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In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Genetic modifiers of upper limb function in Duchenne muscular dystrophy Ascension day special from Journal of Neurology by Sabbatini et al with Luca Bello on the influence of genetic modifiers on upper limb function decline in Duchenne patients. The confirmed suspects for ambulatory loss were assessed for the upper limb. Doi 10.1007/s00415-012-11133-8. While all Duchenne patients go through the relentless loss of one function after another, there is variability in the speed of loss. Eg for Duchenne patients on corticosteroids loss of ambulation can occur before age 10 to after age 15 years. This can be influenced by dystrophin, where patients with very low dystrophin levels have a slower progression than patients without dystrophin (eg exon 44 skippable patients). It can also be influenced by genetic variation in other genes influencing eg fibrosis or inflammation Multiple modifiers have been found to influence loss of ambulation age, where variants are protective vs detrimental. SPP1 was first, but also LTBP4, CD40, ACTN3 and THBS1 and others were reported. So far effects on upper limb function decline was not studied Here authors study the effect of modifiers (SPP1, CD40, LTPB4 and ACTN3) on the performance upper limb (PUL) scale in a cohort of 137 Italian patients (with 636 assessments) and Brooke scale in 340 patients (2895 assessments). They corrected for steroid effects as patients on steroids had significantly better arm function than those not using steroids. There was no significant association for total PUL and the modifiers. For PUL they also looked at subscales for shoulder, elbow and distal arm. CD40 modifier had an effect on shoulder & distal domains, while ACTN3 had an effect on elbow & distal. For the Brooke scale, SPP1 and CD40 influenced outcomes. Authors also looked at dystrophin mutation effects, and were unable to find a protective effect of exon 44 skip mutation They saw protective effects for some exons (exon 45 and exon 8) but these groups are very small and thus this may be influenced by other aspects (e.g. age of the subgroups vs average age etc). Authors discuss that their study shows the natural history of limb function decline Shoulder function decline starts early (~7.5y), followed by elbow and distal function. Interestingly, LTBP4 associations were not found, while this modifier showed the most robust effects on loss of ambulation. For ACTN3 it is the opposite, with a more robust effect on arm function Authors discuss that the ACTN3 modifier has an impact on strength and primarily in type 2 muscle fibers, which are more prominent in upper limb than lower limb in Duchenne patients. I commend the authors for looking into these aspects - arm function is very important for Duchenne I do wonder though why authors did not (also) look in a milestone focused way. e.g. loss of a particular arm function as was done for ambulation. I understand the PUL and Brooke look at this with lower numbers reflecting loss of a function on an aggregated way For genetic modifier discovery a milestone driven approach may be easier (from a statistic/modeling perspective). Since not all ambulation modifiers influence arm function, it would be good to study modifiers not (robustly) influencing loss of ambulation for arm function effects. More work is needed on genetic modifiers in general, and on their effect on various functional aspects in particular. I commend the authors for taking a first step for the upper limb function aspects.

#apaperaday: Genetic modifiers of upper limb function in Duchenne muscular dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Genetic modifiers of upper limb function in Duchenne muscular dystrophy.

Ascension day special from Journal of Neurology by Sabbatini et al with Luca Bello on the influence of genetic modifiers on upper limb function decline in Duchenne patients. The confirmed suspects for ambulatory loss were assessed for the upper limb. Doi 10.1007/s00415-012-11133-8.

While all Duchenne patients go through the relentless loss of one function after another, there is variability in the speed of loss. Eg for Duchenne patients on corticosteroids loss of ambulation can occur before age 10 to after age 15 years.

This can be influenced by dystrophin, where patients with very low dystrophin levels have a slower progression than patients without dystrophin (eg exon 44 skippable patients). It can also be influenced by genetic variation in other genes influencing eg fibrosis or inflammation.

Multiple modifiers have been found to influence loss of ambulation age, where variants are protective vs detrimental. SPP1 was first, but also LTBP4, CD40, ACTN3 and THBS1 and others were reported. So far effects on upper limb function decline was not studied.

Here authors study the effect of modifiers (SPP1, CD40, LTPB4 and ACTN3) on the performance upper limb (PUL) scale in a cohort of 137 Italian patients (with 636 assessments) and Brooke scale in 340 patients (2895 assessments).

They corrected for steroid effects as patients on steroids had significantly better arm function than those not using steroids. There was no significant association for total PUL and the modifiers. For PUL they also looked at subscales for shoulder, elbow and distal arm.

CD40 modifier had an effect on shoulder & distal domains, while ACTN3 had an effect on elbow & distal. For the Brooke scale, SPP1 and CD40 influenced outcomes. Authors also looked at dystrophin mutation effects, and were unable to find a protective effect of exon 44 skip mutation.

They saw protective effects for some exons (exon 45 and exon 8) but these groups are very small and thus this may be influenced by other aspects (e.g. age of the subgroups vs average age etc). Authors discuss that their study shows the natural history of limb function decline.

Shoulder function decline starts early (~7.5y), followed by elbow and distal function. Interestingly, LTBP4 associations were not found, while this modifier showed the most robust effects on loss of ambulation. For ACTN3 it is the opposite, with a more robust effect on arm function.

Authors discuss that the ACTN3 modifier has an impact on strength and primarily in type 2 muscle fibers, which are more prominent in upper limb than lower limb in Duchenne patients. I commend the authors for looking into these aspects – arm function is very important for Duchenne.

I do wonder though why authors did not (also) look in a milestone focused way. e.g. loss of a particular arm function as was done for ambulation. I understand the PUL and Brooke look at this with lower numbers reflecting loss of a function on an aggregated way

For genetic modifier discovery a milestone driven approach may be easier (from a statistic/modeling perspective). Since not all ambulation modifiers influence arm function, it would be good to study modifiers not (robustly) influencing loss of ambulation for arm function effects.

More work is needed on genetic modifiers in general, and on their effect on various functional aspects in particular. I commend the authors for taking a first step for the upper limb function aspects.

European Neuromuscular Centre (ENMC)

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