• Skeletal muscle diseases, or myopathies, are disorders with structural changes or functional impairment of muscle
Clinical Features • proximal, symmetric limb weakness (arms or legs) with preserved reflexes and sensation • asymmetric and predominantly distal weakness can be seen in some myopathies • sensory loss suggests injury to peripheral nerve or the central nervous system (CNS) rather than myopathy. • On occasion, disorders affecting the motor nerve cell bodies in the spinal cord (anterior horn cell disease), the NMJ , or peripheral nerves can mimic findings of myopathy
intermittent weakness • myasthenia gravis • periodic paralyses (hypokalemic, hyperkalemic, and paramyotonia congenita) • metabolic energy deficiencies of glycolysis (especially myophosphorylase deficiency) • fatty acid utilization (carnitine palmitoyltransferase deficiency) • mitochondrial myopathies. • The states of energy deficiency cause activity- related muscle breakdown accompanied by myoglobinuria
persistent weakness • Muscular dystrophy, Polymyositis and Dermatomyositis, – the proximal muscles are weaker than the distal and are symmetrically affected, and the facial muscles are spared, a pattern referred to as limb-girdle. • Facioscapulohumeral dystrophy (FSHD). – Facial weakness (difficulty with eye closure and impaired smile) and scapular winging • Myotonic dystrophy type 1. – Facial and distal limb weakness associated with hand grip myotonia • NMJ disorders, oculopharyngeal muscular dystrophy, mitochondrial myopathies, or some congenital myopathies – cranial nerve muscles are weak, causing ptosis or extraocular muscle weakness
• Muscular dystrophy refers to a group of hereditary progressive diseases each with unique phenotypic and genetic features
Pathogenesis • Dystrophin-glycoprotein complex confer stability to the sarcolemma • deficiency of dystrophin (Duchennes dystrophy) may lead to secondary loss of the sarcoglycans and dystroglycan • Loss of a single sarcoglycan (LGMD) results in secondary loss of other sarcoglycans in the membrane without affecting dystrophin • Disruption of the dystrophin-glycoprotein complexes weakens the sarcolemma, causing membrane tears and a cascade of events leading to muscle fiber necrosis
Duchene’s muscular dystrophy • Most common muscular dystrophy • X-linked recessive disorder • Onset before age 5 Epidemiology • Incidence : ~30 per 100,000 live-born males • Age : Present at birth ,Usually becomes apparent between ages 3 and 5 • Sex : Male Etiology • XR • Deletion mutation of the gene that encodes dystrophin.
Symptoms & Signs • Onset of symptoms typically begins before age 5. • Muscular manifestations – Progressive loss of muscle strength – Predilection for proximal limb muscles and neck flexors (girdle muscles) – involvement of legs is more marked than arms. – Muscle weakness by age 5 is obvious by muscle testing.
– Common early signs and symptoms include: • Frequent falls • Difficulty keeping up with friends when playing • Abnormal running, jumping, and hopping • Use of hands to climb up (Gowers’ maneuver) when getting up from the floor • Contractures of the heel cords and iliotibial bands • Toe walking associated with a lordotic posture • Apparent by age 6– Progressive kyphoscoliosis common– Use of wheelchair typical by age 12– Respiratory failure in second or third decade
• Gowers sign• lordotic posture caused by combined trunk and hip weakness, frequently exaggerated by toe walking• Waddling gait, inability of weak hip muscles to prevent hip drop or hip dip.• Hyperextension of the knee (genu recurvatum or back-kneeing), quadriceps muscle weakness; and a steppage gait, due to footdrop, accompanies distal weakness
• Extramuscular manifestations – Cardiomyopathy in almost all patients • Arrhythmias are rare.• Intellectual impairment common – Average IQ approximately 1 standard deviation below mean – Appears to be nonprogressive – Verbal ability more affected than performance
Laboratory Tests • Serum CK – Elevated to between 20 and 100 times normal – Abnormal at birth but declines late in the disease because of inactivity and loss of muscle mass
Mutation analysis on peripheral bloodleukocytes• Identification of a specific mutation in dystrophin gene – Allows for unequivocal diagnosis – Makes possible accurate testing of potential carriers – Is useful for prenatal diagnosisDiagnostic Procedures• EMG -> Myopathic
Muscle biopsy• Muscle fibers of varying size• Small groups of necrotic and regenerating fibers• Connective tissue and fat replace lost muscle fibers.• Definitive diagnosis is established on the basis of dystrophin deficiency.• Diagnosis can also be made by Western blot analysis of muscle biopsy• specimens. – Abnormalities on the quantity and molecular weight of dystrophin protein
• Immunocytochemical staining of muscle with dystrophin antibodies – Can be used to demonstrate absence or deficiency of dystrophin – localizing to the sarcolemmal membrane – Possible mosaic pattern in carriers of the disease – Dystrophin analysis of muscle biopsy specimens for carrier detection not reliable
Left:Dystrophin immunostain; right:Spectrin (control) immunostain. Myofiber loss
Treatments Prednisone 0.75 mg/kg per d – Significantly slows progression for up to 3 years – Some patients cannot tolerate glucocorticoid therapy • Weight gain is significant – Complications of long-term use often outweigh the benefits.
Katharine Bushby et al; Lancet Neurol 2009; published online Nov 30. DOI:10.1016/S1474-4422(09)70271-6.
Katharine Bushby et al; Lancet Neurol 2009; published online Nov 30. DOI:10.1016/S1474-4422(09)70271-6.
Exon skipping therapy • Duchennes disease may benefit from novel therapies that either replace the defective gene or missing protein or implement downstream corrections (e.g., skipping mutated exons or reading through mutations that introduce stop codons).
Complications • Tendon and muscle contractures • Progressive kyphoscoliosis • Impaired pulmonary function • Cardiomyopathy • Intellectual impairment
Prognosis • Between ages 8 and 10 – Walking may require use of braces. – Joint contractures and limitations of hip flexion, knee, elbow, and wrist extension are worsened by prolonged sitting. • By age 12 – Most patients are wheelchair-dependent. – Contractures become fixed. – Progressive scoliosis often develops. • May be associated with pain – Chest deformity occurs with scoliosis. • Impairs pulmonary function, already diminished by muscle weakness
• By age 16–18 – Predisposition to serious pulmonary infections• Respiratory failure in second or third decade• Causes of death include: – Pulmonary infections – Aspiration – Acute gastric dilation – A cardiac cause of death is uncommon
Becker’s Muscular dystrophy • Less-severe form of XR muscular dystrophy • allelic defects of same gene of Duchenne Epidemiology • Incidence : – 3 per 100,000 live-born males – ~10 times less frequent than Duchenne • Age : – Most between ages 5 and 15 – Onset in the third or fourth decade or even later can occur • Sex : Male
Symptoms & Signs • Onset of symptoms occurs between ages 5 and 15. • Muscular manifestations – Pattern of muscle wasting closely resembles Duchenne. – Progressive weakness of girdle muscles, especially of lower extremities – Weakness becomes generalized as disease progresses. – Hypertrophy, particularly in calves, is an early and prominent finding. – By definition, patients walk beyond age 15 (whereas patients with Duchenne dystrophy are typically in a wheelchair by the age of 12). – Significant facial muscle weakness is not a feature. – Respiratory failure may develop by fourth decade.
• Extramuscular manifestations – Cardiac, may result in heart failure – Mental retardation may occur, not as common as in Duchenne• Other less common presentations – Asymptomatic hyper-CK-emia – Myalgias without weakness – Myoglobinuria
Laboratory Tests • Serum CK – Closely resembles findings in Duchenne dystrophy • Mutation analysis on peripheral blood leukocytes – Deletions or duplications of the dystrophin gene in 65% of patients (same as in Duchennes dystrophy) – 95% of patients, the DNA deletion does not alter the translational reading frame of mRNA. These "in-frame" mutations allow for production of some dystrophin, which accounts for the presence of altered rather than absent dystrophin on Western blot analysis • EMG – Myopathic
• Muscle biopsy – Results closely resemble those in Duchenne dystrophy. – Diagnosis requires Western blot analysis of muscle biopsy samples demonstrating a reduced amount or abnormal size of dystrophin.
Treatments • Use of glucocorticoids has not been adequately studied • Endurance training may be helpful
Limb-Girdle muscular dystrophy • Represents more than 1 genetic disorder • Systematic classification is based on inheritance pattern – Autosomal dominant (LGMD1) – Autosomal recessive (LGMD2) – Classification employs a sequential alphabetical lettering system (LGMD1A, LGMD2A, etc.) • Highly variable range of onset across disorders, although most present in first 3 decades of life
Epidemiology• Incidence – Data have not been systematically gathered for any large heterogeneous population. – Less common than dystrophinopathies• Age – Onset ranging from late in the first decade to the fourth decade• Sex – Affects both male and female
Etiology• Autosomal dominant (LGMD1) – Presently there are 5 autosomal dominant disorders identified.• Autosomal recessive (LGMD2) – Presently there are 12 autosomal recessive disorders identified
Symptoms & Signs • Onset of symptoms varies widely across this group of diseases, usually in first three decades of life. • Muscular manifestations – Slow, progressive weakness of pelvic and shoulder girdle musculature – Respiratory insufficiency from weakness of the diaphragm may occur. • Extramuscular manifestations – Cardiomyopathy may occur. – Intellectual function is unaffected.
Laboratory Tests • Serum CK – As the syndrome represents multiple disorders, CK levels are highly variable. • EMG – Myopathic, with mixed myopathy/neuropathy in LGMD1A
Treatment • Supportive care, including ambulatory aids if necessary, should be offered for neuromuscular disability. • Stretching of contractures is difficult • Management of cardiomyopathy and arrhythmias can save lives.
Complications • Complications (e.g., cardiac, respiratory) vary with the specific subtype of disease
Emery-Driefuss muscular dystrophy Epidemiology • Age – Early childhood and teenage years Etiology • There are 2 genetically distinct forms. – X-linked : • Emerin mutations most common • FHL1 mutation also simila phenotype – AD • Mutations LMNA gene for lamin A/C( LGMD1B) , but clinical symptoms are closely related
Symptoms & Signs • Onset of symptoms occurs in early childhood or teenage years. • Muscular manifestations – Muscle weakness • Affects humeral and peroneal muscles first • Later spreads to a limb-girdle distribution • Prominent contractures in early childhood and teenage years – Often precede muscle weakness – Most commonly occur at the elbow and neck – Persist throughout course of disease
• Extramuscular manifestations – Cardiomyopathy • Potentially life threatening, may result in sudden cardiac death • Likely related to a spectrum of abnormal atrial rhythms and conduction defects (includes atrial fibrillation and atrioventricular heart block) • Some patients have a dilated cardiomyopathy • Female carriers of the X-linked variant may have cardiac manifestations that become clinically significant.
Laboratory Tests • Serum CK – May be elevated 2- to 10-fold • EMG – Myopathic • Muscle biopsy – Nonspecific dystrophic features – Immunohistochemistry reveals absent emerin staining of myonuclei in X-linked Emery- Dreifuss. • EKG – Atrial and atrioventricular rhythm disturbances
Treatment • Supportive care, including ambulatory aids if necessary, should be offered for neuromuscular disability • Stretching of contractures is difficult • Management of cardiomyopathy and arrhythmias can save lives
Complication • Contractures • Cardiomyopathy • A spectrum of atrial rhythm and conduction defects • Includes atrial fibrillation and paralysis and atrioventricular heart block • Sudden death
Congenital Muscular Dystrophy (CMD) • A group of autosomal recessive disorders • Symptoms present at birth or within first few months • Merosin deficiency • Fukutin-related protein deficiency • Fukuyama congenital muscular dystrophy (FCMD) • Muscle-eye-brain (MEB) disease • Walker-Warburg syndrome (WWS) – the most severe, causing death by 1 year of age.
Laboratory Tests Serum CK • Markedly elevated • Merosin deficiency: 5–35 times normal • Fukutin-related protein deficiency: 10–50 times normal • FCMD: 10–50 times normal • MEB disease: 5–20 times normal • WWS: 5–20 times normal EMG • Myopathic
MRI brain• FCMD – Hydrocephalus – Periventricular and frontal hypomyelination• MEB disease – Hydrocephalus – Cobblestone lissencephaly – Corpus callosum and cerebellar hypoplasia – Cerebral hypomyelination• WWS – Cobblestone lissencephaly – Hydrocephalus – Encephalocoele – Absent corpus callosum
• Muscle biopsy – Nonspecific dystrophic features – In merosin deficiency, merosin, or laminin α2 chain (a basal lamina protein), is deficient surrounding muscle fibers. – In other disorders (fukutin-related protein deficiency, FCMD, MEB disease, WWS), abnormal dystroglycan staining in muscle.
Treatment • No specific treatment is available • Proper wheelchair seating is important • Management of epilepsy and cardiac manifestations is necessary for some patients
Complications • Contractures • Respiratory failure • Central nervous system is affected in some forms – Mental retardation – Seizures – Ocular abnormalities impairing vision
Myotonic dystrophy • Also called dystrophia myotonica (DM) • Two autosomal dominant forms have been identified: DM1 and DM2. • unlike other muscular dystrophies because it is a multi-system disorder that presents in a large variety of ways
Epidemiology• Prevalence – 1 in 8,000• Age – Usually second decade – May be infancy if mother affected (DM1 only)Etiology• At least 2 clinical disorders with overlapping phenotype. – DM1: AD – DM2 [also called proximal myotonic myopathy (PROMM)]: AD
Patogenesis • DM1 is transmitted by an intronic mutation consisting of an unstable expansion of a CTG trinucleotide repeat in a serine-threonine protein kinase gene (named DMPK) on chromosome 19q13.3. • The repeat CTG occurs up to 35 times in unaffected individuals. In patients with myotonic dystrophy, the number of repeats is greater than 50. • An increase in the severity of the disease phenotype upon increase in the number of trinucleotide repeats • The unstable triplet repeat in myotonic dystrophy can be used for prenatal diagnosis.
• Congenital disease occurs almost exclusively in infants born to affected mothers• DM2 is caused by a DNA expansion mutation consisting of a CCTG repeat in intron 1 of the ZNF9 gene located at chromosome 3q13.3-q24.• The gene is believed to encode an RNA- binding protein expressed in many different tissues, including skeletal and cardiac muscle.
Nature Reviews Drug Discovery 10, 621-637 (August 2011)
Symptoms & Signs Muscular manifestations • Slowly progressive weakness of face, neck, shoulder girdle, and distal extremities (hands and feet) – Face and neck • Temporalis, masseter, and facial muscle atrophy and weakness – Result in typical "hatchet-faced" appearance – Less consistent in DM2 • Frontal baldness characteristic in men – Less consistent in DM2 – Palatal, pharyngeal, and tongue involvement • Produces dysarthric speech, nasal voice, and difficulty swallowing – Neck muscles, including flexors and sternocleidomastoids, involved early – Distal extremities • Weakness of wrist extensors, finger extensors, and intrinsic hand muscles impairs function. • Ankle dorsiflexor weakness may cause footdrop.
• Proximal muscles remain stronger throughout the course. – Preferential atrophy and weakness of quadriceps may occur. – DM2, or PROMM, has a distinct pattern of muscle weakness affecting mainly proximal muscles.• Some patients have diaphragm and intercostal muscle weakness. – Results in respiratory insufficiency• Myotonia usually appears by age 5. – percussion of the thenar eminence, tongue, and wrist extensor muscles – Causes a slow relaxation of hand grip after a forced voluntary closure – Advanced muscle wasting makes myotonia more difficult to detect
Extramuscular manifestations• Non-neuromuscular – Daytime Hypersomnia – Nocturnal hypoventilation• GI symptom – delayed gastric emptying – smooth muscle and sphincter dysfunction – bile acid malabsorption – small bowel bacterial overgrowth• Endocrine complications – Insulin resistance diabetes mellitus (4 times) – Gonadal atrophy• Respiratory complications – Reduced central drive and respiratory muscle weakness contribute to nocturnal hypoventilation.
• Cardiac involvement – common in DM1 – sudden death 10–30% of patients – Not correlate with the degree weakness or size of repeat expansion – Conduction abnormalities (atrioventricular common CHB) – arrhythmias (atrial more common) – cardiomyopathy is rare – CHF occurs infrequently but may result from cor pulmonale secondary to respiratory failure. – MVP is common. – Conduction defects are less common in DM2• CNS and eyes – Intellectual impairment – reduced drive and reduced ability to sustain interest in activities – Posterior subcapsular cataracts
• Pregnancy and delivery risks – involvement of uterine smooth muscle – impaired fetal swallowing and movement – risk of placenta praevia, polyhydramnios, preterm birth, and postpartum haemorrhage
Laboratory test • Serum CK – May be normal or mildly elevated • EMG – Evidence of myotonia is present in most cases of DM1 but may be more patchy in DM2.
Muscle biopsy• Muscle atrophy – Selectively involves type 1 fibers in 50% of cases – Ringed fibers in DM1 but not in DM2• Typically, numerous internalized nuclei can be seen in individual muscle fibers as well as atrophic fibers with pyknotic nuclear clumps in both DM1 and DM2.• Necrosis of muscle fibers and increased connective tissue not common
• atrophy of type 1 fibers, a profusion of central nuclei (normally myonuclei are under the sarcolemma), and ring fibers.
• EKG – Abnormalities include first-degree heart block and more extensive conduction system involvement.
Complications • increased risk of complications of general anaesthesia, such as hypotension, pulmonary aspiration, and respiratory depression
Treatments • Myotonia in DM1 rarely warrants treatment. • Some patients with DM2 experience significant discomfort related to the associated muscle stiffness. – Phenytoin and mexiletine are preferred agents for the occasional patient who requires an anti-myotonia drug. • Other agents, particularly quinine and procainamide, may worsen cardiac conduction. • Cardiac pacemaker insertion should be considered for patients with: – Unexplained syncope – Advanced conduction system abnormalities with evidence of second-degree heart block – Trifascicular conduction disturbances with marked prolongation of the PR interval
• Molded ankle-foot orthoses – Help prevent footdrop in patients with distal lower extremity weakness• Excessive daytime somnolence with or without sleep apnea: not uncommon, and patient may benefit from: – Sleep studies – Noninvasive respiratory support (BiPAP) – Modafinil
Genetic counselling in myotonic dystrophy • The smallest expansions of 50 to 60 repeats are found in older, unaffected, or mildly affected individuals, in topmost generations of the family • repeat size rises in the mutation next generation. • Relatives of patient are risk – symptomatic DNAbased diagnostic test – asymptomatic discuss the genetic of family history, options such as DNA-based presymptomatic or prenatal testing • symptomatic mother higher chance that infant who inherits the mutation has congenital disease • females have a congenitally affected child, next children inheriting the mutation are always congenitally affected.
• Symptomatic children are assessed by a paediatrician or neurologist• Genetic testing of the asymptomatic child is not recommended• Anxious parents request testing of their healthy children but after detailed discussion, it is usually postponed until the child is mature and can make informed decision.• For couples who avoid affected pregnancy, in vitro fertilisation techniques and pre- implantation genetic diagnosis
Figure 2 Nuclear RNA retention in DM1 causes alteration of the function of MBNL1 and CUGBP1 proteins and subsequent downstream RNA mis-splicingBiology of the Cell 2010 102, 515-523 - Nikolas P. Mastroyiannopoulos, Christos Shammas and Leonidas A. Phylactou www.biolcell.org
Nature Reviews Drug Discovery 10, 621-637 (August 2011)
Facioscapulohumoral (FSH)muscular dystrophy Epidemiology • Prevalence – ~5 in 100,000 • Age – Childhood or young adulthood • Etiology • Autosomal dominant with almost complete penetrance • Each family member should be examined for presence of disease, because ~30% of those affected are unaware of involvement. • Caused by deletions of distal 4q – Mutation permits carrier detection and prenatal diagnosis. – Most sporadic cases represent new mutations.
Symptoms & Signs • Onset of symptoms occurs in childhood or early adulthood. • Muscular manifestations – Slowly progressive weakness of face, shoulder girdle, and foot dorsiflexion – Facial weakness is typically the initial manifestation. • Inability to smile, whistle, or fully close the eyes – Weakness of shoulder girdles usually brings patient to medical attention. • Loss of scapular stabilizer muscles makes arm elevation difficult. • Scapular winging is apparent with attempts at abduction and forward movement of the arms.
• Biceps and triceps muscles may be severely affected. – Relative sparing of the deltoid muscles• Weakness is worse for wrist extension than for wrist flexion.• Weakness of the anterior compartment muscles of the legs may lead to footdrop.• In 20% of patients, weakness progresses to involve pelvic girdle muscles. – Results in severe functional impairment and possible wheelchair dependency
• Extramuscular manifestations – Characteristically, patients do not have involvement of other organ systems. • Labile hypertension common • Increased incidence of nerve deafness • Coats’ disease, a disorder consisting of telangiectasia, exudation, and retinal detachment
Laboratory tests • Serum CK – May be normal or mildly elevated • EMG – Usually indicates a myopathic pattern • Muscle Biopsy – Nonspecific features of a myopathy – A prominent inflammatory infiltrate present in some biopsy samples Often multifocal in distribution
treatment • No specific treatment is available. • Ankle-foot orthoses are helpful for footdrop. • Scapular stabilization procedures – Improve scapular winging but may not improve function
Oculopharyngeal dystrophy Epidemiology • Age – Onset in fifth and sixth decades • Geographic and ethnic distribution – Incidence is high in French-Canadians and in Spanish-American families of the southwestern U.S. – Large kindreds of Italian and of eastern European Jewish descent have been reported.
• AD with complete penetrance• Molecular defect is a subtle expansion of a modest polyamine repeat tract• in a poly-RNA binding protein (PABP2) in muscle.
Symptoms & Signs • Onset of symptoms occurs in fifth and sixth decades of life. • Slowly progressive weakness of: – Extraocular muscles – Pharyngeal muscles – Limb muscles • Progressive external ophthalmoplegia – Slowly progressive ptosis – Limitation of eye movements – Sparing of pupillary reactions for light and accommodation – Patients usually do not complain of diplopia. • Dysphagia – May become debilitating – May result in pooling of secretions and repeated episodes of aspiration • Mild weakness of neck and extremities may also occur.
Laboratory test • Serum CK – May be 2–3 times normal • EMG – Myopathic • Muscle biopsy – Muscle fibers contain vacuoles. – Electron microscopy shows membranous whorls, accumulation of glycogen, and other nonspecific debris related to lysosomes. – A distinct feature is the presence of tubular filaments, 8.5 nm in diameter, in muscle cell nuclei.
Treatment • Cricopharyngeal myotomy – May improve swallowing – Does not prevent aspiration • Eyelid crutches – Can improve vision when ptosis obstructs vision – Candidates for ptosis surgery must be carefully selected. – Those with severe facial weakness are usually not suitable.
Distal Myopathies • A group of muscle diseases, the distal myopathies, are notable for their preferential distal distribution of muscle weakness in contrast to most Muscular Dystrophies and Other Muscle Diseases muscle conditions associated with proximal weakness.
Laboratory test • Serum CK – Miyoshis myopathy is very elevated – In the other conditions, serum CK is only slightly increased. • EMGs – myopathic. – MFMs, myotonic or pseudomyotonic discharges are common. • Muscle biopsy – Often show nonspecific dystrophic features rimmed vacuoles. – MFM is associated with the accumulation of dense inclusions, as well as amorphous material best seen on Gomoris trichrome and myofibrillar disruption on electron microscopy. – MFM Immune staining sometimes demonstrates accumulation of desmin and other proteins – Laings myopathy large deposits of myosin heavy chain in the subsarcolemmal region of type 1 muscle fibers – Miyoshis myopathy reduced or absent dysferlin
Treatment • Occupational therapy is offered for loss of hand function • ankle-foot orthoses can support distal lower limb muscles
Complication • The MFMs can be associated with cardiomyopathy (congestive heart failure or arrhythmias) and respiratory failure • Laings-type distal myopathy can also be associated with a cardiomyopathy