Urizar Elena, McCarron Eamon P, Gadepalli Chaitanya, Bentley Andrew, Woolfson Peter, Lin Siying, Iosifidis Christos, Browning Andrew C, Bassett John, Senarathne Udara D, Indika Neluwa-Liyanage R, Church Heather J, Cooper James A, Menendez Lorenzo Jorge, Farrugia Maria Elena, Jones Simon A, Black Graeme C, Stepien Karolina M
Adult Inherited Metabolic Diseases, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, UK.
Ear Nose and Throat Surgery, Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Salford M6 8HD, UK.
Genes (Basel). 2025 Jul 30;16(8):915. doi: 10.3390/genes16080915.
Lysosomal storage diseases (LSDs) are a genetically and clinically heterogeneous group of inborn errors of metabolism caused by variants in genes encoding lysosomal hydrolases, membrane proteins, activator proteins, or transporters. These disease-causing variants lead to enzymatic deficiencies and the progressive accumulation of undegraded substrates within lysosomes, disrupting cellular function across multiple organ systems. While classical phenotypes typically manifest in infancy or early childhood with severe multisystem involvement, a combination of advances in molecular diagnostics [particularly next-generation sequencing (NGS)] and improved understanding of disease heterogeneity have enabled the identification of attenuated forms characterised by residual enzyme activity and later-onset presentations. These milder phenotypes often evade early recognition due to nonspecific or isolated symptoms, resulting in significant diagnostic delays and missed therapeutic opportunities.
OBJECTIVES/METHODS: This study characterises the clinical, biochemical, and molecular profiles of 10 adult patients diagnosed with LSDs, all representing attenuated forms, and discusses them alongside a narrative review.
Enzyme activity, molecular data, and phenotypic assessments are described to explore genotype-phenotype correlations and identify diagnostic challenges.
These findings highlight the variable expressivity and organ involvement of attenuated LSDs and reinforce the importance of maintaining clinical suspicion in adults presenting with unexplained cardiovascular, neurological, ophthalmological, or musculoskeletal findings. Enhanced recognition of atypical presentations is critical to facilitate earlier diagnosis, guide management, and enable cascade testing for at-risk family members.
溶酶体贮积症（LSDs）是一组由编码溶酶体水解酶、膜蛋白、激活蛋白或转运蛋白的基因变异引起的遗传性和临床异质性先天性代谢缺陷。这些致病变异导致酶缺乏以及未降解底物在溶酶体内的逐渐积累，破坏多个器官系统的细胞功能。虽然经典表型通常在婴儿期或幼儿期出现，伴有严重的多系统受累，但分子诊断技术的进步（尤其是下一代测序技术）以及对疾病异质性的深入了解，使得能够识别出以残余酶活性和较晚发病为特征的轻型形式。这些较轻的表型往往因非特异性或孤立的症状而难以早期识别，导致显著的诊断延迟和治疗机会的错失。
目的/方法：本研究对10例被诊断为溶酶体贮积症的成年患者的临床、生化和分子特征进行了描述，所有患者均代表轻型形式，并结合一篇叙述性综述进行讨论。
描述了酶活性、分子数据和表型评估，以探讨基因型-表型相关性并识别诊断挑战。
这些发现突出了轻型溶酶体贮积症的可变表达性和器官受累情况，并强调了对出现不明原因心血管、神经、眼科或肌肉骨骼症状的成年人保持临床怀疑的重要性。加强对非典型表现的认识对于促进早期诊断、指导管理以及对高危家庭成员进行级联检测至关重要。
