Takuya Hiraide: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan; Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Kazuo Kubota: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan; Division of Clinical Genetics, Gifu University Hospital, Japan.
Yu Kono: Department of Neurology, Fuji City General Hospital, Shizuoka, Japan.
Seiji Watanabe: Department of Pediatric Neurology, Shizuoka Children's Hospital, Shizuoka, Japan.
Tomoko Matsubayashi: Department of Pediatric Neurology, Shizuoka Children's Hospital, Shizuoka, Japan.
Mitsuko Nakashima: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Tadashi Kaname: Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan.
Toshiyuki Fukao: Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan; Division of Clinical Genetics, Gifu University Hospital, Japan.
Nobuyuki Shimozawa: Division of Clinical Genetics, Gifu University Hospital, Japan; Division of Genomics Research, Life Science Research Center, Gifu University, Gifu, Japan.
Tsutomu Ogata: Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Hirotomo Saitsu: Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address: hsaitsu@hama-med.ac.jp.
BACKGROUND: Biallelic variants in POLR3A encoding the largest subunit of RNA polymerase III cause POLR3-related (or 4H) leukodystrophy characterized by neurologic dysfunction, abnormal dentition, endocrine abnormalities and ocular abnormality. Recently, whole-exome sequencing enabled the discovery of POLR3A variants in cases lacking diffuse hypomyelination, the principal MRI phenotype of POLR3-related leukodystrophy. Homozygous c.1771-6C > G variants in POLR3A were recently suggested to cause striatal and red nucleus involvement without white matter involvement. CASE REPORT: Here, we report three cases in two families with biallelic POLR3A variants. We identified two sets of compound heterozygous variants in POLR3A, c.1771-6C > G and c.791C > T, p.(Pro264Leu) for family 1 and c.1771-6C > G and c.2671C > T, p.(Arg891*) for family 2. Both families had the c.1771-6C > G variant, which led to aberrant mRNA splicing. Neuropsychiatric regression and severe intellectual disability were identified in three patients. Two cases showed dystonia and oligodontia. Notably, characteristic bilateral symmetric atrophy and abnormal signal of the striatum without diffuse white matter signal change were observed in brain MRI of all three individuals. CONCLUSIONS: Striatum abnormalities may be another distinctive MRI finding associated with POLR3A variants, especially in cases including c.1771-6C > G variants and our cases can expand the phenotypic spectrum of POLR3A-related disorders.
