PT 830 Muscular Dystrophies 2024 PDF

Muscular Dystrophies PT 830 Neuromuscular Pathology Summer 2024 Objectives  Describe the etiology, pathophysiology and signs & symptoms of the Muscular Dystrophies  Describe the various forms of Muscular Dystrophy (MD) and compare & contrast signs & symptoms  Identify diag...

Muscular Dystrophies PT 830 Neuromuscular Pathology Summer 2024 Objectives  Describe the etiology, pathophysiology and signs & symptoms of the Muscular Dystrophies  Describe the various forms of Muscular Dystrophy (MD) and compare & contrast signs & symptoms  Identify diagnostic parameters and tests used to determine a medical diagnosis of MD  Describe the general course of, and prognosis for, the various forms of Muscular Dystrophy  Discuss the medical and/or surgical management of MD  Identify key rehabilitation considerations for individuals with MD Muscular Dystrophies (MD) Definition A group of genetic disorders characterized by progressive muscle weakness and degeneration  Typically symmetric muscle wasting with increasing deformity and disability Forms of hereditary myopathy  Each form has its own unique genetic and phenotypic characteristics Most common group of inherited progressive neuromuscular disorders of childhood Signs can occur at any point in the lifespan MDs as a whole affect 250,000 individuals in U.S. Classification of Muscular Dystrophy Duchenne Muscular Dystrophy(DMD) Becker’s Muscular Dystrophy (BMD) Limb-girdle Muscular Dystrophy (LGMD) Facioscapulohumeral Dystrophy (FSHD) Scapuloperoneal Muscular Dystrophy Congenital Muscular Dystrophy (CMD) Muscular Dystrophy Congenita (MDC) Myotonic Dystrophy Emery- Dreifuss Muscular Dystrophy (EDMD) Duchenne Muscular Dystrophy (DMD) Duchenne Muscular Dystrophy It is the most common and most severe form of dystrophic disorders Presents in early childhood Characterized by: Rapid progression of weakness Rapid progression of disability/loss of walking Early death (in 20’s – 30’s…) DMD - Incidence 1 in 3500 live male births worldwide Inherited disorder  X-linked inheritance pattern  Male offspring inherit the disease from their asymptomatic mothers DMD - Pathogenesis Genetics The affected gene “dystrophin” is located on the short arm of the X chromosome (Xp21) X-linked, recessive disorder  Males clinically affected  Females are carriers 70% are due to deletion or duplication 30% arise from mutation (1 in 10,000)  No familial history of DMD  DMD - Pathogenesis Dystrophin is a protein located in the muscle membrane (sarcolemma) Links the muscle surface membrane with the actin (contractile muscle protein) Lack of dystrophin results in weakened muscle cell membrane that is easily damaged during muscle contraction – relaxation cycles DMD - Pathogenesis Lack or absence of dystrophin Destabilizes the membrane Allows calcium influx Activation of a calcium-activated proteinase Destruction of the cell Muscle cells are replaced by fatty & connective tissue DMD - Clinical Picture Onset Pathology is evident in utero and neonatal muscles Symptoms remain unnoticed until early childhood  Between ages 2 and 4 years Early clinical features include:  Delayed motor development  Delayed walking  50% are unable to walk at 18 months  DMD - Clinical Picture Child is identified as having DMD when he exhibits: Difficulty getting up from floor Difficulty climbing stairs Difficulty running Tendency to fall Increased lumbar lordosis Walking with wide-based/waddling gait DMD – Clinical Picture Muscle weakness Characteristic gait Calf hypertrophy Difficulty climbing Decreased muscle stairs mass Clumsiness Diminished DTR’s Falls (due to muscle Other wasting) complications Gowers’ sign Scoliosis Difficulty walking Contractures and running Comorbidities DMD – Clinical Picture Muscle weakness Becomes apparent at ages 3 to 5 (demonstrated on MMT) Symmetrical Proximal > distal Lower extremities and torso more affected than upper extremities Shoulder girdle weakness  Excessive scapular winging  Difficulty in performing overhead activities  Inability to use assistive devices for ambulation Steady decline in strength from 6 to 11 years old DMD – Clinical Picture Calf hypertrophy Present at age 5 to 6 years Pseudohypertrophy  Muscle tissue replaced by fat and fibrous tissue Other muscles may look enlarged  Gluteus  Vastus lateralis  deltoid DMD – Clinical Picture Decreased muscle mass Diminished deep tendon reflexes Sensation normal This is a muscular problem only. Effects muscle proteins  DMD – Clinical Picture Gowers’ sign Difficulty rising from the floor Valuable clinical sign Describes the maneuver the child uses to get up from the floor  Standing up with the aid of hands pushing on knees and thighs  “walks hands up the legs” Gowers’ Sign DMD – Clinical Picture Walking is characterized by: Excessive lumbar lordosis  Weak abdominal and hip extensor muscles  Keeps the LOG behind the hip during standing and walking Protruded abdomen  Weak abdominal muscles  Abdomen sticks out because you can’t suck your core in Waddling gait  Wide base of support  Positive Trendelenburg’s sign  Weak hip abductors  DMD – Clinical Picture Walking is characterized by: Knee instability/excessive extension  Weak quadriceps  Hyperextension keeps LOG anterior to the joint Toe walking  Contracture of posterior calf muscles  Weakness of dorsiflexors and quadriceps Loss of ambulation by age 10 -12 years Clinical Progression Weakness is steadily progressive Proximal muscles tend to be weaker earlier in the course of the illness and to progress faster Lumbar lordosis Wide base of support with gait Contracture development Slow functional activities Boys Progress from here….. To There…. 5 year old baseline & 1 year later 6 year old base line & 1 year later  Progression: By age Birth to 2 years: late acquisition of milestones, especially walking 3-5 years: toe walking, clumsiness, pseudohypertrophy of calves, Gower’s Sign 6-8 years: toe walking, lordosis, inability to climb stairs without assistance, wide based waddling gait, can not rise from floor without help. 9-11 years: walks with braces, scoliosis, may have orthopedic surgery, beginning respiratory insufficiency  Progression: By age 12-14 years: Loss of ambulation, increased respiratory difficulties, obesity, contractures, progression of scoliosis, dependent for transfers, needs assist with ADL’s 15-17 years: Dependent in most ADL’s, may need assisted ventilation 18+ years: Totally dependent, assisted ventilation, death comes after a period of declining cardio-respiratory function In Recent Years with Treatment: Survival into the early 30s is becoming more common. DMD – Clinical Picture Complications Contractures Secondary to muscle weakness and muscle imbalance  Ankle plantarflexors  Hip flexors Scoliosis  Occurs at a rate of more than 80%  Progresses more rapidly after loss of ambulation  Spinal fusion considered when spinal curve approaches 40 degrees Fractures (Osteoporosis)  Commonly sustained from falling  Mainly of long bones  DMD - Comorbidities Cognitive impairment average IQ is 85  1/3 of boys with DMD test below 75 Specific reading disorders Specific deficit of verbal intelligence and verbal memory Cardiomyopathy Cardiac muscle fibers can be affected by DMD Present in > 60% of boys with DMD Cardiac conduction problems Dilated cardiac myopathy DMD - Comorbidities Respiratory impairment Weakness of respiratory muscles evident by age 10 to 12 years Contractures of respiratory muscles Scoliosis can prevent ribcage from expanding which we need to breathe Nocturnal hypoventilation one of earliest manifestations of respiratory impairment Progresses very rapidly after loss of ambulation Mechanical ventilation may be used in later stages Leading cause of death DMD - Comorbidities Gastrointestinal dysfunction Results from smooth muscle deterioration in GI tract and gastric dilatation  Constipation  Pseudo-obstruction DMD - Diagnosis Diagnosis based on: Clinical presentation Family history Diagnostic testing  Serum enzymes (CK levels)  Muscle ultrasound  Genetic testing  EMG  Muscle biopsy  DMD - Diagnosis Serum enzyme levels Elevated serum creatine kinase (CK)  Very high levels early in disease (2x – 10x normal)  Elevated CK levels evident at birth prior to onset of clinical symptoms  CK levels decrease over time as muscle mass is lost Muscle ultrasound Used to assess the localization and extent of skeletal muscle damage Genetic testing Prenatal diagnostic tests such as amniocentesis used to remove DNA to determine presence or DMD - Diagnosis EMG Fibrillation potentials Positive sharp waves Long-duration polyphasic motor unit action potentials (MUAP) Full recruitment with low force Low-amplitude MUAP’s NCV normal  DMD - Diagnosis Muscle biopsy Degeneration of muscle fibers Variation in size of muscle fibers Central nuclei Inflammatory cells Fat and connective tissue deposits Muscle stains show absence of dystrophin from muscle tissue Absence of Dystrophin  Newborn Screening DMD is a candidate to be on the recommended screening panel for newborns, as early treatment corticosteroids and new gene therapies improve outcomes Smaller Scale Screening programs here and programs abroad have been successful. CK levels in dried blood spots (routinely taken from newborns) are take for initial screening, then if significantly elevated >3SD referred for further screening / testing DMD – Medical Treatment No known curative treatment Corticosteriod therapy Standard of care to treat individuals with DMD Slows decline of muscle strength and function of DMD Improves muscle force and function in children with DMD  Prolongs ambulation, respiratory function & spinal alignment  Some evidence that use of steroids may help improve/preserve cardiac function as well Common corticosteroid drugs used to treat DMD:  Prednisone  DMD – Medical Treatment Corticosteroid therapy – Side Effects Weight Gain: Obesity, Cushinoid features (round, red, mood face) Acne Growth retardation  Stature in DMD tends to be less that typically developing boys even without Tx Delayed Puberty Osteoporosis and increased risk of fracture of long bones and vertebral compression fractures Behavioral Changes  Mood Behavior, Aggression, ADHD,  Usually worse in the initial 1st few weeks of treatment and subsides Deflazacort and vamorolone appear to result in  DMD – Medical Treatment  Exon-skipping therapies  Drug therapy to cause muscle cells to leave out (skip) the mutated section (called “exon”) of the genetic instructions during the dystrophin protein making process which results in shortened but still functional dystrophin protein strand Four drugs approved by FDA that utilize this therapeutic strategy:  Eteplirsen (Exondys 51) – approved in 2016 to treat patients with DMD who have a confirmed variant of the DMD gene amenable to exon 51 skipping (13% of DMD population)  Golodirsen (Vyondys 53) – approved in 2019 to treat patients with DMD who have a confirmed variant of the DMD gene amenable to exon 53 skipping (8% of DMD population)  Viltolarsen (Viltepso) - approved in 2020 to treat patients with DMD who have a confirmed variant of the DMD gene DMD – Medical Treatment Gene Therapy Elevidys (delandistrogene moxeparvovec-roki): approved by FDA in June 2023 to treat ambulatory patients with DMD ages 4 -5 with a confirmed mutation in the DMD gene  First gene therapy approved for DMD in the U.S.  Administered as one-time IV infusion  Viral vector mediated gene therapy that delivers into the body a gene that leads to the production of a micro- dystrophin protein: a modified, functional version of dystrophin which can be used by muscle cells  Aim is to delay or halt progression of DMD  Drug trials have demonstrated increases in dystrophin expression and functional improvements https://www.elevidyshcp.com/?video=learn_how_elevidys_works  DMD – Medical Treatment Non-steroidal drug therapy Givinostat (Duvyzat): approved by FDA in March 2024 to treat patients with DMD age six years of age and older  First nonsteroidal drug approved to treat all genetic variants of DMD  Reduces inflammation and loss of muscle  In drug trials over 18 months, patients receiving Duvyzat showed less decline in time to climb four stairs and less worsening in North Star Ambulatory Assessment scores as compared to placebo DMD – Medical Treatment Under investigation Research into other drug therapies: Increase utrophin protein levels  Utropin normally made during early muscle development and regeneration but is replaced by dystrophin in mature muscle fibers  Raising utrophin levels in mature muscle may help compensate for lack of dystrophin Experimental drugs to fight muscle inflammation & scarring/fibrosis – may improve muscle regeneration Myostatin inhibitors  Allow muscles to grow larger & stronger Maximize blood flow to muscles  Phosphodiesterase inhibitors DMD – Medical Treatment Under investigation Research into Stem cell transplantation Restoration of dystrophin in muscles from donor stem cells  Some success in animal studies Induced pluripotent stem cells (iPS cells)  DMD – Medical Treatment Supportive treatment Directed towards maintaining function as long as possible Avoid complications  Contractures  Pressure ulcers  Infections Avoid immoblization Avoid deconditioning Submaximal exercise program Breathing exercises/respiratory muscle strengthening Positioning Orthotics DMD – Medical Treatment Surgical Interventions Bony operations  Scoliosis Soft tissue operations  Tendon or muscle releases/lengthening  Muscle transfers DMD - Prognosis Rapidly progressive Death historically occurred between 18 and 25 years of age  Causes of death:  Respiratory failure  Respiratory infection  Cardiac dysfunction BUT recent advances in cardiac & respiratory care have resulted in increased life expectancy  Survival into 30’s becoming more common  Some individuals now living into 40’s and 50’s DMD – Rehabilitation Considerations Overall Goals: Optimize motor function Prevent deformities Prescribe appropriate adaptive equipment Reassessments important: PT should perform serial examinations of muscle strength, ROM and movement capabilities  Adjust interventions as disease progresses  Adapt movement patterns/strategies to compensate for changing muscle strength to preserve function Becker's Muscular Dystrophy (BMD) BMD – Incidence and Etiology 5 in 100,000 live male births X-linked recessive Mutation in dystrophin gene BMD – Clinical Picture Signs & symptoms similar to Duchenne’s MD except: Less common Slower progression Less severe Later life expectancy Onset of symptoms more variable  Usually diagnosed between 5 and 10 years of age; some as late as 25 y.o.a. BMD – Clinical Picture Symptoms begin as: Difficulty in climbing stairs Tendency to fall Muscle weakness Proximal muscles more affected and earlier than distal muscles Primary muscles affected:  Neck, trunk, pelvic & shoulder girdles Muscle cramps common in late childhood/early adolescence BMD – Clinical Picture Walking preserved into mid – teens or later 2nd or 3rd decade or into 30’s May be marked by toe-walking with bilateral calf muscle hypertrophy Gait & posture similar to DMD but with less severe dysfunction Waddling gait Excessive lumbar lordosis Wide base of support Complications of scoliosis, contractures & comorbidities Less frequent & less severe than DMD BMD - Prognosis Slowly progressive Lifespan until adulthood Live into 40’s Death due to: Respiratory dysfunction Heart failure Limb-Girdle Muscular Dystrophy (LGMD) LGMD – Incidence and Etiology 1 in more than 100,000 live births Autosomal recessive or dominant Various types Onset: Late childhood, adolescence or early adulthood  May not manifest until 40’s LGMD – Clinical Picture Affects both proximal & distal muscles Slow course Mild impairment Muscle weakness: Upper arm (biceps & deltoids) Pelvic muscles LGMD – Clinical Picture Later stages: Winging of scapulae Lumbar lordosis Abdominal protrusion Waddling gait Poor balance Inability to raise arms overhead More difficult to diagnosis due to lack of consistent clinical features LGMD - Prognosis Variable course, even in same family Usually slowly progressive Relatively normal lifespan Facioscapulohumeral Dystrophy (FSHD) FSHD – Incidence and Etiology 5 in 100,000 live births Males more often affected than females Females are carriers Autosomal dominant 10% - 30% arise from mutation Onset: Usually early adolescence May occur at any age  FSHD – Clinical Picture Mild form of MD Facial muscle weakness Expressionless face Inability to close the eyes Diffuse facial flattening Pouting lower lip Inability to pucker mouth or whistle Shoulder girdle weakness Scapular winging Forward shoulders Difficulty raising arms overhead FSHD – Clinical Picture Descending progression of muscle weakness Distal anterior leg Hip girdle muscles Weakness of LE’s often delayed for many years Wide variability in side-to- side symmetry Associated manifestations: High-frequency hearing loss Retinal disease FSHD - Prognosis Wide variability in disease severity Slowly progressive May appear stable over a period of years Loss of ambulation later in life Relatively normal lifespan Scapuloperoneal MD Variation of FSHD Involves proximal muscles of shoulder girdle Sparing of facial muscles Slowly spreads to distal LE’s over several years Early symptoms Shoulder weakness Winging of scapula Later symptoms Foot drop Congenital Muscular Dystrophy (CMD) Or Muscular Dystrophy Congenita (MDC) CMD – Incidence and Etiology 4.65 in 100,000 In Italian population Group of inherited disorders Autosomal recessive Onset At birth or shortly after (before age 2) CMD – Clinical Picture Rapid progressive loss of muscle strength Progressive respiratory impairment Mixed central and peripheral symptoms Involvement of:  Brain  Muscles  Visual system Weakness and delayed gross motor skills Only a few achieve ambulation Require wheelchair by age 10 CMD – Clinical Picture Cognitive impairment common Often severe Most prominent clinical feature: Distal laxity mixed with proximal contractures, especially of knee CMD - Prognosis Progressive Death in first years for some More slowly progressive in others Myotonic Dystrophy Myotonic Dystrophy – Incidence and Etiology 13 in 100,000 live births Autosomal dominant Onset Variable Classically in adolescence Some in 20’s & 30’s Most common adult form of MD Myotonic Dystrophy – Clinical Picture Muscle weakness and wasting Delayed relaxation of skeletal muscle Increased excitability Different types: Congenital Myotonic Dystrophy  Most severe type  Weakness and myotonia at birth  Myotonic Dystrophy Most common type characterized by: Weakness & atrophy of facial muscles, especially temporalis & masseter muscles  Slurred speech  Ptosis  Sagging of jaw  Drooping of lip Mild weakness of limb muscles Some degree of disability Mild myotonia (prolonged muscle spasms) Cataracts Baldness Myotonic Dystrophy Multisystem disorder Cardiac conduction defects Respiratory insufficiency Sensorineural hearing loss Hypersomnia Testicular atrophy & sterility Endocrine dysfunction  Myotonic Dystrophy - Prognosis Rate of progression dependent upon age at onset Mild involvement overall Greater functional independence Greater longevity Usually live to 5th or 6th decade Emery-Dreifuss Muscular Dystrophy (EDMD)  Inheritance: Most common x-linked recessive (most seen in males), also autosomal dominant, rare autosomal recessive; all with similar symptoms  Onset: usually by age 10 but some not until mid- 20s  Characterized by: Slowly progressive, symmetric atrophy and weakness of the muscles of shoulder and upper arms and lower legs; mild facial weakness Contractures in the spine, ankles, knees, elbows and back of neck early in the course of the disease.  Cardiac: some form of cardiomyopathy is a common feature of EDMD and requires monitoring. https://www.youtube.com/watch?v=NSWFmD ByqJA https://www.youtube.com/watch?v=G6Y4rZ9 Rgdc https://www.youtube.com/watch?v=WymhaB _xA4k https://www.youtube.com/watch?v=2cbPrlr4 XYM