Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Alberta Newborn Screening and Biochemical Genetics Laboratory, University of Alberta Hospital, Alberta Precision Laboratories, Edmonton, Alberta, Canada.
Am J Med Genet A. 2024 Aug;194(8):e63595. doi: 10.1002/ajmg.a.63595. Epub 2024 Mar 29.
Niemann-Pick disease type C (NPC) is one of the lysosomal storage disorders. It is caused by biallelic pathogenic variants in NPC1 or NPC2, which results in a defective cholesterol trafficking inside the late endosome and lysosome. There is a high clinical variability in the age of presentation and the phenotype of this disorder making the diagnosis challenging. Here, we report a patient with an infantile onset global developmental delay, microcephaly and dysmorphic features, homozygous for c.3560C>T (p.A1187V) variant in NPC1. His plasma oxysterol levels were normal on two occasions. His lyso-sphingomyelin-509 (lyso-SM 509) and urinary bile acid levels were normal. Based on the phenotype and biochemical features, the diagnosis of NPC was excluded in this patient. We emphasize the importance of functional characterization in the classification of novel variants to prevent a misdiagnosis. Matching the phenotype and biochemical evidence with the molecular genomic tests is crucial for the confirmation of genetic diagnoses.
尼曼-匹克病 C 型（NPC）是溶酶体贮积症之一。它是由 NPC1 或 NPC2 的双等位致病性变异引起的，导致晚期内体和溶酶体内部胆固醇转运缺陷。这种疾病的临床表现和表型在发病年龄上存在很大的变异性，使得诊断具有挑战性。在这里，我们报告了一名婴儿期起病的伴有全面发育迟缓、小头畸形和发育异常特征的患者，他 NPC1 中的 c.3560C>T（p.A1187V）纯合变体。他的血浆氧化固醇水平在两次检查中均正常。他的溶磷脂酰丝氨酸-509（lyso-SM 509）和尿胆汁酸水平正常。基于表型和生化特征，排除了该患者 NPC 的诊断。我们强调了在新型变异分类中进行功能特征分析的重要性，以防止误诊。将表型和生化证据与分子基因组测试相匹配对于遗传诊断的确认至关重要。
