Fallatah Wedad, Schouten Monica, Yergeau Christine, Di Pietro Erminia, Engelen Marc, Waterham Hans R, Poll-The Bwee Tien, Braverman Nancy
Department of Human Genetics, McGill University, Research Institute of the McGill University Health Centre, Montreal, Québec, Canada.
Department of Medical Genetics, King Abdul-Aziz University, Jeddah, Saudi Arabia.
J Inherit Metab Dis. 2021 Jul;44(4):1021-1038. doi: 10.1002/jimd.12349. Epub 2021 Jan 26.
Rhizomelic chondrodysplasia punctata (RCDP) is a heterogenous group of disorders due to defects in genes encoding peroxisomal proteins required for plasmalogen (PL) biosynthesis, specifically PEX7 and PEX5 receptors, or GNPAT, AGPS and FAR1 enzymes. Most patients have congenital cataract and skeletal dysplasia. In the classic form, there is profound growth restriction and psychomotor delays, with most patients not advancing past infantile developmental milestones. Disease severity correlates to erythrocyte PL levels, which are almost undetectable in severe (classic) RCDP. In milder (nonclassic) forms, residual PL levels are associated with improved growth and development. However, the clinical course of this milder group remains largely unknown as only a few cases were reported. Using as inclusion criteria the ability to communicate and walk, we identified 16 individuals from five countries, ages 5-37 years, and describe their clinical, biochemical and molecular profiles. The average age at diagnosis was 2.6 years and most had cataract, growth deficiency, joint contractures, and developmental delays. Other major symptoms were learning disability (87%), behavioral issues (56%), seizures (43%), and cardiac defects (31%). All patients had decreased C16:0 PL levels that were higher than in classic RCDP, and up to 43% of average controls. Plasma phytanic acid levels were elevated in most patients. There were several common, and four novel, PEX7, and GNPAT hypomorphic alleles in this cohort. These results can be used to support earlier diagnosis and improve management in patients with mild RCDP.
肢根型点状软骨发育不良（RCDP）是一组异质性疾病，由编码缩醛磷脂（PL）生物合成所需过氧化物酶体蛋白的基因突变引起，特别是PEX7和PEX5受体，或GNPAT、AGPS和FAR1酶。大多数患者患有先天性白内障和骨骼发育异常。在典型形式中，存在严重的生长受限和精神运动发育迟缓，大多数患者未超过婴儿发育里程碑。疾病严重程度与红细胞PL水平相关，在严重（典型）RCDP中几乎检测不到。在较轻（非典型）形式中，残余PL水平与生长发育改善相关。然而，由于仅报道了少数病例，这一较轻组的临床病程在很大程度上仍不清楚。以沟通和行走能力作为纳入标准，我们从五个国家确定了16名年龄在5至37岁之间的个体，并描述了他们的临床、生化和分子特征。诊断时的平均年龄为2.6岁，大多数人患有白内障、生长缺陷、关节挛缩和发育迟缓。其他主要症状为学习障碍（87%）、行为问题（56%）、癫痫发作（43%）和心脏缺陷（31%）。所有患者的C16:0 PL水平均降低，高于典型RCDP患者，最高可达平均对照组的43%。大多数患者的血浆植烷酸水平升高。该队列中有几个常见的以及四个新的PEX7和GNPAT低表达等位基因。这些结果可用于支持轻度RCDP患者的早期诊断并改善管理。
