Dave Usha, Kadali Srilatha, Hussain Tajamul, Radhika Ananthaneni, Patel Sagar, Patel Nirav, Naushad Shaik Mohammad
Navigene Genetic Science Laboratory, MILS International India, Mumbai, India.
Department of Biochemical and Molecular Genetics, Yoda Diagnostics Pvt. Ltd, Hyderabad, 500016 Telangana India.
Indian J Clin Biochem. 2025 Apr;40(2):254-262. doi: 10.1007/s12291-023-01176-7. Epub 2024 Jan 10.
The current study aimed to explore phenotypic evolution in Fabry disease according to demographics, genotype, specific enzyme activity and pathogenicity scores. We integrated clinical, biochemical, and genomic data of 88 Fabry cases (23 from our cohort, 65 from other published data on Indians) to achieve this objective. The affected cases showed profound impairment in the alpha galactosidase enzyme activity (0.73 ± 1.38% mean normal) while carriers showed 15.64 ± 3.68% mean normal activity. The mutation spectrum is highly heterogeneous with eight different mutations identified in eight different patients in our cohort, while the total data is representative of 68 mutations in Indians. The mean CADD score for these mutations was 20.63 ± 10.38. Highly conserved mutations are associated with renal involvement ( = 0.005), while neuropathic pain is observed even in mutations in less conserved regions ( = 0.02). The age of onset showed a positive association with the percentage of specific enzyme activity ( = 0.375, < 0.001), renal disease ( = 0.328, = 0.005), and cardiac problems ( = 0.278, = 0.026). Consistent with this, we had a very early onset neonatal Fabry with 0% specific enzyme activity harbouring c.613C > G (p.Pro205Ala) mutation in the gene. This emphasizes that many patients with rare genetic diseases can experience delays in diagnosis due to their infrequent occurrence and nonspecific symptoms, which are not easily recognizable. A holistic approach with a combination of WES and biochemical assays will be helpful in arriving at the early and accurate diagnosis through rigorous phenotypic evaluation.
本研究旨在根据人口统计学、基因型、特定酶活性和致病性评分来探索法布里病的表型演变。为实现这一目标，我们整合了88例法布里病患者的临床、生化和基因组数据（23例来自我们的队列，65例来自其他已发表的印度人数据）。患病病例的α-半乳糖苷酶活性严重受损（平均正常活性为0.73±1.38%），而携带者的平均正常活性为15.64±3.68%。突变谱高度异质，我们的队列中有8名不同患者鉴定出8种不同突变，而总体数据代表了印度人的68种突变。这些突变的平均CADD评分为20.63±10.38。高度保守的突变与肾脏受累相关（P=0.005），而即使在保守性较低区域的突变中也观察到神经性疼痛（P=0.02）。发病年龄与特定酶活性百分比呈正相关（P=0.375，R²<0.001）、与肾脏疾病呈正相关（P=0.328，R²=0.005）以及与心脏问题呈正相关（P=0.278，R²=0.026）。与此一致的是，我们有一名发病极早的新生儿法布里病患者，其特定酶活性为0%，在 基因中携带c.613C>G（p.Pro205Ala）突变。这强调了许多罕见遗传病患者由于其发病率低和症状不特异而难以识别，可能会出现诊断延迟。结合全外显子测序（WES）和生化检测的整体方法将有助于通过严格的表型评估实现早期准确诊断。
