Dataset Information

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

ABSTRACT:

Context

4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective

To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design

An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting

This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients

A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main outcome measures

Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results

The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions

Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

SUBMITTER: Pelletier F

PROVIDER: S-EPMC7823228 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Pelletier Félixe F Perrier Stefanie S Cayami Ferdy K FK Mirchi Amytice A Saikali Stephan S Tran Luan T LT Ulrick Nicole N Guerrero Kether K Rampakakis Emmanouil E van Spaendonk Rosalina M L RML Naidu Sakkubai S Pohl Daniela D Gibson William T WT Demos Michelle M Goizet Cyril C Tejera-Martin Ingrid I Potic Ana A Fogel Brent L BL Brais Bernard B Sylvain Michel M Sébire Guillaume G Lourenço Charles Marques CM Bonkowsky Joshua L JL Catsman-Berrevoets Coriene C Pinto Pedro S PS Tirupathi Sandya S Strømme Petter P de Grauw Ton T Gieruszczak-Bialek Dorota D Krägeloh-Mann Ingeborg I Mierzewska Hanna H Philippi Heike H Rankin Julia J Atik Tahir T Banwell Brenda B Benko William S WS Blaschek Astrid A Bley Annette A Boltshauser Eugen E Bratkovic Drago D Brozova Klara K Cimas Icíar I Clough Christopher C Corenblum Bernard B Dinopoulos Argirios A Dolan Gail G Faletra Flavio F Fernandez Raymond R Fletcher Janice J Garcia Garcia Maria Eugenia ME Gasparini Paolo P Gburek-Augustat Janina J Gonzalez Moron Dolores D Hamati Aline A Harting Inga I Hertzberg Christoph C Hill Alan A Hobson Grace M GM Innes A Micheil AM Kauffman Marcelo M Kirwin Susan M SM Kluger Gerhard G Kolditz Petra P Kotzaeridou Urania U La Piana Roberta R Liston Eriskay E McClintock William W McEntagart Meriel M McKenzie Fiona F Melançon Serge S Misbahuddin Anjum A Suri Mohnish M Monton Fernando I FI Moutton Sebastien S Murphy Raymond P J RPJ Nickel Miriam M Onay Hüseyin H Orcesi Simona S Özkınay Ferda F Patzer Steffi S Pedro Helio H Pekic Sandra S Pineda Marfa Mercedes M Pizzino Amy A Plecko Barbara B Poll-The Bwee Tien BT Popovic Vera V Rating Dietz D Rioux Marie-France MF Rodriguez Espinosa Norberto N Ronan Anne A Ostergaard John R JR Rossignol Elsa E Sanchez-Carpintero Rocio R Schossig Anna A Senbil Nesrin N Sønderberg Roos Laura K LK Stevens Cathy A CA Synofzik Matthis M Sztriha László L Tibussek Daniel D Timmann Dagmar D Tonduti Davide D van de Warrenburg Bart P BP Vázquez-López Maria M Venkateswaran Sunita S Wasling Pontus P Wassmer Evangeline E Webster Richard I RI Wiegand Gert G Yoon Grace G Rotteveel Joost J Schiffmann Raphael R van der Knaap Marjo S MS Vanderver Adeline A Martos-Moreno Gabriel Á GÁ Polychronakos Constantin C Wolf Nicole I NI Bernard Geneviève G

The Journal of clinical endocrinology and metabolism 20210101 2

<h4>Context</h4>4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.<h4>Objective</h4>To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.<h4>Design</h4>An int ...[more]

PMID: 33005949

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Project description:RNA polymerase III (Pol III)-related hypomyelinating leukodystrophy (POLR3-HLD), also known as 4H leukodystrophy, is a severe neurodegenerative disease characterized by the cardinal features of hypomyelination, hypodontia and hypogonadotropic hypogonadism. POLR3-HLD is caused by biallelic pathogenic variants in genes encoding Pol III subunits. While approximately half of all patients carry mutations in POLR3B encoding the RNA polymerase III subunit B, there is no in vivo model of leukodystrophy based on mutation of this Pol III subunit. Here, we determined the impact of POLR3BΔ10 (Δ10) on Pol III in human cells and developed and characterized an inducible/conditional mouse model of leukodystrophy using the orthologous Δ10 mutation in mice. The molecular mechanism of Pol III dysfunction was determined in human cells by affinity purification-mass spectrometry and western blot. Postnatal induction with tamoxifen induced expression of the orthologous Δ10 hypomorph in triple transgenic Pdgfrα-Cre/ERT; R26-Stopfl-EYFP; Polr3bfl mice. CNS and non-CNS features were characterized using a variety of techniques including microCT, ex vivo MRI, immunofluorescence, immunohistochemistry, spectral confocal reflectance microscopy and western blot. Lineage tracing and time series analysis of oligodendrocyte subpopulation dynamics based on co-labelling with lineage-specific and/or proliferation markers were performed. Proteomics suggested that Δ10 causes a Pol III assembly defect, while western blots demonstrated reduced POLR3BΔ10 expression in the cytoplasm and nucleus in human cells. In mice, postnatal Pdgfrα-dependent expression of the orthologous murine mutant protein resulted in recessive phenotypes including severe hypomyelination leading to ataxia, tremor, seizures and limited survival, as well as hypodontia and craniofacial abnormalities. Hypomyelination was confirmed and characterized using classic methods to quantify myelin components such as myelin basic protein and lipids, results which agreed with those produced using modern methods to quantify myelin based on the physical properties of myelin membranes. Lineage tracing uncovered the underlying mechanism for the hypomyelinating phenotype: defective oligodendrocyte precursor proliferation and differentiation resulted in a failure to produce an adequate number of mature oligodendrocytes during postnatal myelinogenesis. In summary, we characterized the Polr3bΔ10 mutation and developed an animal model that recapitulates features of POLR3-HLD caused by POLR3B mutations, shedding light on disease pathogenesis, and opening the door to the development of therapeutic interventions.

Dataset Information

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Context

Objective

Design

Setting

Patients

Main outcome measures

Results

Conclusions

Publications

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

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