Ngiwsara Lukana, Dhachpramuk Dhachdanai, Sawangareetrakul Phannee, Vongphit Sherry, Pacharn Punchama, Svasti Jisnuson, Vatanavicharn Nithiwat
Laboratory of Biochemistry, Chulabhorn Research Institute, Bangkok, Thailand.
Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Ann Hum Genet. 2025 May;89(2-3):126-131. doi: 10.1111/ahg.12595. Epub 2025 Apr 1.
Galactosialidosis (GS) is a rare lysosomal storage disease (LSD) with variable onset caused by a defect in protective protein/cathepsin A (PPCA) encoded by the CTSA gene. The late-infantile onset is characterized by developmental delay, visceromegaly, coarse facies, and cherry-red macula. We report cases of late-infantile GS in a Thai-Lahu family, with affected members initially presenting with recurrent infections due to T-cell defects. The clinical features of LSD and cherry-red macula led us to perform lysosomal enzyme assays, which showed undetectable activity of PPCA. A novel homozygous missense CTSA variant (NM_000308.4): c.1307A > G (p.Gln436Arg) was identified in affected individuals. In vitro functional analysis suggested that the variant may impair the dimerization process of PPCA, potentially disrupting proper protein maturation or function and leading to significantly reduced PPCA activity. Exome sequencing did not reveal any variants in other genes associated with primary immunodeficiencies. To date, our cases represent the first reported patients with GS and T-cell defects. Our study broadened the clinical and genotype spectrum of this rare disease.
半乳糖唾液酸贮积症（GS）是一种罕见的溶酶体贮积病（LSD），由CTSA基因编码的保护蛋白/组织蛋白酶A（PPCA）缺陷引起，发病情况多样。晚发性婴儿型的特征为发育迟缓、内脏肿大、面容粗糙和樱桃红斑。我们报告了一个泰国拉祜族家庭中的晚发性婴儿型GS病例，患病成员最初因T细胞缺陷而反复感染。LSD的临床特征和樱桃红斑促使我们进行溶酶体酶检测，结果显示PPCA活性无法检测到。在患病个体中鉴定出一种新的纯合错义CTSA变异（NM_000308.4）：c.1307A>G（p.Gln436Arg）。体外功能分析表明，该变异可能会损害PPCA的二聚化过程，可能破坏蛋白质的正常成熟或功能，并导致PPCA活性显著降低。外显子组测序未发现与原发性免疫缺陷相关的其他基因存在变异。迄今为止，我们的病例是首例报告的患有GS和T细胞缺陷的患者。我们的研究拓宽了这种罕见疾病的临床和基因型谱。
