Development of a patient-reported outcome measure for upper limb function in Duchenne muscular dystrophy: DMD Upper Limb PROM.

AIM: To develop a patient-reported outcome measure (PROM) assessing upper limb function related to activities of daily living (ADL) that cannot be observed in a clinical setting, specifically for patients with Duchenne muscular dystrophy (DMD) across a wide age range, applicable in the different stages of the disease. METHOD: The developmental process was based on US Food and Drug Administration guidelines. This included item generation from a systematic review of existing tools and expert opinion on task difficulty and relevance, involving individuals with DMD. Cultural aspects affecting ADL were taken into consideration to make this tool applicable to the broad DMD community. Items were selected in relation to a conceptual framework reflecting disease progression covering the full range of upper limb function across different ADL domains. RESULTS: After pilot testing and iterative Rasch analyses, redundant or clinically irrelevant items were removed. The final questionnaire consists of 32 items covering four domains of ADL (food, self-care, household and environment, leisure and communication). Test-retest reliability was excellent. INTERPRETATION: A DMD-specific upper limb PROM was developed on the basis of clinical relevance and psychometric robustness. Its main purpose is to document the patient self-reported natural history of DMD and assess the efficacy of interventions.

Frequency and Phenotype of Myotubular Myopathy Amongst Danish Patients with Congenital Myopathy Older than 5 Years.

BACKGROUND: Centronuclear myopathy (CNM) is one of four main subtypes of congenital myopathy. X-linked myotubular myopathy (XLMTM) is considered one of the most severe forms, but survivors past infancy have been described. However, detailed information on XLMTM phenotypes in patients who survive infancy is scarce. OBJECTIVE: The aim of the study was to report the genetic findings in patients with a predominant centronuclear finding on muscle biopsy and describe the prevalence, phenotypes and the course of the disease in patients with XLMTM in a Danish cohort of patients with congenital myopathies older than five years. METHODS: Ninety-four out of 119 invited patients older than five years were included in the study and assessed by muscle tests, functional tests, muscle biopsy, plasma creatine kinase levels and genetic testing. Genes related to CNM were sequenced in patients who had centronuclear findings on muscle histology. In patients with MTM1 mutations, medical records from local hospitals were reviewed to obtain information on birth history and course of disease. RESULTS: Sixteen of 94 patients had CNM on muscle biopsy; three male patients, aged 14-25 years, carried a pathogenic MTM1 mutation, six patients carried a pathogenic DNM2 mutation and two carried pathogenic RYR1 mutations. The mutations have all been described before to cause CNM. The MTM phenotypes ranged from severe (classical) to mild; one patient had always been non-ambulant, one had lost ambulation, and one was still ambulant at 25 years. CONCLUSIONS: Our findings show that CNM caused by DNM2 mutations is the most common form of CNM in Danish patients older than 5 years, but XLMTM is not negligible even past age 5 years, and the phenotype may be much milder than generally described - also in patients with the classically described infantile form of the disease.

Change in muscle strength over time in spinal muscular atrophy types II and III. A long-term follow-up study.

Whether muscle strength deteriorates with time in spinal muscular atrophy (SMA) types II and III is still debated. We present a long-term follow-up study on muscle strength in 30 patients with SMA types II and III. Median follow-up time was 17 years. Median number of assessments was four. All patients were assessed by Manual Muscle Testing (MMT), Brooke upper limb scale and EK scale. There was a difference in muscle strength of the upper limbs from first to last assessment in SMA II (p<0.0001) and SMA III patients (p<0.02). In SMA II patients, the rate of yearly decline in strength (% MRC score) was 0.22 units (p<0.03). The decline was independent of the grade of muscle strength at entry. In SMA II patients the decline in muscle strength was reflected in a loss upper limb function as measured by Brooke upper limb scale (p<0.0001) and motor function as measured by EK scale (p<0.0001), a loss of great importance to the patients' need for practical assistance. This study demonstrates loss of muscle strength over time in SMA II and III patients. Because of the very slow deterioration, it takes years to detect this change, which has to be taken into account in future treatment trials.

Physical characteristics and applicability of standard assessment methods in a total population of spinal muscular atrophy type II patients.

The aims of this study were to evaluate muscle strength, functional abilities, contractures and Forced Vital Capacity in a population of 54 spinal muscular atrophy (SMA) type II patients between the ages of 5 and 70, and to evaluate the applicability of conventional assessment methods. The patients were evaluated by means of functional scales, muscles tests, joint motion measurement and Forced Vital Capacity test. There was a significant score difference in functional tests and muscle tests as well as in the sum of contractures between younger individuals (or= 21years). The functional scales were not sensitive enough to differentiate among the most impaired persons. A reduced Manual Muscle Test score of the upper limbs was found to differentiate more precisely among individuals than a total score derived from testing 38 muscle groups. There is a need for clinical tools that can evaluate patients with SMA type II of all ages and with severely reduced functional abilities.

Longitudinal data analysis: an application to construction of a natural history profile of Duchenne muscular dystrophy.

A 30-month prospective study of 27 Scandinavian boys with confirmed diagnosis of Duchenne muscular dystrophy was carried out to construct profiles of the natural history of the disease. Assessments which included measures of voluntary muscle strength and function were done at 3 monthly intervals except for the first and second which were separated by 1 month. Recently developed statistical methods for analysis of longitudinal data with repeated observations on the same individual were used avoiding the problem of induced serial correlations. This allowed for the construction of both reference and prediction profiles for the variables %MRC, motor ability, walking time for 10 m and the sum of myometry of seven muscle groups.

A randomized comparative study of two methods for controlling Tendo Achilles contracture in Duchenne muscular dystrophy.

A 30-month prospective randomized study of 27 Scandinavian boys with confirmed diagnosis of Duchenne muscular dystrophy was done to compare the effect of passive stretching combined with the use of night splints (group A) or passive stretching (group B) on the evolution of Tendo Achilles contractures. Assessments were based on the methodology of Scott et al. (Muscle Nerve 1982;5:291-301)Analysis of the pattern and mechanism of dropout was done to eliminate bias between the two groups. Logistic regression showed that Tendo Achilles contracture was the most important variable (P=0.0020) for dropout. Methods of statistical analysis for longitudinal data avoiding induced serial correlations were used in the analysis. The expected annual change in Tendo Achilles contracture was found to be 23% less in group A than in group B after equalization for total muscle strength (%MRC).