Motor and respiratory heterogeneity in Duchenne patients: Implication for clinical trials

doi:10.1016/j.ejpn.2011.07.001

European Journal of Paediatric Neurology

Volume 16, Issue 2, March 2012, Pages 149-160

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https://doi.org/10.1016/j.ejpn.2011.07.001 Get rights and content

Abstract

Aims

Our objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD).

Methods

The French dystrophinopathy database provided clinical, histochemical and molecular data of 278 DMD patients (mean longitudinal follow-up: 14.2 years). Diagnosis was based on mutation identification in the DMD gene. Three groups were defined according to the age at ambulation loss: before 8 years (group A); between 8 and 11 years (group B); between 11 and 16 years (group C).

Results

Motor and respiratory declines were statistically different between the three groups, as opposed to heart involvement. When acquired, running ability was lost at the mean age of 5.41 (group A), 7.11 (group B), 9.19 (group C) years; climbing stairs ability at 6.24 (group A), 7.99 (group B), 10,42 (group C) years, and ambulation at 7.10 (group A), 9.25 (group B), 12.01 (group C) years. Pulmonary growth stopped at 10.26 (group A), 12.45 (group B), 14.58 (group C) years. Then, forced vital capacity decreased at the rate of 8.83 (group A), 7.52 (group B), 6.03 (group C) percent per year. Phenotypic variability did not rely on specific mutational spectrum.

Conclusion

Beside the most common form of DMD (group B), we provide detailed description on two extreme clinical subgroups: a severe one (group A) characterized by early severe motor and respiratory decline and a milder subgroup (group C). Compared to group B or C, four to six times fewer patients from group A are needed to detect the same decrease in disease progression in a clinical trial.

Highlights

► We study the phenotypic heterogeneity in Duchenne muscular dystrophy. ► The French DMD database provides clinical and molecular data of 278 patients. ► A severe DMD group has early severe motor and respiratory (but not heart) decline. ► Phenotypic heterogeneity must be considered in the design of clinical trials. ► Same efficacy will be detected by 4 to 6 times fewer patients from severe DMD form.

Introduction

Duchenne Muscular Dystrophy (DMD; MIM#310200) is an inherited X-linked muscular dystrophy caused by mutations in the DMD gene (MIM#300377). The classical description of the disease includes progressive loss of muscle strength beginning between 3 and 5 years old, responsible for loss of ambulation between 9 and 10 years old, associated with dilated cardiomyopathy and respiratory failure in the second decade.¹

However, phenotype is not as stereotyped as often imagined.2, 3 Some patients lose ambulation during adolescence, which has led to the individualization of a milder motor phenotype in 1994 named ‘Intermediary Muscular Dystrophy’ (IMD).⁴ Moreover, a high degree of variability in restrictive respiratory insufficiency was noticed by Rideau et al.⁵ in 1981. However, no large-scale studies have been reported since then. Precise assessment of the DMD clinical heterogeneity becomes necessary as clinical trials are being planned now. This requires the survey of a large number of patients with a long follow-up.

Databases may help to achieve this objective. In the field of genetic diseases, new generation of locus-specific databases known as knowledge bases6, 7, 8 are recognized as an essential tool, thanks to their exhaustive and high quality data.⁹ The challenge is now to develop the clinical part of these databases, a crucial step to improve our knowledge about natural history of genetic diseases and phenotype-genotype correlations.

The UMD–DMD France knowledge base collects molecular and clinical data for patients with an identified mutation in the DMD gene at the national level. It currently contains 2 411 mutation records.¹⁰ The analysis of 311 clinical criteria describing the disease course for 347 of these DMD or IMD patients, with a mean longitudinal follow-up of more than 12 years, allowed us to better delineate the clinical heterogeneity of DMD, and in particular motor and respiratory involvement in 278 patients in whom age at loss of ambulation was known.

Section snippets

Patients

Currently, UMD–DMD France contains 2411 entries with molecular data corresponding to 2046 male patients and 38 expressing females. These molecular data have been collected through the network of the 14 molecular diagnostic laboratories in charge of the molecular testing of the DMD gene in France.¹⁰ Clinical data are in the course of collection through the network of the 11 French national reference centers for neuromuscular diseases. This step has been completed for 527 patients, of whom 332

Results

Clinical, histochemical and molecular data of the three groups of patients (total number of patients: 278) are described in Table 1, Table 2, Table 3, Supplementary Tables 1 and 2 and Supplementary Figures 1 and 2. The age at loss of ambulation was 7.10 ± 0.54 [min 5.25 – max 7.75] years in group A, 9.25 ± 0.81 [min 8.00 – max 10.92] years in group B, 12.01 ± 1.05 [min 11.00 – max 15.75] years in group C. The age at last follow-up was 15.51 ± 6.26 [min 7.5 – max 37] years in group A, 18.48 ± 6.67 [min

Motor function decline, orthopedic complications and respiratory insufficiency are correlated with the age at loss of ambulation

In our cohort, the non-acquisition of some motor abilities, the progressive loss of motor abilities, the severity of limb contractures and the occurrence of scoliosis are well correlated with the age at loss of ambulation. This is in agreement with the well-known facts that limb contractures progress in parallel with the increasing motor deficit and the loss of motor abilities,¹⁸ and that scoliosis appears to be most importantly related to the age at loss of ambulation.19, 20, 21 Our results

Conclusion

By analyzing a large cohort with exhaustive clinical data, prolonged longitudinal follow-up and genetically confirmed diagnosis, we observed that DMD phenotype is heterogeneous from the motor, respiratory and survival points of view. Three groups of patients emerged. The larger group has a common DMD presentation. A smaller group that we defined as “severe muscular dystrophy” has a worse clinical presentation, with loss of ambulation before 8 years and earlier and severe respiratory failure.

Acknowledgments

This work is supported by AFM (Association Française contre les Myopathies). VH and DH are the recipients of a grant from AFM. We thank the French network of molecular diagnostic laboratories: Leturcq F. and Chelly J. (Hôpital Cochin, Laboratoire de Biochimie et Génétique Moléculaire, Paris, F-75014, France); Ben Yaou R. (Hôpital Cochin, Laboratoire de Biochimie et Génétique Moléculaire, Paris, F-75014, France; Inserm, U974, Institut de Myologie, GH Pitié-Salpêtrière, Paris, F-75013, France);

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Citation Excerpt :
For example, FVC correlates with upper extremity muscle strength such that patients with upper extremity weakness have lower FVC levels.87 Moreover, Humbertclaude and colleagues86 showed that respiratory phenotypic severity can be predicted by age at loss of ambulation—ie, patients with the most impaired lung function over time also have loss of ambulation at the earliest age (the severe phenotype; appendix p 2). Cardiac phenotypes can be categorised by the age at onset of left ventricular dysfunction (LVD).
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^w: These two authors contributed equally to this work.

^x: Present address: CHU Robert Debré, Service de Neurologie Pédiatrique, Paris, F-75935, France.

^y: Present address: 27 rue Jean Macé, Grenoble, F-38000, France.

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Original articleMotor and respiratory heterogeneity in Duchenne patients: Implication for clinical trials

Abstract

Aims

Methods

Results

Conclusion

Highlights

Introduction

Section snippets

Patients

Results

Motor function decline, orthopedic complications and respiratory insufficiency are correlated with the age at loss of ambulation

Conclusion

Acknowledgments

Lancet

Pathol Biol (Paris)

Neuromuscul Disord

Eur J Paediatr Neurol

Am J Med

Arch Phys Med Rehabil

Resp Med

Neuromuscular Disord

Am Heart J

Eur J Paediatr Neurol

Eur J Paediatr Neurol

Clinical investigation in Duchenne dystrophy – 2. Determination of the power of therapeutic trials based on the natural history

Muscle Nerve

Clinical features

Diagnostic criteria for neuromuscular disorders

Respiratory function in the muscular dystrophies

Muscle Nerve

Time for a unified system of mutation description and reporting: a review of locus-specific mutation Databases

Genome Res

Locus-specific database domain and data content analysis: evolution and content maturation toward clinical use

Hum Mutat

The HUGO mutation database initiative

Pharmacogenomics J

Original article
Motor and respiratory heterogeneity in Duchenne patients: Implication for clinical trials