Inflammatory myopathy can result from a variety of acute infections, including HIV, but the idiopathic forms polymyositis and dermatomyositis are most common. It is important to recognize these, because they are usually treatable.
Polymyositis
Polymyositis typically presents with symmetrical proximal weakness, often associated with myalgia and muscle tenderness. Progression may be rapid, but more indolent forms can occur, particularly in older women. Creatinine kinase is usually but not invariably increased and EMG typically shows a mixed picture of increased insertional and spontaneous activity (‘myogenic denervation’) and ‘myopathic’ changes (rapid recruitment of small amplitude, polyphasic potentials on contraction). Muscle biopsy typically shows lymphocytic infiltration of muscle connective tissues, with fiber necrosis, degeneration and regeneration, but the process is patchy and inflammation may be inconspicuous. Demonstration of HLA class 1 antigens on fibers by immunohistochemistry, indicative of an immune reaction, is then invaluable for diagnosis.
Dermatomyositis is clinically and pathogenetically distinct from polymyositis and is essentially an immune-mediated microangiopathy affecting principally skin and muscle, though childhood dermatomyositis can include gut involvement, resulting in gastrointestinal hemorrhage. The skin lesions are diagnostic (erythema affecting light exposed areas such as the supraorbital ridges, eyelids and malar areas, chest, knuckles, knees and elbows). The skin lesions may sometimes occur without muscle weakness, but careful investigation usually confirms muscle involvement. There is an association between dermatomyositis and underlying malignancy, and this should be a particular consideration in men with dermatomyositis presenting over the age of 55 years.
Management:
Treatment often starts with a course of intravenous immunoglobulin 0.4 g/kg/day for 5 days, followed by high dose oral corticosteroids, 1 mg/kg, with azathioprine, 1–2 mg/kg. The corticosteroid dose should be tapered reasonably rapidly, depending on clinical response and serial creatinine kinase measurements, and switched to an alternate day regimen after about 1 month. Use of an etidronate with calcium supplements can help prevent corticosteroid induced osteoporosis. Avascular necrosis of the femoral heads is a rare complication; the risk is related to the total corticosteroid dose received, particularly in the first month of treatment. MRI of the hips is the best means of detecting this complication. Inclusion body myositis is the most common cause of acquired myopathy in those over 50 years of age. It shares many features with polymyositis, but tends to be indolent in progression, is not associated with myalgia and causes marked muscle wasting, particularly distally. Muscle biopsy is diagnostic. Up to 10% of fibers show ‘rimmed vacuoles’ – areas of probable nuclear dissolution containing a number of aberrant proteins, including bamyloid and hyperphosphorylated tau protein, strikingly reminiscent of changes in the brain in Alzheimer’s disease. Inflammation is commonly seen but may be absent, in which case demonstration of class I HLA expression supports the diagnosis. Ultrastructure typically shows 10–18 nm diameter filaments in nuclei and cytoplasm. Response to immunosuppressive treatment is usually minimal and progression inevitable. Hereditary inclusion body myopathies share clinical and pathological features with inclusion body myositis, but inflammation is not seen.
Myopathies in systemic disease
Muscle constitutes 40% of the body mass and weakness is a common feature of most systemic diseases, though the manifestations of the primary illness are usually predominant and myopathy is often overlooked. Muscle can be involved directly, as in infectious diseases, or indirectly through the effects of metabolic derangement or immune responses. Myopathy can be a feature of any endocrine disorder and can also be affect- ed by a wide variety of drugs.
Other myopathies
There are other forms of myopathy characterized by muscle fiber inclusions and surplus protein accumulations which are presently difficult to classify. Some (e.g. the desminopathies) are hereditary and may cause cardiac disease.
Showing posts with label Myopathies. Show all posts
Showing posts with label Myopathies. Show all posts
Saturday, July 6, 2013
Non limb girdle pattern muscular dystrophies with involvement of cranial musculature - 2
Dystrophic myotonias
Myotonic dystrophy is the most common inherited neuromuscular disease; the prevalence is about 5/100,000. The characteristic phenotype includes, in addition to grip and percussion myotonia: progressive muscular weakness and wasting, starting distally, bilateral ptosis and facial muscle weakness, sternomastoid wasting, cataracts, endocrinopathy, notably insulin resistance, cardiac conduction defects which can lead to sudden death, bulbar and respiratory muscle weakness, dysphagia and gut dysfunction, frontal balding and calcifying epithelioma of Malherbe and in severe cases mental retardation. Gene expression can vary from asymptomatic cases with no clinical signs, to severe congenital onset disease. The disease is associated with a CTG triplet expansion at 19q13.3, from 5–37 repeats in normal individuals to 50 to more than 1000 repeats in disease. The mutation involves the 3' untranslated region of the myotonin-protein kinase gene and the 5' untranslated region of Six5 (myotonic dystrophy associated homeobox protein), which is involved in the regulation of eye formation (and might therefore explain the prominence of cataract in the phenotype). There is a broad correlation between the size of the expansion and disease severity, individuals in successive generations usually inherit larger expansions and thus have more severe and earlier onset disease (genetic anticipation). A second, clinically identical form of myotonic dystrophy has been described recently, linked to chromosome 3q.
Proximal myotonic myopathy is clinically and genetically distinct from myotonic dystrophy but shares a number of phenotypic features. Weakness starts in and is mainly confined to proximal muscles, and cramps and myalgia are common. Non-dystrophic myotonias and periodic paralyses and number of familial muscle diseases have recently been shown to result from mutations of genes encoding muscle ion channels. The defects can lead to a phenotype in which myotonia is the major manifestation, as in myotonia congenita (chloride channelopathy), or to episodic weakness, as in hypokalaemic periodic paralysis (calcium channelopathy). Sodium channel mutations lead to a complex mixture of phenotypes in which myotonic stiffness (as in potassium aggravated myotonia) or periodic weakness (as in hyperkalaemic periodic paralysis and paramyotonia congenita) can occur under various conditions (eg. exercise, exposure to cold). Patients with myotonia congenita may not come to medical attention, unless ‘cramp’ caused by the myotonia is very troublesome. Gross muscular hypertrophy is typically found on examination. Periodic paralyses present with episodic, profound muscular weakness, not involving breathing and with normal consciousness, with appropriate abnormal serum K+. Hyperkalaemic periodic paralysis is associated with myotonia; the hypokalaemic form is not.
Genetically determined metabolic myopathies
Disorders of intermediary metabolism Certain genetic disorders of intermediary metabolism can affect muscle particularly or exclusively. Such diseases may cause progressive myopathic weakness as a result of storage of glycogen (e.g. acid maltase deficiency – Pompe’s disease) or lipids (e.g. carnitine deficiency), or may cause exercise-related myalgia, and sometimes muscle contracture, with swelling and rhabdomyolysis, leading to myoglobinuria with a risk of acute renal failure.
McArdle’s disease is the most common of these disorders. Deficiency of myophosphorylase results in failure to break down glycogen to glucose in muscle. Severe myalgia with ‘cramp’ (which is in fact electrically silent muscle contracture) develops soon after the start of exercise, but the patient may notice easing of symptoms as exercise continues (‘second-wind’ phenomenon), as alternative energy sources are mobilized. The disease can be diagnosed simply and rapidly by demonstrating absent phosphorylase on muscle histochemistry. McArdle’s disease and other rarer forms of glycolytic disorder may also be suggested by the finding of a much reduced increase in plasma lactate following ischemic forearm exercise.
Mitochondrial disorders
Mitochondrial disorders can affect muscle specifically or as part of a multisystem disease, typically involving the central nervous system. Large deletions of mitochondrial DNA commonly underlie Kearns–Sayre syndrome and chronic progressive external ophthalmoplegia. Point mutations cause a wide variety of syndromes, including mitochondrial encephalopathy, lactic acidosis and strokes (MELAS) and myoclonus, epilepsy and ragged red fibres (MERRF). Diagnosis of a mitochondrial disease is suggested by the demonstration of: increased basal plasma lactate and cerebrospinal fluid lactate, an inappropriately large increase in plasma lactate on exercise testing, typical histochemical features (e.g. ragged red fibres and cytochrome oxidase-negative fibres on muscle biopsy). Ultrastructural studies usually demonstrate accumulations of large, bizarrely structured mitochondria, though biochemical features of mitochondrial cytopathy can usually be demonstrated before structural changes can be found.
Other disorders
Metabolic myopathy resulting from myoadenylate deaminase deficiency (involved in purine metabolism) and Brody’s disease (sarcoplasmic reticulum Ca2+ATPase deficiency) are rare, and present with exertional myalgia and ‘cramps’. Malignant hyperthermia, characterized by hyperpyrexia, rhabdomyolysis and severe acidosis induced by anaesthetic agents, is relatively common and genetically heterogeneous. Mutations at one malignant hyperthermia locus on 19q13.1 (ryanodine receptor) also determines a congenital myopathy (central core disease).
Myotonic dystrophy is the most common inherited neuromuscular disease; the prevalence is about 5/100,000. The characteristic phenotype includes, in addition to grip and percussion myotonia: progressive muscular weakness and wasting, starting distally, bilateral ptosis and facial muscle weakness, sternomastoid wasting, cataracts, endocrinopathy, notably insulin resistance, cardiac conduction defects which can lead to sudden death, bulbar and respiratory muscle weakness, dysphagia and gut dysfunction, frontal balding and calcifying epithelioma of Malherbe and in severe cases mental retardation. Gene expression can vary from asymptomatic cases with no clinical signs, to severe congenital onset disease. The disease is associated with a CTG triplet expansion at 19q13.3, from 5–37 repeats in normal individuals to 50 to more than 1000 repeats in disease. The mutation involves the 3' untranslated region of the myotonin-protein kinase gene and the 5' untranslated region of Six5 (myotonic dystrophy associated homeobox protein), which is involved in the regulation of eye formation (and might therefore explain the prominence of cataract in the phenotype). There is a broad correlation between the size of the expansion and disease severity, individuals in successive generations usually inherit larger expansions and thus have more severe and earlier onset disease (genetic anticipation). A second, clinically identical form of myotonic dystrophy has been described recently, linked to chromosome 3q.
Proximal myotonic myopathy is clinically and genetically distinct from myotonic dystrophy but shares a number of phenotypic features. Weakness starts in and is mainly confined to proximal muscles, and cramps and myalgia are common. Non-dystrophic myotonias and periodic paralyses and number of familial muscle diseases have recently been shown to result from mutations of genes encoding muscle ion channels. The defects can lead to a phenotype in which myotonia is the major manifestation, as in myotonia congenita (chloride channelopathy), or to episodic weakness, as in hypokalaemic periodic paralysis (calcium channelopathy). Sodium channel mutations lead to a complex mixture of phenotypes in which myotonic stiffness (as in potassium aggravated myotonia) or periodic weakness (as in hyperkalaemic periodic paralysis and paramyotonia congenita) can occur under various conditions (eg. exercise, exposure to cold). Patients with myotonia congenita may not come to medical attention, unless ‘cramp’ caused by the myotonia is very troublesome. Gross muscular hypertrophy is typically found on examination. Periodic paralyses present with episodic, profound muscular weakness, not involving breathing and with normal consciousness, with appropriate abnormal serum K+. Hyperkalaemic periodic paralysis is associated with myotonia; the hypokalaemic form is not.
Genetically determined metabolic myopathies
Disorders of intermediary metabolism Certain genetic disorders of intermediary metabolism can affect muscle particularly or exclusively. Such diseases may cause progressive myopathic weakness as a result of storage of glycogen (e.g. acid maltase deficiency – Pompe’s disease) or lipids (e.g. carnitine deficiency), or may cause exercise-related myalgia, and sometimes muscle contracture, with swelling and rhabdomyolysis, leading to myoglobinuria with a risk of acute renal failure.
McArdle’s disease is the most common of these disorders. Deficiency of myophosphorylase results in failure to break down glycogen to glucose in muscle. Severe myalgia with ‘cramp’ (which is in fact electrically silent muscle contracture) develops soon after the start of exercise, but the patient may notice easing of symptoms as exercise continues (‘second-wind’ phenomenon), as alternative energy sources are mobilized. The disease can be diagnosed simply and rapidly by demonstrating absent phosphorylase on muscle histochemistry. McArdle’s disease and other rarer forms of glycolytic disorder may also be suggested by the finding of a much reduced increase in plasma lactate following ischemic forearm exercise.
Mitochondrial disorders
Mitochondrial disorders can affect muscle specifically or as part of a multisystem disease, typically involving the central nervous system. Large deletions of mitochondrial DNA commonly underlie Kearns–Sayre syndrome and chronic progressive external ophthalmoplegia. Point mutations cause a wide variety of syndromes, including mitochondrial encephalopathy, lactic acidosis and strokes (MELAS) and myoclonus, epilepsy and ragged red fibres (MERRF). Diagnosis of a mitochondrial disease is suggested by the demonstration of: increased basal plasma lactate and cerebrospinal fluid lactate, an inappropriately large increase in plasma lactate on exercise testing, typical histochemical features (e.g. ragged red fibres and cytochrome oxidase-negative fibres on muscle biopsy). Ultrastructural studies usually demonstrate accumulations of large, bizarrely structured mitochondria, though biochemical features of mitochondrial cytopathy can usually be demonstrated before structural changes can be found.
Other disorders
Metabolic myopathy resulting from myoadenylate deaminase deficiency (involved in purine metabolism) and Brody’s disease (sarcoplasmic reticulum Ca2+ATPase deficiency) are rare, and present with exertional myalgia and ‘cramps’. Malignant hyperthermia, characterized by hyperpyrexia, rhabdomyolysis and severe acidosis induced by anaesthetic agents, is relatively common and genetically heterogeneous. Mutations at one malignant hyperthermia locus on 19q13.1 (ryanodine receptor) also determines a congenital myopathy (central core disease).
Non limb girdle pattern muscular dystrophies with involvement of cranial musculature -1
Facioscapulohumeral muscular dystrophy is an autosomal dominant disease, though a family history may not be evident because expression of the disease can be mild. Phenocopies resulting from spinal muscular atrophy, mitochondrial myopathy and inclusion body myositis have been reported, but diagnosis by DNA analysis has greatly reduced diagnostic uncertainty in recent years. Weakness typically begins in the face (though the face may be unaffected in some individuals) or shoulder muscles, with sparing of the extraocular, pharyngeal and lingual muscles. Inability to whistle is characteristic. In later stages, dramatic scapular winging develops, and weakness of the scapular fixators allows ‘over-riding’ of the scapulae above the shoulders, like a pair of wings. Lower limb weakness may not be conspicuous, but foot drop and later proximal weakness can occur. Creatinine kinase levels, EMG and muscle biopsy may show only minimal abnormalities. Diagnostic confirmation depends on the demonstration of abnormally small 4q35-specific DNA fragments following digestion with restriction site enzymes. Recent evidence suggests an inverse correlation between the size of these fragments and disease severity. The genes responsible have not yet been identified. No treatment is available, but scapulothoracic arthrodesis can improve upper limb function in patients with severe limitation of arm elevation.
Oculopharyngeal muscular dystrophy presents with ptosis and weakness of the extraocular muscles, muscles of the pharynx and larynx (causing progressive dysphagia and dysphonia), and the facial, limb-girdle and even distal muscles. It is an autosomal dominant disorder, but gene penetrance varies considerably. Cases may be mild to severe and can present at almost any age, though typically in the sixth decade and beyond. Creatinine kinase may be only minimally increased and biopsy can show a range of changes which may include rimmed vacuoles and ragged red fibers typical of a mitochondrial myopathy. Ultrastructural studies may reveal pathognomonic accumulations of 8.5 nm filaments in a proportion of myonuclei. Recently, diagnosis by DNA analysis has become available. The disease is associated with a GCG triplet expansion at the poly-A binding protein 2 (PABP2) gene at 14q11. It is suggested that this expansion might cause mutated PABP2 monomers to aggregate in nuclei, resulting in filament accumulations.
Distal myopathies
Several neuromuscular diseases present with distal weakness and wasting of the limbs. This pattern commonly results from peripheral neuropathies, including Charcot–Marie–Tooth disease, and from anterior horn cell diseases such as spinal muscular atrophy. It can also be encountered in primary muscle diseases, notably myotonic dystrophy, congenital myopathies and inclusion body myositis. In addition, several rare forms of genetically determined distal myopathy have been described. These can be distinguished to some degree by mode of inheritance and whether the anterior or posterior compartment of the lower legs is principally affected. A common form is Miyoshi myopathy, which particularly affects the gastrocnemius and soleus muscles. Like LGMD2B, it is a dysferlinopathy. Several of these diseases are rimmed vacuolar myopathies, a feature shared with the hereditary inclusion body myopathies.
Congenital myopathies
Congenital myopathies are classified on the basis of specific histological features. Patients can present at any time from childhood to adult life, usually with distal weakness. A long, thin facies and high arched palate are common. This group of disorders includes centronuclear and myotubular myopathies, nemaline myopathy and central core disease.
Myotonic disorders
Myotonia is prolonged contraction of muscle, with subsequent slowed relaxation, following activation. It results from genetic or acquired changes in excitability of muscle surface membranes and is found in several primary muscle diseases. Neuromyotonia is a clinically similar phenomenon of neurogenic origin.
Oculopharyngeal muscular dystrophy presents with ptosis and weakness of the extraocular muscles, muscles of the pharynx and larynx (causing progressive dysphagia and dysphonia), and the facial, limb-girdle and even distal muscles. It is an autosomal dominant disorder, but gene penetrance varies considerably. Cases may be mild to severe and can present at almost any age, though typically in the sixth decade and beyond. Creatinine kinase may be only minimally increased and biopsy can show a range of changes which may include rimmed vacuoles and ragged red fibers typical of a mitochondrial myopathy. Ultrastructural studies may reveal pathognomonic accumulations of 8.5 nm filaments in a proportion of myonuclei. Recently, diagnosis by DNA analysis has become available. The disease is associated with a GCG triplet expansion at the poly-A binding protein 2 (PABP2) gene at 14q11. It is suggested that this expansion might cause mutated PABP2 monomers to aggregate in nuclei, resulting in filament accumulations.
Distal myopathies
Several neuromuscular diseases present with distal weakness and wasting of the limbs. This pattern commonly results from peripheral neuropathies, including Charcot–Marie–Tooth disease, and from anterior horn cell diseases such as spinal muscular atrophy. It can also be encountered in primary muscle diseases, notably myotonic dystrophy, congenital myopathies and inclusion body myositis. In addition, several rare forms of genetically determined distal myopathy have been described. These can be distinguished to some degree by mode of inheritance and whether the anterior or posterior compartment of the lower legs is principally affected. A common form is Miyoshi myopathy, which particularly affects the gastrocnemius and soleus muscles. Like LGMD2B, it is a dysferlinopathy. Several of these diseases are rimmed vacuolar myopathies, a feature shared with the hereditary inclusion body myopathies.
Congenital myopathies
Congenital myopathies are classified on the basis of specific histological features. Patients can present at any time from childhood to adult life, usually with distal weakness. A long, thin facies and high arched palate are common. This group of disorders includes centronuclear and myotubular myopathies, nemaline myopathy and central core disease.
Myotonic disorders
Myotonia is prolonged contraction of muscle, with subsequent slowed relaxation, following activation. It results from genetic or acquired changes in excitability of muscle surface membranes and is found in several primary muscle diseases. Neuromyotonia is a clinically similar phenomenon of neurogenic origin.
Limb-girdle muscular dystrophies
Limb-girdle muscular dystrophies (LGMDs):
The limb-girdle pattern of muscular weakness is the most common dystrophic phenotype in adults. This syndrome affects perhaps 1/100,000 of the population. However, this clinical picture can result from several pathologies including spinal muscular atrophy and inflammatory and mitochondrial myopathies, in addition to limb-girdle dystrophies, so full investigation is mandatory
Limb-girdle muscular dystrophies are a complex, genetically heterogeneous group of disorders, but can be divided into two broad clinical groups.
Milder forms usually present in the second to third decade, with progressive difficulty walking followed by proximal arm weakness and loss of ambulation after 20–30 years; however, age of onset and progression vary considerably, even within families. Cranial and bulbar musculature is unaffected. The neck muscles become weak. The muscles of the shoulder and pelvic girdles, and the proximal arm and leg muscles become weak and wasted. Distal involvement and calf hypertrophy is vari- able. Bilateral scapular winging is a typical and often early fea- ture. Family history may reveal either dominant or recessive inheritance, but many cases are sporadic.
Severe forms present in childhood. Severe childhood autosomal recessive muscular dystrophy (SCARMD) is clinically similar to DMD and is the most common cause of a DMD-like phenotype in girls. However, cardiac and mental functions are unaffected. Five gene loci for autosomal dominant LGMD and eight genes for autosomal recessive disease have been discovered (LGMD1A–E and LGMD2A–H, respectively). SCARMD has been shown to result from absence of dystrophin-associated glycoproteins (sarcoglycans), which anchor one end of the dystrophin molecule to the sarcolemma. LGMD2A results from deficiency of an enzyme (calpain 3) rather than a structural protein. LGMD2B results from deficiency of dysferlin (dysferlin deficiency is also the cause of Miyoshi myopathy, a form of distal myopathy both phenotypes have been reported within single families). Diagnosis by immunohistochemistry and immunoblotting is now available for some of these diseases. Creatinine kinase levels are increased by tenfold to more than 100-fold, and biopsy findings may range from mild, nonspecific dystrophic changes in milder forms to severe, often very focal fiber necrosis in SCARMD.
Management
There is no specific treatment, but gene therapy trials are planned for sarcoglycanopathies. The genes involved are smaller than the dystrophin gene and should pose less problems with regard to gene vectors.
Emery–Dreifuss muscular dystrophy (EDMD) presents in childhood with progressive weakness and wasting of the scapulohumeral and anterior tibial and peroneal muscle groups. It probably accounts for most forms of ‘scapuloperoneal muscular dystrophy’. Muscle contractures develop at an early stage, leading to a pathognomonic posture with elbow flexion, equinovarus ankle deformities and fixed neck flexion. Cardiac involvement is prominent, leading to serious conduction disorders and sometimes sudden death. Prophylactic pacemaker insertion can be life-saving. In X-linked forms, muscle immunohistochemistry demonstrates deficiency of a nuclear membrane protein (emerin). An autosomal dominant form of EDMD caused by deficiency of lamin A/C, another nuclear membrane protein, has been described. The precise function of these proteins is unknown.
Bethlem myopathy is a relatively benign, autosomal dominant condition that progresses insidiously from infancy, causing increasing difficulty with running, then walking and standing. Significant disability develops in old age. Characteristic flexion contractures of the fingers but not thumbs (‘prayer sign’) are diagnostic, and are associated with contractures of the elbows, equinovarus ankle deformities and other joint contractures in most patients. Increases in CK are modest, and electromyography (EMG) and biopsy findings are of nonspecific myopathic type. The disease is caused by a deficiency of type VI collagen in the extracellular matrix of muscle fibers, and mutations of several collagen VI subunit genes have been identified.
Congenital muscular dystrophies present at birth or in the first few weeks of life, with proximal weakness and delayed milestones. Contractures are common and biopsy shows marked dystrophic features. The main differential diagnosis is spinal muscular atrophy. CNS involvement with mental retardation occurs in some forms. The genetic abnormalities and specific protein deficiencies have been defined for several of these diseases.
The limb-girdle pattern of muscular weakness is the most common dystrophic phenotype in adults. This syndrome affects perhaps 1/100,000 of the population. However, this clinical picture can result from several pathologies including spinal muscular atrophy and inflammatory and mitochondrial myopathies, in addition to limb-girdle dystrophies, so full investigation is mandatory
Limb-girdle muscular dystrophies are a complex, genetically heterogeneous group of disorders, but can be divided into two broad clinical groups.
Milder forms usually present in the second to third decade, with progressive difficulty walking followed by proximal arm weakness and loss of ambulation after 20–30 years; however, age of onset and progression vary considerably, even within families. Cranial and bulbar musculature is unaffected. The neck muscles become weak. The muscles of the shoulder and pelvic girdles, and the proximal arm and leg muscles become weak and wasted. Distal involvement and calf hypertrophy is vari- able. Bilateral scapular winging is a typical and often early fea- ture. Family history may reveal either dominant or recessive inheritance, but many cases are sporadic.
Severe forms present in childhood. Severe childhood autosomal recessive muscular dystrophy (SCARMD) is clinically similar to DMD and is the most common cause of a DMD-like phenotype in girls. However, cardiac and mental functions are unaffected. Five gene loci for autosomal dominant LGMD and eight genes for autosomal recessive disease have been discovered (LGMD1A–E and LGMD2A–H, respectively). SCARMD has been shown to result from absence of dystrophin-associated glycoproteins (sarcoglycans), which anchor one end of the dystrophin molecule to the sarcolemma. LGMD2A results from deficiency of an enzyme (calpain 3) rather than a structural protein. LGMD2B results from deficiency of dysferlin (dysferlin deficiency is also the cause of Miyoshi myopathy, a form of distal myopathy both phenotypes have been reported within single families). Diagnosis by immunohistochemistry and immunoblotting is now available for some of these diseases. Creatinine kinase levels are increased by tenfold to more than 100-fold, and biopsy findings may range from mild, nonspecific dystrophic changes in milder forms to severe, often very focal fiber necrosis in SCARMD.
Management
There is no specific treatment, but gene therapy trials are planned for sarcoglycanopathies. The genes involved are smaller than the dystrophin gene and should pose less problems with regard to gene vectors.
Emery–Dreifuss muscular dystrophy (EDMD) presents in childhood with progressive weakness and wasting of the scapulohumeral and anterior tibial and peroneal muscle groups. It probably accounts for most forms of ‘scapuloperoneal muscular dystrophy’. Muscle contractures develop at an early stage, leading to a pathognomonic posture with elbow flexion, equinovarus ankle deformities and fixed neck flexion. Cardiac involvement is prominent, leading to serious conduction disorders and sometimes sudden death. Prophylactic pacemaker insertion can be life-saving. In X-linked forms, muscle immunohistochemistry demonstrates deficiency of a nuclear membrane protein (emerin). An autosomal dominant form of EDMD caused by deficiency of lamin A/C, another nuclear membrane protein, has been described. The precise function of these proteins is unknown.
Bethlem myopathy is a relatively benign, autosomal dominant condition that progresses insidiously from infancy, causing increasing difficulty with running, then walking and standing. Significant disability develops in old age. Characteristic flexion contractures of the fingers but not thumbs (‘prayer sign’) are diagnostic, and are associated with contractures of the elbows, equinovarus ankle deformities and other joint contractures in most patients. Increases in CK are modest, and electromyography (EMG) and biopsy findings are of nonspecific myopathic type. The disease is caused by a deficiency of type VI collagen in the extracellular matrix of muscle fibers, and mutations of several collagen VI subunit genes have been identified.
Congenital muscular dystrophies present at birth or in the first few weeks of life, with proximal weakness and delayed milestones. Contractures are common and biopsy shows marked dystrophic features. The main differential diagnosis is spinal muscular atrophy. CNS involvement with mental retardation occurs in some forms. The genetic abnormalities and specific protein deficiencies have been defined for several of these diseases.
Myopathies
Muscle disorders may be genetically determined or may result from autoimmune disorders, systemic diseases or the effects of a variety of exogenous toxins. They can be classified in terms of causative genetic mutations, by specific protein deficiencies, on the basis of histopathological changes, by pathogenic mechanisms, and by clinical phenotype. Molecular classifications change as knowledge increases, so a clinicopathological classification remains satisfactory for practical purposes. Only the most common of the very large number of muscle diseases are discussed in this contribution. Genetically determined myopathies There are four main groups of genetic myopathies. Muscular dystrophies are generally characterized by fiber necrosis and replacement of muscle by fat and fibrous connective tissue. However, some diseases classified as ‘dystrophies’ show less conspicuous pathology and in some there is evidence of muscle fiber degeneration by apoptosis (programmed cell death). Different types of muscular dystrophy can sometimes be recognized by clinical features (e.g. muscle hypertrophy, contractures, evidence of cardiac involvement) and by the pattern of involvement of muscle groups. Three main patterns are evident – axial and limb girdle weakness, non-limb girdle weakness pattern with prominent involvement of cranial musculature, and distal weakness. Congenital myopathies are classified by specific histopathological and ultrastructural features. Myotonias and periodic paralyses are associated with dis- orders of muscle ion channels (muscle channelopathies). Genetically determined metabolic myopathies include disorders of glycogen and lipid metabolism, malignant hyperthermia and the mitochondrial cytopathies.
Muscular dystrophies
Muscular dystrophies with predominantly axial and limb girdle weakness.
Patients with Duchenne and Becker dystrophies typically (but not invariably) have muscle hypertrophy, particularly of the calves; limb girdle dystrophies usually feature prominent scapular winging, whereas in Emery–Dreifuss dystrophy and Bethlem myopathies, muscle contractures are a prominent feature, as is the case in some congenital dystrophies.
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD):
DMD is an X-linked disease that nearly always affects only males. The incidence is about 1/3500 live male births. It is diagnosable at birth, but the diagnosis is seldom made until age 3–6 years or later, by which time a carrier mother may already have conceived another affected child. The condition causes delay in motor milestones. Muscle involvement is typically selective, affecting the girdles, axial muscles and proximal limbs, particularly the legs; this results in problems rising from the floor (Gowers’ manoeuvre) and the development of excessive lumbar lordosis. The calf muscles typically become enlarged (sometime termed ‘pseudohypertrophy’, though true fiber enlargement occurs in addition to accumulation of fat and fibrous tissue). The ability to walk is lost by about 12 years of age and death from respiratory or cardiac failure usually occurs in the 20s or early 30s. Some degree of mental retardation occurs in about one-third of patients. BMD has a much more variable clinical picture and can present from childhood to early adult life. Lifespan may be normal. The pattern of muscle involvement is similar to that of DMD but weakness is less severe, patients often remaining ambulant into their 20s. Exertional myalgia is a common presenting symptom. Calf muscle enlargement is typical and often striking. DMD and BMD are forms of dystrophinopathy. Dystrophin, a component of the cytoskeleton lying beneath the muscle fiber sarcolemma, is one of the largest proteins in the body, encoded by a gene of over 2 million base-pairs at Xp21.2. Dystrophin deficiency results in loss of structural integrity of the muscle surface membrane. Mutations of the gene may be ‘out of frame’ resulting in complete absence of dystrophin, causing DMD, or ‘in frame’, producing partial dystrophin deficiency characteristic of BMD. However, phenotypic expression of dystrophinopathies is wide and can also include limb-girdle syndrome, isolated quadriceps weakness, isolated exertional myalgia, isolated cardiomyopathy and asymptomatic ‘hyperCKaemia’. The diagnosis of dystrophinopathy may be suggested by the history and physical signs, with very high serum creatine kinase (CK), and can usually be confirmed by standard DNA analyses, which detect the common dystrophin gene deletions in 70% of patients. Point mutations are more difficult to detect, however, and most patients require muscle biopsy.
Management
Treatment with prednisone, 0.75–1.5 mg/day, has been shown to improve the natural history of DMD for up to 2 years. However, there are problems with long-term corticosteroid use. Gene therapy, using myoblasts and other cells transfected with the dystrophin mini-gene, can restore muscle dystrophin, but clinical trials have been disappointing. There is interest in the possibility of up-regulating the expression of the dystrophin analogue utrophin. Otherwise, physical therapy and the use of orthoses and surgical correction of spinal and other deformities remain the mainstays of treatment.
Muscular dystrophies
Muscular dystrophies with predominantly axial and limb girdle weakness.
Patients with Duchenne and Becker dystrophies typically (but not invariably) have muscle hypertrophy, particularly of the calves; limb girdle dystrophies usually feature prominent scapular winging, whereas in Emery–Dreifuss dystrophy and Bethlem myopathies, muscle contractures are a prominent feature, as is the case in some congenital dystrophies.
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD):
DMD is an X-linked disease that nearly always affects only males. The incidence is about 1/3500 live male births. It is diagnosable at birth, but the diagnosis is seldom made until age 3–6 years or later, by which time a carrier mother may already have conceived another affected child. The condition causes delay in motor milestones. Muscle involvement is typically selective, affecting the girdles, axial muscles and proximal limbs, particularly the legs; this results in problems rising from the floor (Gowers’ manoeuvre) and the development of excessive lumbar lordosis. The calf muscles typically become enlarged (sometime termed ‘pseudohypertrophy’, though true fiber enlargement occurs in addition to accumulation of fat and fibrous tissue). The ability to walk is lost by about 12 years of age and death from respiratory or cardiac failure usually occurs in the 20s or early 30s. Some degree of mental retardation occurs in about one-third of patients. BMD has a much more variable clinical picture and can present from childhood to early adult life. Lifespan may be normal. The pattern of muscle involvement is similar to that of DMD but weakness is less severe, patients often remaining ambulant into their 20s. Exertional myalgia is a common presenting symptom. Calf muscle enlargement is typical and often striking. DMD and BMD are forms of dystrophinopathy. Dystrophin, a component of the cytoskeleton lying beneath the muscle fiber sarcolemma, is one of the largest proteins in the body, encoded by a gene of over 2 million base-pairs at Xp21.2. Dystrophin deficiency results in loss of structural integrity of the muscle surface membrane. Mutations of the gene may be ‘out of frame’ resulting in complete absence of dystrophin, causing DMD, or ‘in frame’, producing partial dystrophin deficiency characteristic of BMD. However, phenotypic expression of dystrophinopathies is wide and can also include limb-girdle syndrome, isolated quadriceps weakness, isolated exertional myalgia, isolated cardiomyopathy and asymptomatic ‘hyperCKaemia’. The diagnosis of dystrophinopathy may be suggested by the history and physical signs, with very high serum creatine kinase (CK), and can usually be confirmed by standard DNA analyses, which detect the common dystrophin gene deletions in 70% of patients. Point mutations are more difficult to detect, however, and most patients require muscle biopsy.
Management
Treatment with prednisone, 0.75–1.5 mg/day, has been shown to improve the natural history of DMD for up to 2 years. However, there are problems with long-term corticosteroid use. Gene therapy, using myoblasts and other cells transfected with the dystrophin mini-gene, can restore muscle dystrophin, but clinical trials have been disappointing. There is interest in the possibility of up-regulating the expression of the dystrophin analogue utrophin. Otherwise, physical therapy and the use of orthoses and surgical correction of spinal and other deformities remain the mainstays of treatment.
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