拓展RNA聚合酶III相关脑白质营养不良的表型和分子谱。
Expanding the phenotypic and molecular spectrum of RNA polymerase III-related leukodystrophy.
作者信息
Perrier Stefanie, Gauquelin Laurence, Fallet-Bianco Catherine, Dishop Megan K, Michell-Robinson Mackenzie A, Tran Luan T, Guerrero Kether, Darbelli Lama, Srour Myriam, Petrecca Kevin, Renaud Deborah L, Saito Michael, Cohen Seth, Leiz Steffen, Alhaddad Bader, Haack Tobias B, Tejera-Martin Ingrid, Monton Fernando I, Rodriguez-Espinosa Norberto, Pohl Daniela, Nageswaran Savithri, Grefe Annette, Glamuzina Emma, Bernard Geneviève
机构信息
Department of Neurology and Neurosurgery (S.P., L.G., M.A.M.-R., L.T.T., K.G., L.D., M. Srour, K.P., G.B.), McGill University; Child Health and Human Development Program (S.P., M.A.M.-R., L.T.T., K.G., L.D., M. Srour, G.B.), Research Institute of the McGill University Health Centre; Department of Pediatrics (L.G., L.T.T., K.G., L.D., M. Srour, G.B.), McGill University, Montreal, Quebec, Canada; Division of Clinical and Metabolic Genetics (L.G.), Division of Neurology, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Pathology (C.F.-B.), CHU Sainte-Justine, Université de Montreal, Quebec, Canada; Division of Pathology and Laboratory Medicine (M.K.D.), Phoenix Children's Hospital, AZ; Department of Human Genetics (L.T.T., K.G., L.D., G.B.), McGill University, Montreal, Quebec, Canada; McGill University (K.P.), Brain Tumour Research Center Montreal Neurological Institute and Hospital, Quebec, Canada; Department of Neurology (D.L.R.), Department of Clinical Genomics, Department of Pediatrics, Mayo Clinic, Rochester, MN; Department of Pediatrics (M. Saito), University of California Riverside School of Medicine, Riverside Medical Clinic, CA; Department of Pediatrics (S.C.), Beaver Medical Group, Redlands, CA; Division of Pediatric Neurology (S.L.), Department of Pediatrics, Klinikum Dritter Orden, Munich, Germany; Institute of Human Genetics (B.A., T.B.H.), Technische Universität München, Munich, Germany; Institute of Medical Genetics and Applied Genomics (T.B.H.), University of Tübingen, Germany; Department of Neurology (I.T.-M., F.I.M., N.R.-E.), Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Canary Islands, Spain; Department of Neurology (D.P.), Children's Hospital of Eastern Ontario, University of Ottawa, Ontario, Canada; Department of Pediatrics (S.N.) and Department of Neurology (A.G.), Wake Forest School of Medicine, Winston-Salem, NC; Adult and Paediatric National Metabolic Service (E.G.), Starship Children's Hospital, Auckland, New Zealand; and Division of Medical Genetics (G.B.), Department of Specialized Medicine, Montreal Children's Hospital and McGill University Health Centre, Quebec, Canada.
出版信息
Neurol Genet. 2020 May 11;6(3):e425. doi: 10.1212/NXG.0000000000000425. eCollection 2020 Jun.
OBJECTIVE
To expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes.
METHODS
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.
RESULTS
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 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.
CONCLUSIONS
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.
目的
通过对具有极其严重表型的患者进行研究，扩大POLR3相关脑白质营养不良严重程度的表型谱，并确定基因型与表型的相关性。
方法
我们对基因确诊的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，他们具有与通常报道的相比极其严重的表型。对所有患者进行了临床、放射学和分子特征评估，并对1名患者进行了功能和神经病理学研究。
结果
每位患者在1至3个月大时出现生长发育迟缓、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均显示出一种具有非典型特征的新模式，包括进行性基底神经节和丘脑异常。神经病理学研究显示，大脑半球、小脑、脑干和脊髓存在散在的髓鞘减少区域，白质中有星形胶质细胞增生和小胶质细胞活化。在丘脑和基底神经节中观察到细胞空泡化，在壳核和尾状核中神经元丢失明显。所有6名患者之间也存在基因型相似性，一个等位基因包含一个导致过早终止密码子的变体，另一个等位基因包含一个特定的内含子剪接变体（c.1771-7C>G），它产生2种异常转录本以及一些野生型转录本。
结论
我们描述了POLR3相关脑白质营养不良谱严重程度极端情况下的基因型与表型的相关性，并揭示了复杂疾病的病理生理学。
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