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#apaperaday: Characterization of Phenotypic Variability in Becker Muscular Dystrophy for Clinical Practice and Towards Trial Readiness

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled:  Characterization of Phenotypic Variability in Becker Muscular Dystrophy for Clinical Practice and Towards Trial Readiness: A Two-Years Follow up Study

Today’s pick was read en route to Zurich where I gave a lecture on individualized ASO treatment at the children hospital. The pick is from @journal_nd  by Ricci et al on the natural history of an Italian Becker muscular dystrophy patient cohort. Doi 10.3233/JND-221513

Becker is caused by mutations in the dystrophin gene that allow production of partially functional dystrophins, unlike Duchenne where no functional dystrophin is produced. Becker is milder when compared to Duchenne, but severity is variable.

Also, it is mild compared to Duchenne, not mild in general. Becker is not well studied, though that is now changing. ~70% of mutations are deletions of one or more exons, meaning that different Becker patients can make different dystrophins with different functionality.

In addition to muscle problems, about 70% of Becker patients also has cardiac problems. There is limited natural history available. Authors here report 1 or 2 year follow up of a group of 32 Becker patients from 30 families.

Age range is 21-70 years at baseline, with an average of 21 years since symptom onset. 47% of patients had a deletion starting with exon 45 (indeed deletions of exon 45-47 are very common). The cohort started to have motor symptoms generally before the age of 30 years.

6 patients did not have motor problems. 3 others lost ambulation at age 25, 30 and 51 years and also had upper limb weakness. Individuals with a deletion starting at exon 45 appeared to have a more severe disease, with lower baselines for the 6 minute walk test and NSAA.

During 1 & 2 year followup no decline could be detected for the 6 minute walk test or NSAA. Authors did see an age effect, where older individuals generally performed worse than younger. Also the patients with a deletion starting with exon 45 did show some decline in function.

2 individuals had dilated cardiomyopathy with reduced ejection fraction and 10 patients had other forms of heart pathology. For those patients with heart problems and 2 year follow up, the ejection fraction was reduced in 3/9 patients.

MRI showed fat infiltration in leg muscles as expected. Higher levels of fat were found for mutations starting with exon 45. Some patients worsened during follow up. There was a correlation between MRI fat infiltration & functional performance in the 6 minute walk test and NSAA.

Authors discuss that while Becker is milder than Duchenne, it is also much more variable. This is clear from the report. Having natural history data and a genotype phenotype correlation is important for clinical trial design.

If a treatment slows down disease progression & patients are stable for 2 years, you will not be able to detect a treatment effect in 2 years of trialing. Authors discuss that @LucaBello2 already found patients with a deletion starting at exon 45 to be more severely affected.

Those individuals may be indicated as a subgroup in a clinical trial where treatment effects are more easily picked up. Another question is what happens in longer term followup. A 5 year followup takes 5 years , but now natural history studies have started these data will come.