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DYSTROPHINOPATHIES
Different mutations in the dystrophin gene produce different allelic disorders, most commonly the lethal Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), a milder myopathy. Rarely exercise intolerance associated with myalgias, muscle cramps, or myoglobinuria; quadriceps myopathy; cardiomyopathy with mild muscle weakness; dilated cardiomyopathy without muscle weakness; and asymptomatic elevation of serum creatine kinase (CK) have also been identified (Siddique et al., 1999 and Barohn, 2000).
The different dystrophin phenotypes are determined by the site of the mutation in the dystrophin gene and the effect or lack of the effect of the mutation on the expression of the cardiac isoform of dystrophin (Barohn, 2000).
Dystrophin gene is a large genetic locus including over 2.5 million base pairs of a human X-chromosome. This gene is approximately 10 times larger than the next largest identified gene. It encodes 79 exons of coding sequence. The large size of the gene is believed to be the cause of the high mutation rate (Nelson, 2000).
The molecular defects in the dystrophinopathies are of various types : intragenic deletions, duplications, or point mutations of nucleotides. About 65% of patients have deletions, and only 7% exhibit duplications. The site or size of the intragenic abnormality does not always correlate well with the phenotypic severity; in both Duchenne and Becker forms, the mutations are mainly near the middle of the gene, involving deletions of exons 46 – 51 (Sarnat, 2000).
A427 Kd cytoskeletal protein known as dystrophin is encoded by the gene at the Xp21 locus. This subsarcolemmal protein attaches to the sarcolemmal membrane overlying the A band and M band of the myofibrils and consists of four distinct regions or domains (Sarnat, 2000). It has an I-beam shape with globular domains at each end and a rod-like segment in the middle. At the amino-terminal end, it binds to cytoplasmic actin filaments, whereas at the other end, it binds to a complex proteins and glycoproteins called dystrophin-associated proteins and dystrophin-associated glycoproteins (Siddique et al., 1999). These include two that span the membrane (the dystroglycans), at least five within the membrane (the sarcoglycans), and a submembrane protein (utrophin) (Brown, 1997). Dystrophin mRNA normally is detected in cardiac and smooth muscle as well as in skeletal muscle and brain (Sarnat, 2000).
Dystrophin and the associated proteins are believed to play an important role in membrane stability and maintenance during muscle contraction and relaxation (Betto et al., 1999).
Dystrophin deficiency weakens the sarcolemma, permitting the influx of calcium-rich extracellular fluid, which then activates intracellular proteases and complement, leading to fiber necrosis (Barohn, 2000). Absence of dystrophin leads to a secondary reduction in several dystrophin-associated glycoproteins in the sarcolemma which results in loss of linkage to the extracellular matrix and renders the sarcolemma even more susceptible to necrosis (Sarnat, 2000).
Mutations disrupting the translational reading frame of the gene result in near-total loss of dystrophin (Duchenne muscular dystrophy), whereas in-frame mutations result in the translation of semifunctional dystrophin of abnormal size or amount (Becker muscular dystrophy) (Griggs, 2001).
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease of muscle caused by an absence of the protein dystrophin (Sussman, 2002). DMD has an incidence of 1 in 3500 live male births with a prevalence approximately 3 per 100,000 live males. Approximately one-third of DMD cases are thought to occur secondary to a spontaneous mutation (Nelson, 2000).
The absence or severe abnormality of the protein dystrophin is the cause of DMD. This is due to abnormality on the short arm of the X chromosome at the Xp21 locus (Munsat, 1988). Because of gene deletions (55 – 65% of cases), duplications (5 – 10% of cases), or point mutation (30 – 40%) (Miller and Hoffman, 1994), dystrophin and its associated sarcolemmal glycoproteins are absent in the skeletal muscle fibers of DMD patients.
Abnormal expression of the cytoskeletal protein dystrophin has deleterious consequences for skeletal muscle, cardiac muscle, and the central nervous system. A complete failure to express the protein produces DMD, in which there is extensive and progressive skeletal muscle necrosis, the development of a life-threatening dilated cardiomyopathy and mild mental retardation (Carlson, 1998).
CLINICAL FEATURES
The hallmarks of DMD are progressive proximal muscle weakness with pseudohypertrophy of the calves. The myocardium is involved, whereas bulbar muscles are spared. There may be mild mental retardation. DMD is universally fatal, usually either from respiratory or cardiac complications (Siddique et al., 1999).
DMD typically becomes clinically evident at approximately 3 to 5 years of age. The weakness is generally symmetrical. It begins in the pelvic and then the shoulder girdle muscles and finally progresses to the respiratory and distal limb muscles (Nelson, 2000).
As the lower limb weakness progresses, the gait becomes more and more waddling and the abdomen protuberant because of increasing lumbar lordosis. Climbing stairs is difficult and the child rises from the floor in a characteristic fashion (Gower’s manoeuver) – first turning prone and then placing his hands on his knees and thighs to push himself erect. Symptomatic shoulder girdle weakness develops within 2 – 3 years but is evident on examination much earlier. Ambulation is lost at about 10 years of age (Hilton – Jones, 2001).
Proximal muscles continue to be more severely affected than distal muscles, with neck flexors becoming more involved than extensors, wrist extensors more than flexors, biceps and triceps more than deltoid, quadriceps more than hamstrings, and the tibialis anterior and peroni more than the gastrocnemius and soleus. Tendon reflexes decrease and disappear as muscle weakness progresses (Siddique et al., 1999).
Enlargement of the calves (pseudohypertrophy) and wasting of thigh muscles is a classic feature. The enlargement is due to hypertrophy of some muscle fibers, infiltration of muscle by fat, and proliferation of collagen (Sarnat, 2000).
Significant contractures of the iliotibial bands, hip flexors, and heel cords are present in 70% of the children by the age of 10 years (Siddique et al., 1999).
Scoliosis occurs in approximately 90% of DMD boys (Sussman, 2002). In a study of untreated scoliosis in DMD, the curves progressed to severe deformity (Smith et al., 1989). The progression of scoliosis causes problems in several areas, including skin ulceration, back pain, decreased sitting balance, possible limitations on cardiopulmonary reserve, cosmotic difficulties, wheelchair seating problems, and limitations of the variety of assisted ventilation techniques that can be used (Nelson, 2000).
Respiratory muscle weakness develops early (as shown by forced vital capacity measurement) and respiratory function is later further compromised by the spinal deformity. The cough becomes weak, leading to aspiration and increased risk of chest infection (Hilton – Jones, 2001).
Cardiac muscle is also affected, and although patients are generally asymptomatic, congestive heart failure and arrhythmias can occur late in the disease. Up to 90% of DMD patients have an abnormal ECG with tall right precordial R waves and deep left precordial Q waves. Echocardiography shows either hypokinesis or dilatation of ventricular walls (Barohn, 2000).
The smooth muscle of the gastrointestinal tract is also involved, commonly causing esophageal and intestinal hypomotility, symptoms of reflux, and constipation (Leon et al., 1986 and Jaffe et al., 1990).
Intelligence is affected by DMD, although the exact cause of this is unknown. Twenty-five percent of boys with DMD have intelligence quotients (IQ) lower than 75, which is not a progressive loss (Munsat, 1988). Bardoni et al. (2000) suggested that impairment of cognitive abilities in DMD might be related to a dysfunction of Dp140 brain dystrophin isoform.
Patients with DMD and other myopathies have been reported as having malignant hyperthermia as an adverse response to general anesthesia. This is manifested by tachycardia, cardiac arrhythmia, tachypnea, unstable blood pressure, cyanosis, fever, and possibly convulsions. Seventy-five percent of the patients develop rigidity secondary to severe muscle contractures, frequently in the masseter muscles, with metabolic acidosis as a consequence. Myoglobinuria and renal failure can result with a mortality of 60% (Nelson, 2000).
INVESTIGATIONS
1] Biochemical investigations :
Creatine kinase (CK) occurs in high concentration in the sarcoplasm of skeletal and cardiac muscle. The MM isoenzyme of CK predominates in skeletal muscle, MB occurs primarily in cardiac muscle, and BB is mainly in brain. When skeletal muscle is injured, CK can leak into the blood. Therefore, an elevated serum CK level is present in many muscle diseases (Barohn, 2000). The most useful laboratory finding in DMD is an elevated CK, which can be 300 to 400 times normal. This decreases with age as muscle mass declines with disease progression. CK is mildly elevated in 70% of female carriers (Munsat, 1988). Other lysosomal enzymes present in muscle, such as aldolase and aspartate aminotransferase (AST), are also increased but are less specific (Sarnat, 2000).
2] Neurophysiological studies :
Needle electromyography (EMG) and nerve conduction studies (NCSs) are useful part of evaluation of DMD. Sensory NCSs are normal. Motor NCSs have normal latencies, conduction velocities, and F-wave latencies, but the amplitude of the compound muscle action potential (CMAP) typically decreases as the disease progresses. The EMG shows an increase in insertional activity early in the disease, which can decrease later as fibrotic tissue replaces muscle. Fibrillations and positive sharp waves can be seen at rest. Complex repetitive discharges (CRDs) can be observed. Motor units in DMD show the classic short-duration, low-amplitude polyphasicity (often called “myopathic”). Typically there is early motor unit recruitment (Nelson, 2000).
3] Muscle biopsy :
Muscle biopsy in DMD shows increased variability of fiber size, rounding of fibers, fiber splitting, increased numbers of central nuclei, hyaline fibers, muscle fiber necrosis, phagocytosis and regeneration, and replacement by fat and fibrous tissue (Hilton – Jones, 2001). Analysis of dystrophin protein is demonstrated by Western blot analysis or in tissue sections by immunohistochemical methods. In classic DMD, levels of less than 3% of normal are found. In BMD, the molecular weight of dystrophin is reduced to 20 – 90% of normal in 80% of patients, but in 15% the dystrophin is of normal size but reduced in quantity, and 5% have abnormally large protein (Sarnat, 2000). The immunohistochemical examination for dystrophin is the gold-standard method for DMD / BMD diagnosis (Werneck et al., 2001).
4] Molecular genetic studies :
A dystrophin gene deletion (or rarely a duplication) can be detected by analysis of DNA from leukocytes by the polymerase chain reaction (PCR) in a blood sample in approximately two-thirds of DMD patients. If the patient falls into the one-third of patients in whom a deletion can not be detected, a muscle biopsy is required to demonstrate dystrophin deficiency by either Western blot or immunostaining (Barohn, 2000).
5] Skin biopsy :
Niiyama et al. (2002) studied the expression of dystrophin in skin biopsy samples from 19 patients with neuromuscular diseases. They suggested that skin biopsy is very useful for the diagnosis of Duchenne/Becker muscular dystrophy and manifesting carrier of Duchenne muscular dystrophy, and can be performed even at an advanced stage of the disease.
6] Imaging studies :
Quantitative computed tomography (CT) offers a method of quantifying muscle damage. It measures the degree of muscle fiber loss and fatty replacement using percent cross-sectional area (% CSA) of muscle and fat. The % CSA of muscle is decreased as muscle strength decreases and as disability progresses. The rate of progression varies with different muscles (Liu et al., 1993).
The introduction of ultrasound imaging as a screening procedure for muscular dystrophy has proved useful in clinical practice. From an early stage of the disease it shows an increase in echogenicity in some muscles, with a corresponding reduction in the underlying bone echo (Dubowitz, 1995).
MANAGEMENT
Until treatment of the basic genetic defect is available, medical, rehabilitative and surgical approaches can be used to maintain patient function and comfort (Sussman, 2002).
Medical treatment :
Corticosteroids, including prednisone and a related compound, deflazacort, have recently been shown to markedly delay the loss of muscle strength and function in boys with DMD (Sussman, 2002). A long-term study demonstrated that the duration of independent ambulation was prolonged in boys treated with predinsone as compared to a control group (De Silva et al., 1987).
Corticosteroids decrease the rate of apoptosis or programmed cell death of myotubules during ontogenesis and theoretically may decelerate the myofiber necrosis in muscular dystrophy. Strength usually improves initially, but the long-term complications of chronic steroid therapy, including considerable weight gain and osteoporosis, may offset this advantage or even resulting in greater weakness than might have occurred in the natural course of the disease (Sarnat, 2000).
Deflazacort (a derivative of prednisone) was used in children with DMD in an attempt to have the benefits of steroids with fewer side effects than found with prednisone. It was used for a 2 year trial with positive outcome. Both an improvement in functional ability and a delay in the loss of ambulation were noted, along with fewer side effects than prednisone (Angelini et al., 1994).
Oxandrolone, an anabolic steroid more potent than testosterone, may be useful in DMD with efficacy similar to prednisone, according to a small pilot study (Fenichel et al., 1997).
Cyclosporines improve strength to a degree similar to prednisone, and also with the pattern of a decline in strength over time. Doses of 5 mg/kg/day taken orally are typically effective within two weeks, with transient, minor side effects (Miller and Hoffman, 1994).
Management of contractures :
Night time use of bilateral ankle-foot orthoses (AFOs) along with a regular stretching program has been shown to delay development of contractures of the Achillis tendon. Boys who regularly wear AFOs and stretch their legs walk independently for a longer period of time, and children who do not stretch or use splints lose the ability to ambulate much earlier. Stretching of the tensor fascia lata is crucial. Good positioning includes lying prone to promote extension of the hips and knees (Nelson, 2000).
A standing program with knee-ankle-foot orthoses (KAFOs) or standing frames or tilt tables or even swivel walkers (Sibert et al., 1987) provides prolonged stretching as well as opportunities to participate in school and home activities in the upright position. Brooke et al. (1989) found a significant correlation between the use of leg braces and the prevention of contractures in the gastrocnemius – soleus, hamstrings, and iliotibial band.
Management of weakness :
Exercise :
The effect of exercise on muscle – both its beneficial effects and possible detrimental side effects – has long been the subject of research, and a source of controversy. Therapeutic strengthening exercise should be performed at a submaximal level of intensity and duration in order to avoid overuse weakness (Thomas et al., 1988).
In supervised resistive exercise programs there is no negative effect on muscle in DMD. Objective increases in muscle strength are found, but these diminish as the disease advances. The pre-exercise strength level determines the amount of increase possible, with stronger muscles able to increase more. Patients maintaining ambulation have larger increases in strength with exercise (Nelson, 2000).
Electrical stimulation :
Zupan (1992) stimulated muscles in DMD patients with low-frequency electrical stimulation (LFES) twice daily in an attempt to confer a protective effect on the muscle fibers of DMD and prevent degeneration. Half of the children in this small study had no significant changes in 3 months, and the remaining children demonstrated short-term increased strength that was greatest after 5 months of stimulation. There was no change in the level of fatigue with stimulation and no adverse effects. Scott et al. (1986) also found increases in maximal contractions in stimulated versus non-stimulated muscles in boys with DMD.
Provision of functional mobility :
Maintained mobility, particularly ambulation, is a focus of a good deal of attention and research in DMD. Many attempts have been made to maximize ambulation time for boys with DMD. Ankle-foot orthoses (AFOs) or ischial weight-bearing plastic knee-ankle-foot orthoses (KAFOs) are often used to maximize gait. The KAFOs are frequently used with locked knees (Nelson, 2000).
Surgical intervention for contracture release has also been used to maximize and prolong ambulation. The timing for surgical intervention has been a frequent point of dispute, the concern being that surgery can prematurely halt ambulation (Bach and McKeon, 1991).
Bach and McKeon (1991) showed that a single early procedure of tendon surgical releases with short-term intensive rehabilitation could prolong ambulation, reduce falls, and improve contractures. Surgical release of the iliotibial band, tensor fascia lata, gluteus maximus and hamstrings was performed, as well as Achillis tendon lengthening. They recommended that this surgery be done while ambulation and stair climbing difficulties are minimal and while quadriceps strength is at least antigravity, to minimize the need for bracing postoperatively.
Management of scoliosis :
Bracing is not effective in the prevention of scoliosis or its progression in DMD. The most effective treatment for severe scoliosis is prevention by intervening with early spinal fusion utilizing segmental instrumentation as soon as curves are ascertained and before the onset of severe pulmonary or cardiac dysfunction (Sussman, 2002).
Self – care :
Hand function is critical in DMD because the hands are useful not only for activities of daily living (ADL), but also for assistance in mobility as the disease progresses (Nelson, 2000).
Older children with DMD exhibit some common physical abnormalities in the wrist and hand that can contribute to decreased upper limb function. Ability to perform ADL is influenced primarily by decreased strength of wrist extensors and decreased active radial deviation. The goals of therapy are to maintain optimal range of motion of the wrist, prevent wrist ulnar deviation contractures, and maintain wrist extensors strength. Therapy includes stretching exercises and positioning of the wrist and fingers. Splint use is necessary in some cases (Wagner et al., 1993).
A balanced forearm orthosis can allow hand-to-mouth function when hand function is intact, but there is poor proximal strength (Kirsteins and Kolaski, 2000).
Robotic arms mounted on the wheelchair tray can be used with only finger movements for wheelchair operation, feeding devices, and environmental controls (Bach et al., 1990). Mouthsticks can be used for turning pages, painting, buttoning and maneuvering smaller objects. Voice, eye-, and blink-operated environmental controls are available to give patients access to all appliances, computers, and telecommunication equipment (Bach, 1995).
Pulmonary management :
Maximizing ventilatory assistance in patients with DMD is critical. Respiratory assistance is typically initiated when vital capacity (VC) decreases to approximately 20% of predicted normal and symptoms of hypercapnia begin. Some caregivers recommend the use of mouth intermittent positive pressure breathing (MIPPB) with the use of an intermittent positive pressure breathing (IPPB) device. This intervention is designed to obtain maximal lung expansion, with a goal of minimizing the microatelectasis and maintaining the chest wall compliance. It is also used for management of acute respiratory infections (Fukunaga et al., 1993).
Vaccination in order to avoid infections by Hemophilus influenzae and pneumococcus should be a routine part of the care of DMD patients (Thomas et al., 1988).
During upper respiratory infections, antibiotics, chest physical therapy, postural drainage and assisted cough with suction should be used. Supplemental oxygen might be necessary during these times (Nelson, 2000).
Psychosocial management :
Psychosocial management is crucial in the care of a DMD patient and his family. When a child has an incurable progressive disease, his family requires varying amounts of support from and interaction with professionals (and others) from the time of diagnosis onward (Nelson, 2000).
Myoblast transfer therapy :
The discovery of the dystrophin molecule, the gene encoding it, and the specific mutations in Duchenne and Becker muscular dystrophies raises the theoretical potential of a cure by molecular genetic engineering. One experimental approach is myoblast transfer therapy, in which normal myoblasts from the muscle of a genetically close relative, usually the father are cultured in vitro and then injected into dystrophic muscles with the expectation that they will form healthy myofibers with normal dystrophin to replace degenerating fibers (Sarnat, 2000).
Myoblast transfers have been attempted in patients with DMD, but without success. Part of the failure in these attempts can be secondary to immune rejection problems (Huard et al., 1992 and Huard et al., 1994).
Pilot studies with donor myoblasts from male relatives showed slightly increased dystrophin in a minority of boys. Increased strength has been documented, although both the myoblast – implanted leg and placebo leg showed improvement; hence, the increase was believed to be secondary to the use of cyclosporine (Miller et al., 1992).
Achieving immunological tolerance to transplanted myoblasts would reduce the adverse effects associated with the sustained immunosuppression required for this experimental therapeutic approach in DMD (Camirand et al., 2002).
Gene therapy :
Gene therapy involves the direct implantation of a normal, cloned dystrophin gene, either directly or via some transfer agents such as a virus vector, liposome, or myoblast (Wolff et al., 1990 and Clemens and Caskey, 1994).
Gene therapy for muscular dystrophy (MD) presents significant challenges, including the large amount of muscle tissue in the body, the large size of many genes defective in different muscular dystrophies, and the possibility of a host immune response against the therapeutic gene. Overcoming these challenges requires the development and delivery of suitable gene transfer vectors (Hartigan – O’Connor and Chamberlain, 2000).
Researchers are attempting gene transfers by transplanting portions of a dystrophin copy DNA (cDNA) into skeletal muscle fibers. If the dystrophin is produced, then the muscle fibers are protected from necrosis. If gene transfers and long-term expression of the gene product dystrophin do occur in the future, the skeletal fibers would acquire a normal phenotype. Areas under study include direct injection of dystrophin cDNA; viral vectors for transfer of a mini-gene of the large dystrophin gene or utrophin, a smaller, related gene, and genetic engineering of myoblasts (Nelson, 2000).
Some of the viral vectors, such as adeno-associated virus vectors or lentiviral vector, have been proven to enable the long-term expression of the exogenous gene without overt host immune reactions (Takeda and Miyagoe – Suzuki, 2001). Recombinant adeno-associated virus (rAAV) vectors allow efficient gene transfer and expression in the muscle; therefore, rAAVs represent a potential gene therapy vector for muscular dystrophies (Cordier et al., 2001).
Encouraging progress has been made in modifying adenovirus (Ad) vectors to reduce immune response and increase capacity. Recently, developed gutted Ad vectors can deliver full-length dystrophin cDNA expression vectors to muscle tissue. Adeno-associated virus (AAV) vectors can deliver small genes to muscle without provocation of a significant immune response, which should allow long-term expression of several MD genes. AAV vectors have also been used to deliver sarcoglycan genes to entire muscle groups (Hartigan – O’Connor and Chamberlain, 2000).
Studies in transgenic mdx mice, a model for DMD, demonstrated that the dystrophic pathology can be both prevented and reversed by gene therapy using micro-dystrophins (Harper et al., 2002).
Genetic counseling and prenatal diagnosis :
The diagnosis of new DMD cases always demands provision of proper genetic counseling to all female family members at potential risk of having a DMD (or carrier) offspring. If the investigation determines that a woman is a carrier for DMD, half of her sons will have DMD, and half of her daughters will be carriers. The options that a carrier can follow for the prevention of the birth of a DMD boy include prevention of all future pregnancies or prenatal diagnosis. Prenatal diagnosis may simply determine the sex of the fetus, and the carrier may terminate all male pregnancies. Alternatively, DNA from amniocytes or from a chorionic villus biopsy is analyzed for the known mutation (Molnar and Karpati, 1999).
BECKER MUSCULAR DYSTROPHY
Becker muscular dystrophy (BMD) is a more benign phenotype of DMD. There is involvement of both skeletal and cardiac muscle, but the course is more slowly progressive and the associated impairments and disabilities are less severe. BMD is less common than DMD, with an estimated incidence of 1 per 20,000 male births. BMD is also inherited through an X-linked mechanism and is related to a mutation, typically a deletion, on the same gene as in DMD. This results in dystrophin of abnormal size or reduced amounts of normal dystrophin (Kirsteins and Kolaski, 2000).
Clinical features :
The onset of weakness generally manifests between 10 and 15 years of age (Nelson, 2000). The pattern of muscle weakness parallels that seen in DMD, with early involvement of hip flexors and extensors, quadriceps, pectoralis major, latissimus dorsi, and brachioradialis (Hilton-Jones, 2001). Pseudohypertrophy of the claves is commonly seen (Munsat, 1988).
Cardiac involvement is a frequent finding in patients with BMD (Finsterer et al., 2001). ECG changes identical to those in DMD are found in 45% of BMD patients, while 17% have echocardiographic changes consistent with a dilated cardiomyopathy (Yoshida et al., 1993). The major risk of early death in BMD has been related to cardiac and not pulmonary complications (McDonald et al., 1995).
Investigations :
1] Biochemical investigations :
An elevated CK is noted in BMD, but it is usually lower than in boys with DMD (Nelson, 2000).
2] Electromyography (EMG) :
Needle EMG can show primarily symmetrical changes in the proximal limb muscles, including positive sharp waves, fibrillations, and CRDs. Paraspinal muscles can demonstrate CRDs earlier than limb muscles. Motor unit potentials (MUPs) generally are small, polyphasic, and have early recruitment (Nelson, 2000).
3] Muscle biopsy :
Results of immunostaining and Western immunoblot for dystrophin in muscle extracts reveal the protein is not absent, as in DMD, but is reduced in amount or abnormal in size (Barohn, 2000).
4] Molecular genetic studies :
Most BMD patients have a non-frame shift mutation, so that a reduced amount of an abnormal dystrophin is produced, resulting in a milder syndrome than DMD. DNA analysis from blood leukocytes will show a Xp21 deletion in about 60% (Barohn, 2000).
Treatment :
Since the course of BMD is milder than that of DMD, the treatment is less aggressive. Medications are not used except in those persons with the most severe form of the disease. AFOs for ambulation and a wheelchair for mobility can become necessary as the disease progresses. Stretching to prevent contractures is important as independent mobility declines. Surgical treatment of severe contractures can be helpful when they interfere with gait or posture (Nelson, 2000).
Johnsen (2001) suggested that a small percentage of patients with BMD have a dramatic and sustained improvement in strength with the therapeutic use of corticosteroids. All patients with BMD should be given a careful trial of prednisone to define those who benefit.
Patients with BMD can gain significant increases in muscle strength, endurance, and work capacity with a weight training program (Milner – Brown and Miller, 1988).
Particular attention needs to be paid to the heart and to ventilatory function. Respiratory failure and its associated symptoms occurs only in late stages, long after ambulation has been lost – nocturnal positive pressure ventilation with a mask affords symptomatic relief (Hilton – Jones, 2001).
Neumeyer et al. (1998) evaluated myoblast implantation therapy in three subjects with BMD who received 60 million myoblasts in one tibialis anterior (TA) muscle 2 months after beginning cyclosporine immunosuppression (5 to 10 mg/kg) that continued for one year. In this pilot study, myoblast implantation did not improve strength of the implanted TA muscles.
X-LINKED MYALGIA AND CRAMPS SYNDROME
Cramps and myalgias are frequent presentations of many disorders whose diagnosis is generally difficult. Among the unusual causes stand the milder phenotypes of dystrophinopathies, which are caused, just as Duchenne and Becker dystrophy, by mutations in the dystrophin gene (Kleinsteuber et al., 2000).
This disorder represents a new clinical phenotype associated with a deletion in the dystrophin gene. This deletion affects a portion of the dystrophin molecule that clinically does not appear to significantly alter its function. Other patients with deletions in this region may have truncated dystrophin without clinical signs of progressive muscle disease (Gospe et al., 1989).
Gospe et al. (1989) reported a family with an X-linked recessive disorder characterized by muscle cramps and myalgia. Nine affected male family members had high resting serum levels of creatine kinase, and well-developed musculature with calf hypertrophy but no evidence of muscular weakness. Symptoms began in childhood and did not progress. Electromyographic findings were consistent with myopathy while muscle biopsies showed non-specific myopathic changes without evidence of storage of glycogen or lipid. Analysis of DNA revealed a deletion in the first third of the dystrophin gene. Western blot analysis revealed that dystrophin was smaller than that in normal samples, with no reduction in the amount of the protein present.
Emphasis is made to include dystrophinopathies in the differential diagnosis of myalgias and the usefulness of molecular genetic techniques in the identification of these disorders (Kleinsteuber et al., 2000).
Dystrophin analysis by Western blot and/or DNA analysis should be included in the evaluation of patients with exertional muscle pain syndrome without deficient muscle energy metabolism, particularly those with pseudohypertrophy of the calf muscles or high serum CK levels (Drouet et al., 2002).
X-LINKED DILATED CARDIOMYOPATHY
X-linked dilated cardiomyopathy (XLDC) is a severe and rapidly progressive myocardial disease that affects young men in their teens or early twenties. Typically, affected males present with severe congestive heart failure that results in death or cardiac transplantation within 1 or 2 years of diagnosis (Ortiz-Lopez, 1997).
XLDC represents a well known genetic disease, allelic to Duchenne and Becker muscular dystrophies and caused by dystrophin gene mutations. XLDC is a rare disease and only few families have been fully characterized. In several of them, the dystrophin mutations show a different pattern of expression in cardiac compared to skeletal muscle. In the families with the most severe cardiac phenotype, the cardiac muscle is usually unable to produce dystrophin, due to a specific effect that the mutation(s) have on the gene transcription in this tissue (Ferlini et al., 1999).
Isolated cardiomyopathy without skeletal muscle involvement, apart from increased serum CK, has been observed in patients with mutations selectively affecting the heart dystrophin (Ferlini et al., 1998).
Dystrophin should be evaluated in males with dilated cardiomyopathy, even in the absence of muscle weakness (Siddique et al., 1999).
DYSTROPHINOPATHIES IN FEMALES
Duchenne muscular dystrophy (DMD) is seen rarely in females. Since this is an X-linked recessive disorder, it can occur in a girl with Turner’s syndrome and an XO karyotype or with an X autosomal translocation and a break at the Xp21 locus (Nelson, 2000).
Female carriers :
The mothers of affected children who also have a family history of Duchenne or Becker muscular dystrophy, and the daughters of males with a dystrophinopathy are obligate carriers of the mutated dystrophin gene. Mothers and sisters of isolated Duchenne or Becker dystrophy patients are at risk for being carriers. There is a 50% chance that males born to carrier females will inherit the disease, and 50% of the daughters born will become carriers themselves. Female carriers are usually asymptomatic, but rarely they may demonstrate moderate limb girdle weakness (Barohn, 2000). Clinical manifestation of muscle weakness, dilated cardiomyopathy, or both can be found in about a fifth of carriers of DMD and BMD. Muscle weakness is primarily proximal and asymmetric (Hoogerwaard et al., 1999).
Various laboratory tests were performed by Hausmanowa-Petrusewicz et al. (2000) to establish carriership in 24 familial and sporadic carriers of DMD and BMD. The activity of creatine kinase was in all females but one, very high and significantly higher in isolated carriers; quantitative EMG indicated myopathic changes, muscle biopsies revealed different degrees of changes – from a variability of muscle fibers size and central nuclei to severe dystrophic features. Immunohistochemical evaluation of dystrophin revealed, in all females but one, mosaic pattern of staining - a mixture of dystrophin-positive and dystrophin-negative fibers, the latter consist 15-30% of all fibers. Quantitative evaluation of dystrophin showed a reduced abundance with normal or abnormal molecular weight. The detection of sporadic carriers, particularly the non-manifesting clinical, is a very important progress – it permits the correct diagnosis and supply them with the benefit of genetic counseling.
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