Center for Research and Diagnosis of Genetic Diseases - Department of Biophysics, Universidade Federal de São Paulo, São Paulo, Brazil.
Inborn Errors of Metabolism Reference Center, Department of Pediatrics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
Orphanet J Rare Dis. 2024 Nov 26;19(1):439. doi: 10.1186/s13023-024-03419-z.
α-mannosidosis is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme α-mannosidase, which is encoded by the MAN2B1 gene and inherited in an autosomal recessive manner. The impairment of affected individuals is multisystemic and very similar to the observed in some mucopolysaccharidosis (MPS) patients. The aim of this study was to search for α-mannosidosis cases in individuals with clinical suspicion of MPS without a confirmed diagnosis. Biochemical and molecular analysis were standardized by our group for this study. Two hundred and fifty samples from patients with clinical suspicion of MPS, but with inconclusive MPS biochemical and/or molecular analysis, were screened for α-mannosidase activity. Subsequently the MAN2B1 gene was sequenced in samples from 53 patients by the Sanger method.
The measurement of enzymatic activity detected fifty-three samples with abnormal results, suggesting α-mannosidosis. Molecular analysis confirmed three affected families, which presented the nonsense variant p.Ser899Ter. This variant generates a premature stop codon in exon 22, resulting in a truncated protein with no residual enzymatic activity.
In conclusion, this work brings data for the beginning of a genetic characterization of α-mannosidosis in the Brazilian population. It also shows that α-mannosidosis cases may be underdiagnosed due to the clinical similarity to MPS and the lack of information about this ultra-rare disease. Based on our data, we strongly recommend to all screening centers to consider α-mannosidosis testing together with screening for MPS as a tool for diagnosis to MPS-like phenotype individuals, since the phenotype similarity between these diseases poses a significant challenge for clinicians worldwide and often leads to the failure of the correct clinical diagnosis and treatment.
α-甘露糖苷贮积症是一种由于溶酶体酶α-甘露糖苷酶缺乏引起的先天性代谢缺陷，该酶由 MAN2B1 基因编码，呈常染色体隐性遗传。受影响个体的损伤是多系统的，与某些黏多糖贮积症（MPS）患者观察到的非常相似。本研究的目的是在临床疑似 MPS 但未确诊的个体中寻找α-甘露糖苷贮积症病例。我们的研究小组对生化和分子分析进行了标准化。对 250 例临床疑似 MPS 但 MPS 生化和/或分子分析结果不确定的患者样本进行α-甘露糖苷酶活性筛查。随后，采用 Sanger 法对 53 例患者的 MAN2B1 基因进行测序。
酶活性测量检测到 53 个异常结果的样本，提示存在α-甘露糖苷贮积症。分子分析证实了三个受影响的家族，这些家族存在无义变异 p.Ser899Ter。该变异在第 22 外显子产生一个提前终止密码子，导致没有残留酶活性的截断蛋白。
总之，本研究为巴西人群中α-甘露糖苷贮积症的遗传特征分析奠定了基础。这也表明，由于与 MPS 的临床相似性以及对这种超罕见疾病缺乏了解，α-甘露糖苷贮积症病例可能被漏诊。基于我们的数据，我们强烈建议所有筛查中心将α-甘露糖苷贮积症检测与 MPS 筛查相结合，作为诊断类似 MPS 表型个体的工具，因为这些疾病之间的表型相似性对全球临床医生构成了重大挑战，经常导致正确的临床诊断和治疗失败。
