mutations. We found a marked loss of oligodendrocytes, varying in severity in different brain regions, and accompanied by severe loss of myelin, moderately severe loss of axons, and patchy perivascular regions of better preserved white matter. There was relatively mild white matter astrogliosis and microgliosis. A macrophage reaction involving viable normal-appearing oligodendroglia suggests the possibility of an immunologic process in this disorder. Cortical laminar astrogliosis and mineralization of Layers I and II in particular were present. Thus, despite the uniformly hypomyelinating pattern seen on magnetic resonance imaging, neuropathologic examination reveals a complex heterogeneous leukodystrophy with prominent neuroaxonal and glial involvement in this disorder.

Vanderver A, Tonduti D, Bernard G, Lai J, Rossi C, Carosso G, Quezado M, Wong K, Schiffmann R.

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4H syndrome with late-onset growth hormone deficiency caused by POLR3A mutations.

Arch Neurol. 2012 Jul;69(7):920-3.

Abstract

Objective: To report a novel clinical and genetic presentation of a patient with 4H syndrome, which is a recently described leukodystrophy syndrome characterized by ataxia, hypomyelination, hypodontia, and hypogonadotropic hypogonadism.

Design: Case report.

Setting: University teaching hospital.

Patient: A 20-year-old male patient with 4H syndrome.

Results: The patient was found to have delayed tooth eruption and a late-onset growth hormone deficiency without overt growth failure. He was a compound heterozygote for the novel missense mutations R1005H and A1331T of POLR3A, which codes for the largest subunit of RNA polymerase III.

Conclusion: This is the first report of this type of leukodystrophy from southeastern Europe, which suggests that POLR3A mutations should be suspected in patients with hypomyelination and various central nervous system–based endocrine abnormalities.

Potic A, Brais B, Choquet K, Schiffmann R, Bernard G.

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Central hypomyelination, hypogonadotrophic hypogonadism and hypodontia: a new leukodystrophy.

Rev Neurol. 2008 Aug 16-31;47(4):204-8.

Abstract

Aim: To report one patient with slowly progressive encephalopathy, ataxia, central hypomyelination, hypodontia and hypogonadotropic hypogonadism, the 4H syndrome. This clinical picture has been described recently and there are only four patients reported previously.

Case Report: A girl with a previously normal early psychomotor development, presented a slowly progressive deterioration since 15 months of age. Now, she is 14 years old, and has a severe cerebellar ataxia, with tremor and dysmetria. She can’t neither walk nor remain standing alone. She has lost the sphincter control and has an immature expressive language. She has no puberal development and definitive hypodontia of upper central incisors. The brain magnetic resonance imaging shows a diffuse hypomyelination, that is confirmed with diffusion and spectroscopy studies.

Conclusion: The hypomyelinating leukoencephalopathies are disorders with abnormally low amount of myelin. The diagnosis is difficult in most of the patients. The hypomyelinating leukoencephalopathies include classic disorders and new leukoencephalopathies, described in the past few years.

Vázquez-López M, Ruiz-Martín Y, de Castro-Castro P, Garzo-Fernández C, Martín-del Valle F, Márquez-de la Plata L.