RT Journal Article
SR Electronic
T1 Clinical spectrum of POLR3-related leukodystrophy caused by biallelic <em>POLR1C</em> pathogenic variants
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams &amp; Wilkins
SP e369
DO 10.1212/NXG.0000000000000369
VO 5
IS 6
A1 Gauquelin, Laurence
A1 Cayami, Ferdy K.
A1 Sztriha, László
A1 Yoon, Grace
A1 Tran, Luan T.
A1 Guerrero, Kether
A1 Hocke, François
A1 van Spaendonk, Rosalina M.L.
A1 Fung, Eva L.
A1 D'Arrigo, Stefano
A1 Vasco, Gessica
A1 Thiffault, Isabelle
A1 Niyazov, Dmitriy M.
A1 Person, Richard
A1 Lewis, Kara Stuart
A1 Wassmer, Evangeline
A1 Prescott, Trine
A1 Fallon, Penny
A1 McEntagart, Meriel
A1 Rankin, Julia
A1 Webster, Richard
A1 Philippi, Heike
A1 van de Warrenburg, Bart
A1 Timmann, Dagmar
A1 Dixit, Abhijit
A1 Searle, Claire
A1 ,
A1 Thakur, Nivedita
A1 Kruer, Michael C.
A1 Sharma, Suvasini
A1 Vanderver, Adeline
A1 Tonduti, Davide
A1 van der Knaap, Marjo S.
A1 Bertini, Enrico
A1 Goizet, Cyril
A1 Fribourg, Sébastien
A1 Wolf, Nicole I.
A1 Bernard, Geneviève
YR 2019
UL http://ng.neurology.org/content/5/6/e369.abstract
AB Objective To determine the clinical, radiologic, and molecular characteristics of RNA polymerase III-related leukodystrophy (POLR3-HLD) caused by biallelic POLR1C pathogenic variants.Methods A cross-sectional observational study involving 25 centers worldwide was conducted. Clinical and molecular information was collected on 23 unreported and previously reported patients with POLR3-HLD and biallelic pathogenic variants in POLR1C. Brain MRI studies were reviewed.Results Fourteen female and 9 male patients aged 7 days to 23 years were included in the study. Most participants presented early in life (birth to 6 years), and motor deterioration was seen during childhood. A notable proportion of patients required a wheelchair before adolescence, suggesting a more severe phenotype than previously described in POLR3-HLD. Dental, ocular, and endocrine features were not invariably present (70%, 50%, and 50%, respectively). Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including 1 individual with clear Treacher Collins syndrome (TCS) features. Brain MRI revealed hypomyelination in all cases, often with areas of pronounced T2 hyperintensity corresponding to T1 hypointensity of the white matter. Twenty-nine different pathogenic variants (including 12 new disease-causing variants) in POLR1C were identified.Conclusions This study provides a comprehensive description of POLR3-HLD caused by biallelic POLR1C pathogenic variants based on the largest cohort of patients to date. These results suggest distinct characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.POLR3-HLD=RNA polymerase III-related leukodystrophy; TCS=Treacher Collins syndrome