Duchenne muscular dystrophy

Introduction

Duchenne muscular dystrophy or Pseudohypertrophic muscular dystrophy or Muscular dystrophy- Duchenne type is an X-linked neuromuscular disorder of muscle caused by an absence of the protein dystrophin. DMD was named in recognition of Dr. G. Duchenne de Boulogne from France around 150 years ago. He was the first person to attribute the signs and symptoms to a distinct familial disease entity. The gene responsible for it is DMD gene which is known to be the largest gene encoding the muscle protein, dystrophin the discovery of this gene was made around 20 years ago. Dystrophin provides structural stability to the dystroglycan complex (DGC) present on the cell membrane as it attaches with the inner surface of the muscle fiber membrane. A mutation in the DMD gene residing in Xp21 region of the X-chromosome, hampers the production of dystrophin protein causing progressive loss of muscle function and weakness (Partridge, 2007). It starts with the lower limbs and gradually covers the entire musculature. DMD is rapidly progressing form of muscular dystrophy affecting male with a frequency of 1 in 3500 infants. It is observed that the affected boys start manifesting symptoms of disease early in life usually before 5 years of age. They become powerless and are unable to walk and are restricted to wheel chair during their late childhood or early teen years. Patients usually develop various complications related with respiratory insufficiency and/ or cardiomyopathy as the disease progresses. Death occurs at by late teen age or in the early twenties. It is essential to provide appropriate treatment to overcome the basic genetic defect, either through medical, surgical, and rehabilitative approaches to make the patient comfortable.  

Symptoms

Before the age of 6 years symptoms start becoming obvious, although they are visible in early infancy. There are three clinical stages: an ambulatory stage, an early nonambulatory stage, and a late nonambulatory stage.

Ambulatory Stage- This is between two and four years of age, at this stage, symptoms start appearing. Symptoms show weakness of forward head flexion and a inadequate capability to sit up persist beyond infancy leading to poor motor development, deficient memory skills and they gradually reduce their ability to cope with their peers both physically and mentally. Heel cord and elbow flexion contractures are also apparent. In rare cases, obstructive sleep apnea also develops along with facial soiling. The ECG readings show- Q waves leads in the lateral precordial while tall R and deep S waves leads in early precordial. If glucocorticoids are not given then by the age of nine years, the child starts lacking ability to rise from supine to standing position and to climb stairs or arise from a chair and are able to ambulate with braces.

Early Nonambulatory Stage- This stage is between 10 and 12 years, the patient becomes dependent on wheel chair and flexion contractures at the ankle and elbow becomes more obvious. In this stage aquatic therapy may slow the progression. The dependency on wheel chair develops scoliosis and the patient needs orthopedic consultation along with radiological evaluation. The average strength of the patient starts declining at the age of 9 years.

Late Nonambulatory Stage- a wheelchair to bed life style is observed in the patients. At this stage other serious conditions are also prevalent encompassing respiratory insufficiency/ failure, cardiac problems, scoliosis. Respiratory insufficiency is observed in the patients belonging to the age group of 11- 20 years and is not receiving corticosteroid therapy. The forced vital capacity is reduced to > 60% of normal. This decrease paves the way for pneumonia, decreased power of coughing, reduced effective night-time ventilation during sleep and hence reducing the survival rate of the patient. Cardiomyopathy- ECG abnormalities worsen further leading to atrial arrhythmias of varying degrees. Resting tachycardia becomes more prevalent all through the stage causing autonomic dysfunction of left ventricle. Gastrointestinal dysfunction- the esophageal and gastrointestinal complaints involve voluntary and involuntary muscles causing delayed gastric emptying, acute gastric dilatation cause risk of respiratory insufficiency. Further, chronic intestinal dysfunction occurs, with constipation, distention, hypomobility, impaction, hypokalemia and insufficient fluid intake obstruct ventilation and diaphragmatic movement during sleep.

Pathogenesis

Duchenne muscular dystrophy is caused by a mutation of the dystrophin gene at  Xp21. Dystrophin is responsible for the connection of muscle fibers to the extracellular matrix through a protein complex containing many subunits. The absence of dystrophin permits excess calcium to penetrate the cell membrane/ sarcolemma. In a complex cascading process that involves several pathways and is not clearly understood, increased oxidative stress within the cell damages the sarcolemma and eventually results in the death of the cell. Muscle fibers undergo necrosis and are ultimately replaced with adipose and connective tissue.

Treatment

It is manifested that corticosteroids (prednisone and deflazacort) show a remarkable delay in fetching the loss of muscle strength and function in boys with DMD (Sussman, 2002). It is manifested that surgical release of lower extremity contractures provides benefit and relief to some patients. It is also observed that around 90% of DMD individuals develop severe scoliosis, and this is not agreeable to control by nonsurgical means such as bracing or adaptive seating. The most successful cure for severe scoliosis is to prevent it with early spinal fusion using segmental instrumentation immediately when curves are determined and before any kind of severe pulmonary or cardiac dysfunction occurs. Approaches related to gene therapy to procure the functions of missing gene/ protein is on the way. Recent stem-cell research is showing promising vectors that may replace damaged muscle tissue. Treatment is generally aimed at controlling the onset of symptoms to maximize the quality of life. Utrophin up regulation is found to compensate for muscle cells lacking dystrophin expression .

Anesthesia in DMD

 It is observed that patients with DMD show respiratory insufficiency at the late stage and respiratory failure causes bronchopneumonia; this becomes the leading cause of death of the patient also, cardiac abnormalities are observed in majority of the cases. It is apparent that DMD patients undergo orthopedic procedures of lower limb therefore anesthesia becomes another hazard for the patient and combination of obesity and spinal deformity creates lumber spinal and extradural anesthesia technically challenging. The sacral canal is less affected and in young children caudal extradural blockade may be the technique of choice. In cases where GA is unavoidable then the pulmonary and cardiac status of the patient becomes imperative. Anesthesia may induce sudden cardiac arrest. It is also manifested that there could be mild elevation in temperature in patients with DMD undergoing anesthesia. It is evident that neuromuscular functions must be monitored (Lane, 1996).