Gaucher disease: clinical phenotypes and refining GBA mutational spectrum in Thai patients

Orphanet Journal of Rare Diseases

Naruwan Noentong¹  Pimlak Charoenkwan²  Adisak Tantiworawit³  Kanya Suphapeetiporn⁴  Saisuda Noojarern⁵  Thipwimol Tim-Aroon⁵  Arthaporn Khongkraparn⁵  Duangrurdee Wattanasirichaigoon⁵  Tim Phetthong⁶  Achara Sathienkijkanchai⁷  Khunton Wichajarn⁸  Chulaluck Kuptanon⁹ 

[1] Department of Pediatrics, Surin Hospital, Surin, Thailand;Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand;Division of Hematology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand;Division of Medical Genetics and Metabolism, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand;Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama 6 Road, 10400, Bangkok, Thailand;Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Rama 6 Road, 10400, Bangkok, Thailand;Division of Medical Genetics, Department of Pediatrics, Phramongkutklao Hospital and Phramongkutklao College of Medicine, Bangkok, Thailand;Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand;Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;Genetics Section, Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok, Thailand;Department of Pediatrics, College of Medicine, Rangsit University, Bangkok, Thailand;

关键词: Asian;    GBA;    GBAP;    L444P;    p.L483P;    Recombinant allele;    Rec1a;    Prevalence;   

DOI  :  10.1186/s13023-021-02151-2

来源: Springer

【 摘 要 】

BackgroundGaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010–2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before.ResultsThere were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa.ConclusionsNeuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

【 授权许可】

CC BY