Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy

<div><p>The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers.</p></div

Revised version of the NSAA with items ordered according to the age when they can be performed.

<p>Revised version of the NSAA with items ordered according to the age when they can be performed.</p

Frequency distribution of controls reaching a full score on individual NSAA items at different age points.

<p>The shaded cells indicate the activities that were achieved by at least 85% of the boys at that age point and were therefore considered as age appropriate.</p

NSAA scores in controls boys compare to DMD NSAA scores subdivided by age of evaluation.

<p>NSAA scores in controls boys compare to DMD NSAA scores subdivided by age of evaluation.</p

Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy

<div><p>Objective</p><p>Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the <i>SPP1</i> promoter, rs10880 and the VTTT/IAAM haplotype in <i>LTBP4</i>) also modify DCM onset.</p><p>Methods</p><p>A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m² as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up.</p><p>Results</p><p>Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at <i>SPP1</i> rs28357094 and recessive T allele at <i>LTBP4</i> rs10880, which was statistically significant in steroid-treated patients for <i>LTBP4</i> rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027).</p><p>Conclusions</p><p>We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts.</p></div

Median age at DCM onset by <i>SPP1</i> and <i>LTBP4</i> genotype.

<p>*Significant difference between genotypes (log-rank p<0.05).</p><p>§DCM onset was observed in less than 50% of patients, so no median value can be calculated.</p><p>Total n for <i>LTBP4</i> differs due to limited DNA availability in a few patients. For <i>SPP1</i>, patients included in the previous report about loss of ambulation (Pegoraro et al, 2011) were also excluded. <i>SPP1</i>: Secreted PhosphoProtein 1. <i>LTBP4</i>: latent transforming growth factor beta binding protein 4. DCM: dilated cardiomyopathy.</p><p>Median age at DCM onset by <i>SPP1</i> and <i>LTBP4</i> genotype.</p

Scatter plot of age at LoA and DCM onset in 57 patients shows no strong correlation (r = 0.31).

<p>Scatter plot of age at LoA and DCM onset in 57 patients shows no strong correlation (r = 0.31).</p

Kaplan-Meier plots of LoA by genotypes and steroid treatment.

<p>Triangles indicate censoring. (A) <i>SPP1</i> rs28357094 genotype: T/T red, T/G-G/G blue; (B) <i>LTBP4</i> rs10880: T/T red, C/C-C/T blue; (C) LTBP4 haplotype: IAAM/IAAM red, VTTT/VTTT grey, other blue; (D) rs28357094 genotype and steroid treatment: T/T red, T/G-G/G blue, solid treated (>1 year before LoA), dashed untreated; (E) rs10880 and steroid treatment: T/T red, C/C-C/T blue, solid treated, dashed untreated; (F) LTBP4 haplotype and steroid treatment: IAAM/IAAM red, other (including VTTT) grey, solid treated, dashed untreated.</p

Risk of losing ambulation within 2 years in relation to different cut-off points of 6MWD and NSAA scores at baseline.

<p>Risk of losing ambulation within 2 years in relation to different cut-off points of 6MWD and NSAA scores at baseline.</p

Mean changes in 6MWT and in NSAA scores in patients below the age of 7 years at baseline (grey line) and above (black line).

<p>Mean changes in 6MWT and in NSAA scores in patients below the age of 7 years at baseline (grey line) and above (black line).</p