PT  - JOURNAL ARTICLE
AU  - Gauquelin, Laurence
AU  - Cayami, Ferdy K.
AU  - Sztriha, László
AU  - Yoon, Grace
AU  - Tran, Luan T.
AU  - Guerrero, Kether
AU  - Hocke, François
AU  - van Spaendonk, Rosalina M.L.
AU  - Fung, Eva L.
AU  - D'Arrigo, Stefano
AU  - Vasco, Gessica
AU  - Thiffault, Isabelle
AU  - Niyazov, Dmitriy M.
AU  - Person, Richard
AU  - Lewis, Kara Stuart
AU  - Wassmer, Evangeline
AU  - Prescott, Trine
AU  - Fallon, Penny
AU  - McEntagart, Meriel
AU  - Rankin, Julia
AU  - Webster, Richard
AU  - Philippi, Heike
AU  - van de Warrenburg, Bart
AU  - Timmann, Dagmar
AU  - Dixit, Abhijit
AU  - Searle, Claire
AU  - ,
AU  - Thakur, Nivedita
AU  - Kruer, Michael C.
AU  - Sharma, Suvasini
AU  - Vanderver, Adeline
AU  - Tonduti, Davide
AU  - van der Knaap, Marjo S.
AU  - Bertini, Enrico
AU  - Goizet, Cyril
AU  - Fribourg, Sébastien
AU  - Wolf, Nicole I.
AU  - Bernard, Geneviève
TI  - Clinical spectrum of POLR3-related leukodystrophy caused by biallelic <em>POLR1C</em> pathogenic variants
AID  - 10.1212/NXG.0000000000000369
DP  - 2019 Dec 01
TA  - Neurology Genetics
PG  - e369
VI  - 5
IP  - 6
4099  - http://ng.neurology.org/content/5/6/e369.short
4100  - http://ng.neurology.org/content/5/6/e369.full
SO  - Neurol Genet2019 Dec 01; 5
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