P.075 Clinical spectrum of POLR3-related leukodystrophy caused by biallelic POLR1C pathogenic variants. (June 2019)

• Record Type: Journal Article
• Authors: Gauquelin, L; Cayami, FK; Sztriha, L; Yoon, G; Tran, LT; Guerrero, K; Hocke, F; van Spaendonk, RM; Fung, EL; D'Arrigo, S; Vasco, G; Thiffault, I; Niyazov, DM; Person, R; Lewis, KS; Wassmer, E; Prescott, T; Fallon, P; McEntagart, M; Rankin, J; Webster, R; Philippi, H; van de Warrenburg, B; Timmann, D; Dixit, A; Searle, C; Thakur, N; Kruer, MC; Sharma, S; Vanderver, A; Tonduti, D; van der Knaap, MS; Bertini, E; Goizet, C; Fribourg, S; Wolf, NI; Bernard, G;
• Is Part Of: Canadian journal of neurological sciences. Volume 46(2019)Supplement 1
• Page Start: S34
• Page End: S34
• Publication Date: 2019-06
• Subjects: Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Electronic journals; 616.8
• DOI: 10.1017/cjn.2019.175
• Languages: English
• ISSNs: 0317-1671

Abstract

Abstract : Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.