AUTHOR=Liu Jing , Niu Yue , Qin Jiong , Yang Zhixian 

TITLE=POLR3-related leukodystrophy caused by biallelic POLR3A and 1C pathogenic variants: a single-center experience

JOURNAL=Frontiers in Neurology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1355484

DOI=10.3389/fneur.2024.1355484

ISSN=1664-2295

ABSTRACT=<sec><title>Objectives</title><p>This study aimed to investigate the clinical, radiological, and genetic features of POLR3-related leukodystrophy caused by mutations in <italic>POLR3A</italic> or <italic>POLR1C</italic>.</p></sec><sec><title>Methods</title><p>Fourteen Chinese patients with POLR3-related leukodystrophy were enrolled in this cross-sectional observational study. The clinical manifestations, brain MRI and genetic tests of the patients were evaluated.</p></sec><sec><title>Results</title><p>Thirteen patients had biallelic variants in <italic>POLR3A</italic> (92.9%), and one had biallelic variants in <italic>POLR1C</italic> (7.1%). The median age at disease onset was 9 months. A total of 85.7% of the patients presented with motor delay, abnormal gait, and intelligence disability in the first 2 years of life. Intellectual disability can be categorized based on its severity. It varied from mild (which involves difficulty concentrating) to very severe (with no smiling or laughing or never being able to speak since birth). Short stature was observed in all patients, and delayed dentition was observed in 64.3% of them. Furthermore, three out of 14 patients had myopia. Hypomyelination was invariably present in all patients, whereas myelination of the basal ganglia was preserved in only six out of 14 patients. All the mutations were compound heterozygous and included missense (<italic>n</italic> = 25), deletion (<italic>n</italic> = 1), and splice site variants (<italic>n</italic> = 2). A total of 78.6% of the patients with <italic>POLR3A</italic> were identified as carrying the c.1771-6C&gt;G variant or the c.1771-7C&gt;G variant.</p></sec><sec><title>Conclusion</title><p>The phenotypic diversity of POLR3-HLD associated with pathogenic variants ranges from mild to very severe for neurological and non-neurological symptoms. Most patients presented symptoms in the first 2 years of life. The c.1771-6C&gt;G or c.1771-7C&gt;G variant is the most frequent mutation site in <italic>POLR3A</italic> in Chinese individuals.</p></sec>