To expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.

We performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely severe phenotype compared with that typically reported. Clinical, radiologic, and molecular features were evaluated for all patients, and functional and neuropathologic studies were performed on 1 patient.

Each patient presented between 1 and 3 months of age with failure to thrive, severe dysphagia, and developmental delay. Four of the 6 children died before age 3 years. MRI of all patients revealed a novel pattern with atypical characteristics, including progressive basal ganglia and thalami abnormalities. Neuropathologic studies revealed patchy areas of decreased myelin in the cerebral hemispheres, cerebellum, brainstem, and spinal cord, with astrocytic gliosis in the white matter and microglial activation. Cellular vacuolization was observed in the thalamus and basal ganglia, and neuronal loss was evident in the putamen and caudate. Genotypic similarities were also present between all 6 patients, with one allele containing a POLR3A variant causing a premature stop codon and the other containing a specific intronic splicing variant (c.1771-7C>G), which produces 2 aberrant transcripts along with some wild-type transcript.

We describe genotype-phenotype correlations at the extreme end of severity of the POLR3-related leukodystrophy spectrum and shed light on the complex disease pathophysiology.

通过对极严重表型患者的研究，扩大 POLR3 相关脑白质营养不良严重程度的表型谱，并确定基因型-表型相关性。

我们对经基因证实的 POLR3 相关脑白质营养不良和非典型表型的患者进行了一项国际横断面研究，以确定 6 名儿童，3 名男性和 3 名女性，与通常报道的表型相比，表型极为严重。对所有患者的临床、放射学和分子特征进行了评估，并对 1 名患者进行了功能和神经病理学研究。

每位患者在 1 至 3 个月大时出现发育迟缓、严重吞咽困难和发育迟缓。6 名儿童中有 4 名在 3 岁前死亡。所有患者的 MRI 显示具有非典型特征的新模式，包括进行性基底节和丘脑异常。神经病理学研究显示大脑半球、小脑、脑干和脊髓中髓磷脂减少的斑片区域，白质中的星形胶质细胞增生和小胶质细胞激活。在丘脑和基底神经节中观察到细胞空泡化，在壳核和尾状核中观察到明显的神经元丢失。所有 6 名患者之间也存在基因型相似性，其中一个等位基因包含POLR3A导致过早终止密码子的变体和另一个包含特定内含子剪接变体（c.1771-7C>G）的变体，其产生2个异常转录物以及一些野生型转录物。

我们描述了 POLR3 相关脑白质营养不良谱的极端严重程度的基因型-表型相关性，并阐明了复杂的疾病病理生理学。