Plain language summary of a study looking at whether genetic testing can help doctors diagnose the severity of mucopolysaccharidosis type I (MPS I)

Abstract

What is MPS I & what is this study about?

Mucopolysaccharidosis type I (MPS I) is a rare genetic condition, resulting from disease-causing changes in the IDUA gene called pathogenic variants. There are two different types of variants:

• Null variants – cells cannot make the alpha-L-iduronidase enzyme

• Missense variants – cells make a partly functional or severely reduced amount of the fully functional enzyme

The alpha-L-iduronidase enzyme breaks down large sugar molecules called glycosaminoglycans (GAGs). In people with MPS I, the enzyme is unable to break down GAGs and they build up in cells. Based on the severity of the condition, doctors categorise MPS I into two types, called phenotypes:

• Attenuated MPS I

• Severe MPS I

Treatment options differ depending on MPS I phenotype. There are currently no tests that accurately determine MPS I phenotype. Using information from the MPS I Registry, researchers wanted to find out whether knowing the specific combination of the 2 disease-causing gene variants (genotype) can help predict whether a person has an attenuated or severe phenotype.

What were the results?

In people with attenuated MPS I:

• 19 in 20 had genotypes where at least one of the gene copies was a missense variant. The cell makes a partly functional or a severely reduced amount of the fully functional enzyme, and is unable to completely break down GAG

• No-one had 2 null variants

• 2 in 5 had unique genotypes (their genotype was only seen in one person)

In people with severe MPS I:

• 2 in 3 had genotypes where both copies of the gene contained null variants. The cell is not able to make any enzyme

• 1 in 5 had unique genotypes

What do the results mean?

This study showed that genotype can predict phenotype in some people with MPS I. For example, if a person has inherited two copies of the genes containing null variants, they will have severe MPS I. However, due to the large number of unique gene variants found in this study, doctors cannot predict the severity of MPS I from just the genotype for some people.

Keywords: :

• genetic disease
• genotype
• lysosomal storage disease
• mucopolysaccharidosis type I (MPS I)
• newborn screening
• phenotype
• plain language summary
• rare disease

Financial disclosure

Lorne A Clarke is a member of the MPS I Registry advisory board (supported by Sanofi) and receives speaker's fees from Sanofi for educational events related to lysosomal disease. Roberto Giugliani receives honorarium from Sanofi for expert advice, travel grants from Sanofi to attend scientific meetings, investigator fees from Sanofi and unrestricted grants from Sanofi to promote educational events. Joseph Muenzer serves on advisory boards and consults for Sanofi and BioMarin. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the plain language summary apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the plain language summary. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

Writing support, funded by Sanofi, was provided by Nikita Vekaria, PhD, of Elevate Scientific Solutions.

Ethical disclosure

All the people in the Registry have given written consent to their doctor for their information to be included in the MPS I Registry and to be used in studies. Registry protocols and informed consent forms and procedures are reviewed and approved by local institutional review boards or independent ethics committees.

Acknowledgments

The authors would like to thank the patients, physicians, and registry sites' staff who participate in the MPS I Registry; Ana Lorena Flores, Veronica Munoz, Danielle Dong, Julie Batista and Jan Markind (Sanofi) for their critical review of data analyses, content and editing of the plain language summary; and the authors of the primary paper (Nathalie Guffon, Simon A Jones, Hillary A Keenan, Maria V Munoz-Rojas, Torayuki Okuyama, David Viskochil, Chester B Whitley and Frits A Wijburg).