Muscular Dystrophy

(Zohair Ali Nanjiani MD)

Summary

Progressive hereditary muscle diseases, generally due to abnormality of structural proteins, are called muscular dystrophies. They may be classified according to the pattern of inheritance, muscle distribution, age of presentation, structural or biochemical defect, histopathological changes or neurophysiological abnormalities. Multisystem symptoms are frequent and cardiac and smooth muscles may also be involved. Most muscular dystrophies are, as yet, incurable; the pitfall, however, is to confuse the words ‘cure’ and ‘treatment’. Treatment modalities, primarily directed towards maintenance of strength and function and prevention of secondary complications, are essential. It is crucial, as much as possible, to maintain the patient’s independence, sense of well-being and social inclusiveness and to decelerate the rate of progression with the hope that the patient may stay well enough to benefit from therapeutic strategies emerging in the future. Gene therapies hold promise but remain consistently elusive.

Definition

Muscular dystrophies are genetic and hereditary disorders characterized by progressive muscle weakness and non-inflammatory, myopathic changes evident on muscle histopathology. The cause in most cases is an absence, decrease or abnormality of an essential structural or functional protein component of the muscle.

Genetics

Muscular dystrophy inheritance patterns can be autosomal-dominant (AD), autosomal-recessive (AR) or X-linked. In order to make clinical classification facile, muscular dystrophies having the classical proximal weakness phenotype with or without distal weakness are classified according to the inheritance pattern as follows

a) Limb-Girdle Muscular Dystrophy Type 1 (LGMD1) – AD
b) Limb-Girdle Muscular Dystrophy Type 2 (LGMD2) – AR
c) X-linked e.g. dystrophinopathies
d) Other e.g. mitochondrial myopathies

Presenting features (signs and symptoms)

Neonatal symptoms of significant severity are more characteristic of congenital myopathies (central core, nemaline, congenital md, severe myotonic md) and include severe hypotonia, arthrogryposis, respiratory distress, high arched palate and C02 retention.

Most well-known muscular dystrophies are of subtler onset, however, and progress slowly over decades, have variable severity and some, though being inherited, may not have physical manifestations till well into adulthood. A somewhat chronological presentation of signs and symptoms include

- Hypotonia
- Muscle hypertrophy/pseudohypertrophy (bulky muscle replaced by fat tissue, mostly calf muscles)
- Delayed walking
- Toe-walking (early dynamic Achilles contractures)
- Difficulty running
- Frequent falls
- Waddling gait
- Difficulty climbing stairs, getting up from the floor (Gower’s sign)
- Prominent lumbar lordosis
- Muscle cramps and pain (especially calves)
- Mental retardation
- Progressive muscle wasting and contractures
- Loss of ambulation
- Sleep hypopnea (disturbed sleep, snoring and daytime fatigue)
- Respiratory difficulties (restrictive lung disease)
- Hypophonia, nasal voice, weak cough and possible ptosis
- Kyphoscoliosis
- Cardiac failure due to cardiomyopathy and/or arrhythmias
- Difficulty controlling oropharyngeal secretions and feeding difficulties
- Death due to respiratory failure

Types

Although there are more than a hundred or more diseases with characteristic features consistent with muscular dystrophy, the following nine disease types are the more putative ones classified as such

1) Duchenne muscular dystrophy
2) Becker muscular dystrophy
3) Limb-girdle muscular dystrophy (itself further sub-classified into several types)
4) Congenital muscular dystrophy
5) Fascioscapulohumeral muscular dystrophy
6) Myotonic muscular dystrophy
7) Oculopharyngeal muscular dystrophy
8) Distal myopathies
9) Emery-Dreifuss muscular dystrophy

Most muscular dystrophies are multi-system disorders with involvement of the brain, cardiac muscle and smoth muscle resulting in manifestations in body systems including the heart, gastrointestinal and nervous systems, endocrine glands, skin, eyes and other organs.

Diagnosis

Meticulous clinical history and physical examination are the primary means of narrowing the differential diagnoses initially. Signs and symptoms have been described earlier. When phenotype does not show predominantly proximal muscle involvement, prominent neck flexor weakness in supine position and scapular winging and lumbar lordosis , when present, are almost always characteristic of a myopathic process. Pseudohypertrophy (build up of fat and connective tissue that makes the muscle appear larger) is also typical of some pediatric-onset muscular dystrophies.

Further aiding the clinical diagnosis are the pattern of distribution of weakness (e.g limb-girdle, OPMD, FSHMD, distal myopathies), age of onset, myotonia, early contractures (e.g. EDMD) and accompanying signs of multisystemic involvement.

The initial laboratory test a clinician obtains is a serum creatine-phosphokinase (CPK) level that is usually significantly higher than normal but can, at times, be normal or only slightly elevated in late-onset muscular dystrophies and in those with limited and focal muscle involvement. A nerve conduction study and an electromyogram (NCS-EMG) are neurophysiological tests that further help differentiate between neuropathic and myopathic processes. In certain myopathies e.g. OPMD and inclusion body myositis, a mild neuropathy on NCS and/or signs of muscle denervation on EMG can be observed.

Blood sample genetic testing for most well-known and common types of muscular dystrophies is available in the west. Patients who are diagnosed through these are generally spared the need for a muscle biopsy. A muscle biopsy, when done appropriately with the clinician guiding muscle selection, helps diagnose a dystrophic process but further diagnosis of the specific type of dystrophy require immunostaining and Western (immuno) blot testing.

Unfortunately, except for dystrophin, most immunostains are not widely available except at specialized tertiary laboratories in the west. It is imperative that needless, invasive testing, that may not even provide conclusive results, not be done as a matter of routine in all, especially pediatric, patients. At times, if definitive tests are not available, a clinical history and exam and an unequivocally high cpk level may suffice to diagnose a dystrophic process. However, if resources do permit, use of international laboratories should be encouraged in order to confirm the specific type of muscular dystrophy. Even if a particular muscular dystrophy is yet untreatable, the knowledge allows the patient, parents and the clinician alike to keep abreast of the research and therapeutic advances occurring in the west for that particular dystrophy allowing the probability of instituting treatment soon after it becomes available somewhere.

Prognosis

The prognosis for people with muscular dystrophy varies according to the type and progression of the disorder. Some cases may be mild and progress very slowly over a normal lifespan (e.g. distal myopathies, Becker’s) while others produce severe muscle weakness, functional disability, loss of the ability to walk and early death due to respiratory failure (e.g. Duchenne). Some children with muscular dystrophy die in infancy while others live into adulthood with only moderate disability.

Treatment

There is no known cure yet for muscular dystrophy. The course can be variable but relentlessly progressive, nevertheless. Long-term high-dose (0.75mg/kg/day of body weight) steroid therapy is now officially recommended by the American Academy of Neurology for children with duchenne muscular dystrophy to retard the inflammatory process and has been shown to prolong ambulation by as much as three years. Continuation of walking also serves to protect against complications that result from loss of walking and inactivity namely muscle contractures, restrictive lung disease, bedsores and depression. Furthermore, the emphasis is on keeping the patient walking and relatively in good functional health so s/he can potentially benefit from future possibly curative therapies were they to become available soon enough. Extensive research is & has been occurring for multifaceted interventional therapy in the west comprising drug trials, pharmacogenomics, stem-cell therapy, myoblast transfer and exon-skipping strategies for point mutation defects but a cure still remains elusive.

Specific temporizing and symptomatic interventions specific for various muscular dystrophies include initial ACE inhibitor use for cardiomyopathy followed by, if required, cardiac transplant in Becker’s and Emery-Dreifuss type 2. Arrhythmias in edmd and myotonic dystrophy may require pacemaker placement. Myotonia itself may be treated somewhat with medications such as quinine, phenytoin or mexiletine.

Restrictive lung disease in many muscular dystrophies presents as fitful and restless speech, sleep apnea and daytime fatigue. Pulmonary function tests and, if indicated, sleep studies help assess the severity and need for respiratory assistive devices. Significant sleep hypopneas and apneas merit the use of a non-invasive bipap (bi-level positive airway pressure) device along with chest percussion and cough assisting devices. If decreased lung capacity is the result of kyphoscoliosis, corrective spinal fusion surgery may be indicated (Note: since muscular dystrophies can often be associated fatal malignant hyperthermia triggered by neuromuscular blocking anaesthetic agents, these should be prohibited in case of muscular dystrophy patients and special precautions e.g. availability of dantrolene and hyperthermia remedial measures, should be taken. Further progression of respiratory insufficiency requires more invasive measures such as a tracheostomy and portable ventilation.

The mainstay of muscular dystrophy ‘treatment’ comprises of rehabilitative and nutritional measures. Low-intensity physical therapy in order to maintain independence with ADL’s (activities of daily living) and quality of life, maintain joint flexibility, muscle tone and to prevent joint contractures and deformities such as scoliosis, is essential throughout the course of the disease. Hydrotherapy/aquatic therapy can be exceedingly beneficial as water provides buoyancy as well as resistance. The former helps a weak patient stand in the pool and possibly take steps maintaining function and improving his overall sense of wellbeing somewhat. The latter helps strengthen muscles in a low-impact, non-jarring fashion. (Note: high-intensity, isometric, weight-training exercises are strictly NOT RECOMMENDED for muscular dystrophy patients as they do not have the capacity to overcome the wear and tear induced by such. Any exercise involving ‘eccentric’ muscle contraction (stretching of an already contracted muscle by manual resistance or weight loading) is unequivocally prohibited.

As the functional strength, gross and fine motor control and independence in daily tasks diminish, the services of an occupational therapist may become essential in helping the patient be as self-sufficient as possible. At various stages of the disease, the muscular dystrophy patient may need orthotics (to prevent joint contractures), canes, walkers, standing frames, wheelchairs or motorized scooters, air mattress (to prevent bedsores), custom-made or modified utensils, aids for writing, turning book pages or for computer use as well as toilet and shower modifications and safety devices as well as accessibility needs such as ramps, chairlifts and car/van modifications.

Lastly, the importance of adequate and balanced nutrition in muscular dystrophy cannot be understated. It is crucial that the patient maintain muscle mass but not gain weight in the form of fat that can further hamper mobility. A dietitian can recommend a balanced diet high in protein with adequate water intake to prevent protein load on the kidneys in addition to the muscle breakdown products already present. For those on steroids and/or those who have lost ambulation, frequent weight measurements are necessary and excessive weight gain needs to be prevented by cutting down calories. A stage may also come where the patient’s calorie intake may drop as a result of loss of self-feeding ability due to upper extremity weakness or inability to swallow. An astute dietitian anticipating this can liberalize the diet to prevent muscle and weight loss in such cases. Eventually, parenteral nutrition may become a necessity and a gastrostomy tube (‘PEG’) may need to be placed.

It is important to consider that muscular dystrophy is a dynamic process causing significant pathophysiological changes to the patient’s body that need to be anticipated, prevented and remedied in order to provide him with the best possible quality of life and chance of survival and possible benefit from emerging therapies. A clinician’s involvement, therefore, does not end at the time of giving the family the dire diagnosis but actually truly begins at that stage and requires ensuring that the affected individual has the best chance of living a comfortable, complication-free life.