In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Associations Between Self-Reported Behavioral and Learning Concerns and DMD Isoforms in Duchenne Muscular Dystrophy
Today’s themed pick is from Journal of Neuromuscular Diseases by Counterman et al on the association of dystrophin isoform expression & learning & behavioral concerns. Doi 10.3233/JND-220821
Duchenne patients experience progressive muscle wasting & loss of function. However dystrophin is also expressed in the brain and many patients also experience learning difficulties and behavioral issues. All Duchenne patients lack the full length brain dystrophins (Dp427c & Dp427p)
Depending on mutation location about half also miss Dp140 and a small group misses all isoforms including Dp71. Dp71+Dp140 are involved in embryonic brain development. Previous studies revealed patients lacking more isoforms are more at risk for learning and behavioral issues.
Here authors want to add to this work analyzing the Duchenne Patient Registry (USA) that is one of the federated registries from TREAT_NMD Authors analyzed data from 2007-2019.
For learning and behavioral issues families self reported
- Concern and diagnosis
- Concern and no diagnosis
- No concern
Authors are aware of the peculiarity of Dp140: its first exon is in intron 44, but translational start in exon 51.
It is unknown what mutations between exon 45-50 do. In theory they should still allow translation of Dp140, but it is possible the long 5’ untranslated region is required for proper production of Dp140. Authors gave mutations between exon 45 and 50 their own bin.
Authors included 1381 patients, 65% were ambulatory, 74% from the USA and 64% were on steroids. 57% could not produce Dp140 and 3% could not produce Dp71. 40% of patients had behavioral concerns and 39% learning difficulties.
Patients lacking all isoforms (so no Dp71) were 3.3 times more likely to have behavioral concerns than those missing only the full length dystrophin. Those missing Dp140 1.6 times more likely. Patients over 6 were 2.6 times more likely to have behavioral concerns than those <6 yrs. Those on steroids (now or in the past) were 2 times more likely to have behavioral concerns. There was no difference between prednisone and deflazacort.
For learning concerns patients lacking all dystrophin forms were 9.5 times more likely to have concerns than those lacking only the full length form. Those lacking Dp140 3.3 times more likely. Authors discuss their analysis confirming Duchenne patients are at risk for behavioral+learning difficulties. They stress more awareness is needed so relevant interventions can be offered. The BIND Project is studying this in more detail & Jos Hendriksen has been studying this for decades.
Authors discuss also that patients with mutations between exon 45-50 have similar risks as those missing only the full length isoform. This suggests that the long UTR is not crucial and that these patients can produce Dp140. Authors also discuss it is difficult to know whether lack of each isoform separately contributes to the problems or that combined absence does. Maaike van Putten has an NWONieuws and ZonMw VIDI grant to study exactly this.
Authors discuss that the fact that concerns are more common in patients >6 is that these are in schools where learning difficulties are more easily picked up. Behavioral concerns increase as well with age as patients become more aware of their disease and lose ambulation.
Authors outline that other work suggests that behavioral concerns are more likely for prednisone than deflazacort. However they found no difference in their large study here. They outline limitations: little details were available on the nature of the concerns or steroid regimen. They stress that the large size is an advantage. I agree! And kudos for getting the genetics of Dp140 right!