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

Published online by Cambridge University Press:  05 June 2019

L Gauquelin
Affiliation:
(Toronto)
FK Cayami
Affiliation:
(Semarang)
L Sztriha
Affiliation:
(Szeged)
G Yoon
Affiliation:
(Toronto)
LT Tran
Affiliation:
(Montreal)
K Guerrero
Affiliation:
(Montreal)
F Hocke
Affiliation:
(Bordeaux)
RM van Spaendonk
Affiliation:
(Amsterdam)
EL Fung
Affiliation:
(Hong Kong)
S D’Arrigo
Affiliation:
(Milan)
G Vasco
Affiliation:
(Rome)
I Thiffault
Affiliation:
(Kansas City)
DM Niyazov
Affiliation:
(New Orleans)
R Person
Affiliation:
(Gaithersburg)
KS Lewis
Affiliation:
(Phoenix)
E Wassmer
Affiliation:
(Birmingham)
T Prescott
Affiliation:
(Skien)
P Fallon
Affiliation:
(London)
M McEntagart
Affiliation:
(London)
J Rankin
Affiliation:
(Exeter)
R Webster
Affiliation:
(Westmead)
H Philippi
Affiliation:
(Frankfurt)
B van de Warrenburg
Affiliation:
(Nijmegen)
D Timmann
Affiliation:
(Essen)
A Dixit
Affiliation:
(Nottingham)
C Searle
Affiliation:
(Nottingham)
N Thakur
Affiliation:
(Houston)
MC Kruer
Affiliation:
(Tempe)
S Sharma
Affiliation:
(New Delhi)
A Vanderver
Affiliation:
(Philadelphia)
D Tonduti
Affiliation:
(Milan)
MS van der Knaap
Affiliation:
(Amsterdam)
E Bertini
Affiliation:
(Rome)
C Goizet
Affiliation:
(Bordeaux)
S Fribourg
Affiliation:
(Bordeaux)
NI Wolf
Affiliation:
(Amsterdam)
G Bernard
Affiliation:
(Montreal)
DDD Study
Affiliation:
(Toronto) (Semarang) (Szeged) (Montreal) (Bordeaux) (Amsterdam) (Hong Kong) (Milan) (Rome) (Kansas City) (New Orleans) (Gaithersburg) (Phoenix) (Birmingham) (Skien) (London) (Exeter) (Westmead) (Frankfurt) (Nijmegen) (Essen) (Nottingham) (Houston) (Tempe) (New Delhi) (Philadelphia)
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Abstract

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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.

Type
Poster Presentations
Copyright
© The Canadian Journal of Neurological Sciences Inc. 2019