Mucopolysaccharidosis type VI in the Russian registry: Further insights and considerations

Abstract

This commentary evaluates the recent registry-based study of mucopolysaccharidosis type VI by Vechkasova et al, highlighting several methodological and reporting concerns that limit the interpretation of the findings. Although the establishment of a national registry is commendable and need of the time, the authors report an absence of correlations between clinical severity, age of onset, enzyme activity, and nucleotide variants without presenting any supporting statistical analyses or genotype-phenotype assessments. The dataset also appears affected by survivorship bias, and inconsistencies in reporting patient outcomes. Important clinical and genetic details, such as gender-stratified characteristics, variant zygosity and phasing, and American College of Medical Genetics and Genomics-based variant interpretation, are missing. Additionally, the use of inaccurate terminology and unclear prevalence calculations further complicates the interpretation. While the registry represents an important step toward understanding mucopolysaccharidosis type VI in Russia, improved methodological transparency, consistent terminology, and clearer data presentation are essential to strengthen the utility of these findings.

Key Words: Mucopolysaccharidosis type VI; Metabolic disorder; Maroteaux-Lamy syndrome; Russian National registry; Genotype-phenotype correlation; Enzyme replacement therapy; Mutation

Core Tip: This commentary highlights major methodological and reporting limitations in the recent mucopolysaccharidosis type VI Russian national registry study by Vechkasova et al, including missing statistical analyses, unclear genotype-phenotype correlations, inconsistent data reporting, and survivorship bias. Improving data transparency, variant interpretation, and clinical documentation is essential for the registry to generate reliable insights and guide patient care.

TO THE EDITOR

I read with great interest the article by Vechkasova et al[1] which presents data on mucopolysaccharidosis type (MPS) VI from the Russian national registry. Establishing a national disease registry is of paramount importance for estimating the true disease burden. However, it is equally crucial that the data be presented with accuracy and clarity to ensure appropriate interpretation. While the topic of this article is valuable, several issues warrant more closer attention.

In the Abstract, the authors state that “no correlation was observed between age of onset, severity of clinical manifestations, enzyme activity, or nucleotide variants”. However, the manuscript does not present any statistical correlation analyses. Variant frequencies are listed, but there is no attempt to relate genotypes to clinical parameters such as age at first symptoms, growth delay, cardiac involvement, or response to enzyme replacement therapy (ERT)[2,3]. Secondly, considering that 90.5% of patients received ERT, survivorship bias is also highly likely, as the registry largely reflects treated individuals rather than the natural history of untreated disease[4,5]. The manuscript states that 48/53 (90.5%) patients received ERT, of whom 46 were alive and 2 had died, and that three patients had not received ERT. By this calculation, two patients remain unaccounted for. Moreover, earlier in the text only two total deaths are reported, raising inconsistencies in outcome reporting.

Furthermore, the section “clinical characteristics of patients with MPS VI” would be clearer if presented in tabular form with gender-wise distribution. Similarly, Table 3 would be more informative if it included variant zygosity, allele frequency, and phasing information. Although 19 cases with a positive family history are reported, no information is provided on parental consanguinity, which is epidemiologically relevant. Moreover, the methods section lists only Sanger sequencing, yet the authors report a 2.6 Mb deletion. No methodology for copy-number variant detection (e.g., multiplex ligation-dependent probe amplification, quantitative polymerase chain reaction, or array analysis) is described. Additionally, details of American College of Medical Genetics and Genomics-based curation and the assessment of compound heterozygosity are missing. The term “Hurler phenotype” is used to describe patients with severe MPS VI. This terminology is inaccurate, as “Hurler” refers specifically to the severe form of MPS I. The authors should clarify which clinical criteria they applied, since imprecise terminology complicates interpretation and comparison across studies.

The statement that “the average prevalence of MPS VI in the Russian Federation is 3.9 per 100000 newborns or 0.036 per 100000 population” is confusing without clearly defined denominators, time frames, or an assessment of case completeness. Furthermore, many clinical features are reported with reduced denominators (e.g., hepatomegaly in 23/38 patients, cardiac involvement in 26/32), meaning that 15%-40% of the data are missing for most parameters. This raises concerns about selection bias and the representativeness of the registry data.

What is more perplexing is that the same group recently published another study on MPS VI in Russia[6], which reported 68 patients from 57 families. In contrast, the current article analyzes 53 patients. The correspondence and overlap between these two datasets are not explained. Would it not be worthwhile to present a unified overview of all patients? Clarifying this issue is essential for understanding the novelty and added value of the current study.

Additional points to be clarified: Page 9 contains an unclear statement: “According to the registry data, heart involvement…”. Abstract: “Type VI” should be consistently used (rather than “type 6”). The Online Mendelian Inheritance in Man number for MPS VI should be cited. Replace the outdated term “mental retardation” with “intellectual disability.”

CONCLUSION

This registry study is valuable, as national data on MPS VI are rare, and the researchers consider such studies as baseline reference. Nevertheless, inconsistencies in reporting, incomplete methodological details, lack of genotype-phenotype analyses, and imprecise terminology weaken the validity of the conclusions. Hence, a more cautious interpretation, along with improved data presentation and methodological transparency, would substantially strengthen the manuscript.