Duchenne muscular dystrophy (DMD) is a severe, progressive disease that aff ects 1 in 3600–6000 live male births. Although guidelines are available for various aspects of DMD, comprehensive clinical care recommendations do not exist. The US Centers for Disease Control and Prevention selected 84 clinicians to develop care recommendations using the RAND Corporation–University of California Los Angeles Appropriateness Method. The DMD Care Considerations Working Group evaluated assessments and interventions used in the management of diagnostics, gastroenterology and nutrition, rehabilitation, and neuromuscular, psychosocial, cardiovascular, respiratory, orthopaedic, and surgical aspects of DMD. These recommendations, presented in two parts, are intended for the wide range of practitioners who care for individuals with DMD. They provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care. In part 1 of this Review, we describe the methods used to generate the recommendations, and the overall perspective on care, pharmacological treatment, and psychosocial management.

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Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management

http://sdevoto.web.wesleyan.edu/343/readings/emery2002.pdf

The muscular dystrophies.

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and α-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.

Function and genetics of dystrophin and dystrophin-related proteins in muscle

Optimum management of Duchenne muscular dystrophy (DMD) requires a multidisciplinary approach that focuses on anticipatory and preventive measures as well as active interventions to address the primary and secondary aspects of the disorder. Implementing comprehensive management strategies can favourably alter the natural history of the disease and improve function, quality of life, and longevity. Standardised care can also facilitate planning for multicentre trials and help with the identification of areas in which care can be improved. Here, we present a comprehensive set of DMD care recommendations for management of rehabilitation, orthopaedic, respiratory, cardiovascular, gastroenterology/nutrition, and pain issues, as well as general surgical and emergency-room precautions. Together with part 1 of this Review, which focuses on diagnosis, pharmacological treatment, and psychosocial care, these recommendations allow diagnosis and management to occur in a coordinated multidisciplinary fashion.

/pdf/diagnosis-and-management-of-duchenne-muscular-dystrophy-part-1wbd89m4hv.pdf

Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care

Summary A large and complex gene on the X chromosome encodes dystrophin. Many mutations have been described in this gene, most of which affect the expression of the muscle isoform, the best-known protein product of this locus. These mutations result in the Duchenne and Becker muscular dystrophies (DMD and BMD). However, there are several other tissue specific isoforms of dystrophin, some exclusively or predominantly expressed in the brain or the retina. Mutations affecting the correct expression of these tissue-specific isoforms have been associated with the CNS involvement common in DMD. Rare mutations also account for the allelic disorder X-linked dilated cardiomyopathy, in which dystrophin expression or function is affected mostly or exclusively in the heart. Genotype definition of the dystrophin gene in patients with dystrophinopathies has taught us much about functionally important domains of the protein itself and has provided insights into several regulatory mechanisms governing the gene expression profile. Here, we focus on current understanding of the genotype–phenotype relation for mutations in the dystrophin gene and their implications for gene functions.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(03)00585-4.pdf

Dystrophin and mutations: one gene, several proteins, multiple phenotypes

One hundred and sixty-two patients with Duchenne muscular dystrophy (DMD) were followed over a 10-yr period to provide a profile of impairment and disability. The median height and weight of DMD boys were normally distributed before ages 9-10, but during the second decade height was markedly reduced, and weight was no longer normally distributed. Younger boys gained more weight than normals, whereas older individuals actually showed weight loss. Manual muscle test (MMT) measurements showed loss of strength in a fairly linear fashion from ages 5-13 yr, -0.25 MMT units per year. Upper extremity muscles were stronger than lower extremity muscles, proximal muscle groups were weaker than distal muscle groups, and extensor muscles were weaker than flexor muscles. There was no side dominance. There was a change in the rate of strength loss at 14-15 yr, and the decline slowed to only -0.06 MMT units per year. Although MMT and quantitative strength measurement profiles were similar, the latter were far more sensitive. In general, by the time strength declined to MMT grade 4, isometrically measured strength was 40-50% of normal control values. Joint contractures were rare before age 9, increased in frequency and severity with age, and were present in most individuals older than 13. Lower extremity contractures were strongly related to onset of wheelchair reliance, but there was no association between muscle imbalance around a joint. The prevalence of scoliosis increased between ages 11 and 16, with about 50% of the boys acquiring scoliosis between ages 12 and 15, corresponding to the onset of the adolescent growth spurt. Wheelchair reliance and scoliosis were both age-related. Percent predicted forced vital capacity declined at different yearly rates: ages 7-10, -0.3%; ages 10-20, -8.5%; after age 20, -6.2%. There was a direct relationship between percent predicted FVC and MMT scores. Decreased airway pressures, especially maximal expiratory pressure, appeared earlier than reductions in FVC but followed the same pattern. Thirty percent of the DMD boys had a history of respiratory complications, and the frequency increased with age. Spine deformity did not have a significant additive effect on the age-related decrement in pulmonary function. There was a high occurrence (79%) of abnormal electrocardiograms with age-related progression of some abnormalities, but only 30% of the patients had a history of cardiovascular complications. Functional level grades and timed motor performance measurements had a nonlinear relationship with strength and age.(ABSTRACT TRUNCATED AT 400 WORDS)

Profiles of neuromuscular diseases. Duchenne muscular dystrophy.

Ninety-two individuals with myotonic dystrophy (MD) were evaluated prospectively over a 10-yr period and separated into two types, 75 noncongenital (NC-MD) and 17 congenital (C-MD) MD. Muscle weakness was relatively mild and similar in both types, 4.0 +/- 0.7 manual muscle test (MMT) scores for NC-MD and 3.8 +/- 0.7 in C-MD. However, weakness was progressive in the former, -0.36 MMT units per decade, and nonprogressive in C-MD. Weakness was usually generalized in both types, with no significant differences between upper and lower extremities or the proximal and distal muscles. Flexor and extensor differences were variable. Quantitative strength measurements showed a similar pattern but were more sensitive showing marked strength losses of 40-50% in muscle groups with MMT scores of four or more. There was a high frequency (47%) of relatively mild, nonprogressive scoliosis in C-MD, whereas spine deformity was unusual in NC-MD. Contractures, usually at the ankles, were also more common in C-MD. In NC-MD and C-MD, respectively, there was a low frequency of severe restrictive lung disease (14 and 20%) but a high percentage of significant electrocardiographic (ECG) abnormalities (75 and 81%), including conduction defects. There was a marked difference between the two types of MD in intellectual and cognitive function. Seventy-five percent of C-MD subjects showed impairment, frequently severe, compared with 35% impairment, usually mild, for NC-MD individuals. Functional evaluation was not markedly affected, but timed motor performance showed significant disability especially for individuals with C-MD.

B. J. Sigford

Papers

Profiles of neuromuscular diseases. Duchenne muscular dystrophy.

Profiles of neuromuscular diseases. Myotonic dystrophy.