Messina Martina, Manea Emanuela, Cullup Thomas, Tuschl Karin, Batzios Spyros
Metabolic Medicine Department Great Ormond Street Hospital for Children London UK.
North Thames Genomic Laboratory Hub Great Ormond Street Hospital for Children London UK.
JIMD Rep. 2022 Nov 22;64(1):42-52. doi: 10.1002/jmd2.12347. eCollection 2023 Jan.
Glycosylphosphatidylinositol anchored proteins (GPI-APs) represent a class of molecules attached to the external leaflet of the plasma membrane by the GPI anchor where they play important roles in numerous cellular processes including neurogenesis, cell adhesion, immune response and signalling. Within the group of GPI anchor defects, six present with the clinical phenotype of Hyperphosphatasia with Mental Retardation Syndrome (HPMRS, Mabry Syndrome) characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures and persistent hyperphosphatasia. We report the case of a 5-year-old female with global developmental delay associated with precocious puberty and persistently raised plasma alkaline phosphatase. Targeted next generation sequencing analysis of the HPMRS genes identified novel compound heterozygous variants in the gene (c.103del p.(Leu35Serfs*90)and c.134A > Gp.(His45Arg)) consistent with the diagnosis of HPMRS type 3. Cerebrospinal fluid (CSF) neurotransmitter analysis showed low levels of pyridoxal phosphate and 5-methyltetrahydrofolate and raised homovanillic acid. Supplementation with pyridoxine and folinic acid led to normalization of biochemical abnormalities. The patient continues to make developmental progress with significant improvement in speech and fine motor skills. Our reported case expands the clinical spectrum of HPMRS3 in which multisystem involvement is being increasingly recognized. Furthermore, it shows that miss-targeting GPI-APs and the effect on normal cellular function could provide a physiopathologic explanation for the CSF biochemical abnormalities with management implications for a group of disorders that currently has no treatment that can lead possibly to improved clinical outcomes.
糖基磷脂酰肌醇锚定蛋白（GPI-APs）是一类通过GPI锚定连接到质膜外小叶的分子，它们在包括神经发生、细胞黏附、免疫反应和信号传导在内的众多细胞过程中发挥重要作用。在GPI锚定缺陷组中，有六种表现为高磷酸酶血症伴智力发育迟缓综合征（HPMRS，马布里综合征）的临床表型，其特征为中度至重度智力残疾、畸形特征、肌张力减退、癫痫发作和持续性高磷酸酶血症。我们报告了一例5岁女性患者，患有全面发育迟缓，并伴有性早熟和血浆碱性磷酸酶持续升高。对HPMRS基因进行靶向二代测序分析，在该基因中发现了新的复合杂合变异（c.103del p.(Leu35Serfs*90)和c.134A > G p.(His45Arg)），符合3型HPMRS的诊断。脑脊液（CSF）神经递质分析显示磷酸吡哆醛和5-甲基四氢叶酸水平较低，高香草酸升高。补充吡哆醇和亚叶酸导致生化异常恢复正常。患者在言语和精细运动技能方面有显著改善，持续取得发育进步。我们报告的病例扩展了HPMRS3的临床谱，其中多系统受累越来越受到认可。此外，它表明GPI-APs的错误靶向及其对正常细胞功能的影响可能为CSF生化异常提供病理生理学解释，对目前尚无有效治疗方法的一组疾病具有管理意义，可能会改善临床结局。
