Abstract
BackgroundMorquio 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.ResultsA 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.ConclusionsIn 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.
Highlights
Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multisystem impairments and high medical burden
Demographic and baseline clinical characteristics We evaluated 33 patients with Morquio A syndrome from Quebec who provided consent to participate in the study (Table 1)
We demonstrated a founder effect in French Canadians from Quebec with Morquio A, which manifests as a non-classical form of the disease related to the founder pathogenic variant in about half of the study population
Summary
Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multisystem impairments and high medical burden. 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. Morquio A syndrome, called mucopolysaccharidosis IVA (MPS IVA), is an ultra-rare, genetically transmitted lysosomal storage disorder caused by a deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme [1, 2]. The result of the GAG accumulation is a progressively debilitating and potentially life-threatening disorder, with multi-system impairments and a high medical burden [3]. Morquio A patients typically have a shortened life expectancy, with the main cause of death being respiratory failure [6, 8]
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