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

  • L Gauquelin (a1), FK Cayami (a2), L Sztriha (a3), G Yoon (a1), LT Tran (a4), K Guerrero (a4), F Hocke (a5), RM van Spaendonk (a6), EL Fung (a7), S D’Arrigo (a8), G Vasco (a9), I Thiffault (a10), DM Niyazov (a11), R Person (a12), KS Lewis (a13), E Wassmer (a14), T Prescott (a15), P Fallon (a16), M McEntagart (a16), J Rankin (a17), R Webster (a18), H Philippi (a19), B van de Warrenburg (a20), D Timmann (a21), A Dixit (a22), C Searle (a22), N Thakur (a23), MC Kruer (a24), S Sharma (a25), A Vanderver (a26), D Tonduti (a8), MS van der Knaap (a6), E Bertini (a9), C Goizet (a5), S Fribourg (a5), NI Wolf (a6), G Bernard (a4) and DDD Study (a1) (a2) (a3) (a4) (a5) (a6) (a7) (a8) (a9) (a10) (a11) (a12) (a13) (a14) (a15) (a16) (a17) (a18) (a19) (a20) (a21) (a22) (a23) (a24) (a25) (a26)...

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.

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Canadian Journal of Neurological Sciences
  • ISSN: 0317-1671
  • EISSN: 2057-0155
  • URL: /core/journals/canadian-journal-of-neurological-sciences
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