Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disease which affects 1:5000 live newborn males.¹ Delay in gross motor milestones is commonly reported as a presenting symptom of DMD. The three motor milestones most likely to be delayed in DMD are sitting alone, walking, and climbing stairs.^{2, 3} Although many studies report gains in motor function over the first years, young males with DMD do not achieve the same functioning level compared with typically developing children and, after the age of 7 years, motor functions start to decline.^4-6 However, the time when males with DMD reach a plateau in motor skills or when they start declining is not yet fully defined and varies from individual to individual and for different functional skills.⁷

Several outcome measures have been applied to assess functional motor performance of males with DMD.^{8, 9} Timed function tests, time to rise from the floor (TRF), and the 10-metre walk/run test (10 m walk/run) are often used in clinical practice and research to assess motor function in young males with DMD as these measures seem to be sensitive to detecting changes over time.^{5, 10, 11} The 6-minute walk test (6MWT) is a further tool that is widely used to assess functional capacity and submaximal endurance in paediatric populations, including ambulant males with DMD.^12-14 The North Star Ambulatory Assessment (NSAA) was developed specifically for DMD and is used to monitor disease progression and treatment effects both in clinical settings and in investigational trials.^{7, 15, 16}

Only two studies, including small numbers of participants, have compared different motor outcomes in young, steroid-naïve males with DMD with those in age-matched typically developing males.^{17, 18} Most studies on functional motor outcomes in young males with DMD include those receiving corticosteroids or do not include a comparison group.^{19, 20} Reference curves for typically developing males are available for some functional motor outcomes.²¹ However, we know that young males with DMD develop motor skills in a different way and at a different pace.¹⁹ No reference curves specific to DMD exist at the moment. Therefore, the primary objective of this study was to compare motor performance of a large cohort of young, steroid-naïve males with DMD and that of age-matched typically developing males, using different standardized and reliable outcome measures. Second, we aimed to develop DMD-specific reference curves for each outcome measure. These estimated reference curves, based on reliable and standardized collected data, will help in understanding where on the ‘spectrum’ the performance of a male of a certain age at steroid-naïve stages is located compared with peers with DMD of the same age. Finally, we investigated the associations between anthropometric values (height, weight, and body mass index [BMI]) and motor performance in both groups.

METHOD

RESULTS

Between-group comparisons

Males with DMD in all age groups performed significantly worse on all functional motor outcomes than typically developing males (p < 0.001) (Table 2 and Appendix S2). The median times to perform the timed function tests in the typically developing males decreased over the total age range (Table 2). In the DMD group, median times first decreased between males aged 4 to 5 years, followed by slower times in males aged 6 to 7 years (Table 2). Consequently, the gap between typically developing males and males with DMD widened in the older age groups. Appendix S3 provides additional information on the corresponding velocities of the TRF and 10 m walk/run test. Median 6-minute walking distance (6MWD) in the typically developing group increased from ages 5 to 7 years. In the DMD group, median 6MWD also increased between males aged 4 to 6 years, followed by a decrease in the older males (Table 2). Finally, in the typically developing group, the median total NSAA scores increased from 27 to 34 between the youngest and oldest groups (Table 2). All but four 5-year-old typically developing males obtained the maximum score of 34. Four males scored 33 out of 34: one male used compensation while standing on one foot (left), two males lifted the head only partly or with compensation, and one male was not able to raise both feet completely while standing on heels. The median NSAA scores of the DMD group first increased between the 4- and 6-year-olds and then decreased. None of the steroid-naïve males with DMD achieved the maximum total score of 34 at any age (Table 2). Items that were difficult for them were rise from the floor, with only 2.6% of the males with DMD being able to do so without any compensation (NSAA-item 11: score 2) and 94.4% using compensatory movements (score 1); lifts head (NSAA-item 12), with only 17.3% receiving a score 2; getting to sitting position, with 76.5% of the males with DMD using a modified method (NSAA-item 10: score 1); hopping, with only 8.2% to 9.2% being able to hop with the left or right leg respectively without any compensation (NSAA-items 15 and 16: score 2); and 44% to 46% of the males unable to hop (score 0) (Appendix S4).

Individual results of timed function tests and 6MWT from males with DMD are plotted on the typically developing estimated reference curves in Figure 1. Males with DMD showed a wider variability in performance than typically developing males. No reference curve was made for the NSAA because 89.5% of the typically developing males received the maximum total NSAA score by the age of 5 years.

Figure 2 shows DMD-specific estimated reference curves for the timed function tests, 6MWT, and NSAA with individual data plots of the males with DMD. Clean DMD-specific estimated reference curves for clinical use are shown in Appendix S5.

DISCUSSION

This study provides a detailed picture of functional motor outcomes in young steroid-naïve males with DMD compared with typically developing males. In addition, the estimated reference curves for functional outcomes will enable assessment of a young male with DMD in relation to the expected performance in aged-matched typically developing males as well as other males with DMD.

We found that males with DMD needed significantly more time to complete the timed function tests and walked less distance in 6 minutes than their typically developing peers. For example, 91% and 95% of the males with DMD needed more time than the 5% slowest typically developing males for the TRF and 10 m walk/run respectively. Similarly, starting from the age of 5 years, 89% of the males with DMD walked a shorter 6MWD than the 5th centile of the typically developing males. Males with DMD, as young as 4 years, received significantly lower scores on the NSAA than typically developing males. These results are in line with previous findings.^4-6 We also found that young males with DMD between 4 and 8 years old were not able to attain the maximum score on the NSAA, whereas 89.5% of the 5-year-old typically developing males did. Our findings confirm results of previous studies showing that young steroid-naïve males with DMD have a delay in reaching some motor milestones, such as standing on one leg, while they rarely achieve other motor skills, such as hopping and rising from the floor without compensation, irrespective of age (Appendix S4).^{18, 30} An explanation of the lower scores on functional outcomes in young males with DMD might be muscle weakness that is already present in males with DMD between 4 and 7 years old.³¹ Beenakker et al. showed that a small reduction in muscle force can be accompanied by a large reduction in functional ability.¹¹ Also, the more general developmental delay, often seen in DMD, might affect their performance at the early stages as well as the presence of contractures at the ankle.^32-34 Young males with DMD show a functional plateau or decline in functioning starting from the age of 6 years to 6 years 6 months old, whereas typically developing males show better scores in all motor functional outcomes with increasing age. Consequently, there is an increasing gap in performance between males with DMD and their typically developing peers with increasing age. This supports the importance of the development of DMD-specific estimated reference curves to assess how a male with DMD performs compared with peers with DMD.

The DMD-specific estimated reference curves were developed on the basis of the cross-sectional FOR-DMD data. Younger males up to the age of 6 years to 6 years 6 months performed better in the timed function tests and the NSAA than older children. On the 6MWT higher variability was observed, with some 7-year-olds with DMD walking longer distances. These results confirm those of previous studies, including both steroid-treated and -naïve males, which showed that early functional improvements in young males with DMD were followed by waning performance with advancing age caused by disease progression.^{4, 19, 20} The timed function tests primarily measure muscle strength, whereas the 6MWT was developed to evaluate cardiopulmonary function and endurance. While children with DMD are expected to show muscle weakness starting from a young age, cardiopulmonary function and endurance are not expected to be compromised in these young males. Moreover, the 6MWT requires attention and child compliance which can improve with age and practice. A higher variability in all the motor performances was also observed in the older groups, aged 6 years to 6 years 6 months and above, compared with the younger males. The increasing variability in performance over time can be explained by DMD disease progression which affects each male differently.⁴

Current care recommendations for DMD support the initiation of corticosteroids before the functional decline starts.¹⁵ Moreover, early treatment seems to be associated with better long-term effects on motor outcomes.¹⁵ Our study confirms that males with DMD already show a functional plateau or decline from the age of 6 years, supporting the initiation of corticosteroids at a young age. An early initiation of steroids in males on the lower centiles for their age group might be considered to optimize motor function benefits. While a comprehensive evaluation of motor skills in young children remains key to drive clinical management, our study suggests that timed function tests might be more sensitive in detecting early signs of functional decline than the NSAA and 6MWT.

Finally, no or weak associations were found between the anthropometric values and functional motor outcomes in both groups. This indicates that in young, steroid-naïve males with DMD other factors such as age and the associated maturational effects might be important explanatory factors for the evolution of the functional motor outcomes. Slight differences in correlations might be explained by the fact that males with DMD do not follow the same growth curves as typically developing males. Moreover, the improvement in motor performance with maturation in typically developing children might not be seen in those with DMD as maturational improvements might be overtaken by progressive disease-related loss of functional capacity. In typically developing children, a strong association is found between height and stride length which can be captured in the 6MWD and 10 m walk/run. Change in stride length is a major determinant of change in 6MWD over time.⁴ McDonald et al. indicated that young males with or without disease may show improvements in 6MWD, presumably because of the increasing stride lengths in association with greater height and strength-to-bodyweight ratios.⁴ However, starting from around the age of 7 years these gains seem to be eclipsed by disease progression in males with DMD. Males with DMD will then lose stride length despite increasing height.⁴ Also, BMI seems not to be associated with functional motor outcome in typically developing males or males with DMD aged 4 to 8 years.

This study has some limitations. The estimated reference curves were developed using cross-sectional and not longitudinal data. Subsequently, the group of males with DMD was very heterogeneous, which might have affected the generalizability of the data. Larger collaborative studies, including steroid-naïve males between 4 and 8 years from different sources and natural history studies, could address this limitation and validate the findings of this study. Also, related to the sample size, we acknowledge that the confidence intervals of the lower and upper quantiles that are far from the median, especially of the males with DMD, are large. So, the estimators of these quantiles have to be interpreted with caution. The curves only show the behaviour of functional outcome measures in steroid-naïve males with DMD. Performance of males treated with corticosteroids might deviate from the centiles shown in these curves. However, these data can be used as a reference to describe how far treated males are developing from age-matched steroid-naïve males with DMD, with the caveat that these males, especially the older ones, are a highly select subset given their steroid-naïve status. Reproducing the analyses using longitudinal data from steroid-treated males with DMD, after adjusting for covariates such as steroid regime and age of onset of steroid treatment, could complement the present work and be used as a reference for males with DMD treated with either steroids or novel drugs intended to restore dystrophin. Data on functional outcomes were available for typically developing males from the age of 2 years 6 months, but only from the age of 4 years for those with DMD. The data from the younger typically developing males are helpful for comparing the motor function of males with DMD with that of younger typically developing males, because we know that infants and young males with DMD achieve several motor milestones later than typically developing children. It is also of added value to know how the functional motor outcomes evolve in typically developing children. However, it might also be interesting to include young males with DMD starting from the age of 2 years 6 months in future studies. Another possible limitation is that the typically developing males were evaluated by master's students. Intensive face-to-face training was provided to each master's student before the assessment; moreover, each master's student was supervised by a neuromuscular expert physiotherapist during the evaluation. However, master's students might not have the same level of expertise as specialist neuromuscular physiotherapists. Finally, we did not consider other factors that might affect motor performance in young children (previous medical history, other illnesses, mutation type, environmental factors, cognitive impairment, etc.). However, the FOR-DMD eligibility criteria exclude males with previous significant medical history and severe learning difficulties; and no association between outcome measures and mutation types could be detected in this steroid-naïve population at baseline.³⁵

Despite the limitations, this study has demonstrated significant differences in motor function outcomes between a large cohort of young steroid-naïve males with DMD between 4 and 8 years old and typically developing males. This study is also the first to establish DMD-specific estimated reference curves for the TRF, 10 m walk/run time, 6MWD, and NSAA in a cohort of steroid-naïve males with DMD. The different estimated reference curves can show the functional motor performance of a young male with DMD in relation to typically developing males as well as within the heterogeneous group of males with DMD. These curves can support the consultation with families at the time of diagnosis. They can also aid in decision-making about time to treatment initiation based on assessment of baseline, pre-steroid functional motor performance compared with the expected motor performance in males with DMD. Moreover, the estimated curves can support the evaluation of treatment for reaching motor skills and functional motor outcomes compared with typically developing males.

CONFLICT OF INTEREST STATEMENT

The other authors declare no conflicts of interest.

FUNDING INFORMATION

Jasmine Hoskens has received a grant by Duchenne Parent Project, NL and the Stichting Marguerite-Marie Delacroix during the conduct of the study. Marianela Schiava has received a grant by Duchenne UK through Newcastle University. Katrijn Klingels has received a grant by Duchenne Parent Project, NL during the data-acquisition the study.