Division of Medical Genetics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.
Medical Genetics Division, Centre Hospitalier Universitaire Sherbrooke, Sherbrooke, QC, Canada.
Orphanet J Rare Dis. 2020 Sep 29;15(1):270. doi: 10.1186/s13023-020-01545-y.
Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa.
A total of 33 patients, aged 5-63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease.
In Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.
黏多糖贮积症 A 型（MPS-A）是一种罕见的常染色体隐性进行性致残疾病，多系统受损，医疗负担重。加拿大魁北克省有大量 MPS-A 患者，由于存在创始性致病性变异，被认为具有独特性。本研究的目的是记录魁北克 MPS-A 患者的遗传和临床异质性，更好地描述具有法国加拿大创始性致病性变异（NM_000512.5：c.1171A>G，p.Met391Val）患者的表型，并描述接受艾拉司琼酶替代治疗患者的自然病史。对 MPS-A 患者进行溶酶体酶 N-乙酰半乳糖胺-6-硫酸酯酶的致病性变异基因分型。临床数据从患者的病历中回顾性收集，包括病史、身高、体格检查、呼吸功能检查、心电图、超声心动图、6 分钟步行试验（6MWT）耐力和日常生活活动（ADL），采用黏多糖贮积症健康评估问卷（MPS-HAQ）进行评估。对接受艾拉司琼酶替代治疗的患者进行了回顾性和前瞻性的纵向数据收集。
共纳入 33 名年龄 5-63 岁的患者。17 名携带创始性致病性变异的患者通常表现为非典型黏多糖贮积症 A 型。与携带非创始性致病性变异的患者（n=16）相比，这些患者一般身高较高，耐力更好，ADL 能力更强。然而，他们仍然存在严重的肌肉骨骼疾病。26 名接受艾拉司琼酶替代治疗的患者中，无论致病性变异如何，耐力和 ADL 均有改善。治疗 5-12 个月后，6MWT 自基线的平均改善率为 23%，14 名患者中有 10 名至少在一个 MPS-HAQ 领域得到改善。耐力和 ADL 在长期（最长 7 年）内通常持续改善或保持稳定。在接受后续超声心动图检查的 19 名治疗患者中，有 4 名患者的心脏疾病出现进展。
在加拿大魁北克省，由于存在创始效应，黏多糖贮积症 A 型常表现为非典型综合征形式。接受艾拉司琼酶替代治疗的患者，无论致病性变异如何，耐力和功能均有长期改善或稳定。
