Muscular Dystrophies

What is Muscular Dystrophy? (MD) Muscular Dystrophy is a group of genetic disorders that cause progressive muscle weakness. MD is caused by a genetic mutation. The protein in the muscle is deformed which causes the patients muscle to deteriorate. MD is characterized by degeneration and regeneration of muscle fibers (in contrast with static or structural myopathies) progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissue

Symptoms Lack of coordination Muscle weakness Loss of mobility

General Diagnostic Testing Creatine kinase : greatly elevated (50 times normal) Increased in DMD, BMD, polymyositis, and rhabdomyolysis Nonspecific if mildly elevated 2-3x normal Lower late in MD course due to severely reduced muscle mass Not helpful for carrier detection

General Diagnostic Testing Electromyography Useful if diagnosis not clear (biopsy has mixed features) Differentiates neuropathic vs. myopathic Characteristic myotonic discharges in adults with myotonia – “dive bomber” sound Perform after the CK

General Diagnostic Testing Muscle biopsy Dystrophic changes include necrosis, degeneration, regeneration, fibrosis and fatty infiltration, sometimes mild inflammation Specific diseases may have inflammation, intracellular vacuoles, rods, and other inclusions on biopsy

General Diagnostic Testing Biochemical muscle protein analysis Useful for specific identified protein that is missing and many specific mutations may cause the same deficiency Immunohistochemical protein staining Western blot – quantitates percent of normal protein present

General Diagnostic Testing Genetic analysis PCR for specific known defects Southern blot for nucleotide repeats

CLASSIFICATION X-linked muscular dystrophy Duchenne muscular dystrophy Becker muscular dystrophy Emery-Dreifuss syndrome Autosomal recessive muscular dystrophy Congenital muscular dystrophy Limb-girdle muscular dystrophy Autosomal dominant muscular dystrophy Fascioscapulohumeral muscular dystrophy

Differential Patterns of Initial Muscle Weakness in MD Duchenne MD Emery-Dreifuss MD Congenital MD Limb Girdle MD FSHD Facio- Scapulo- humeral OPMD Oculopharyngeal MD

Duchenne Muscular Dystrophy (DMD) Presentation: 3-5 y/o with frequent falls, slow running, Prevalence of 1:3500 Etiology single gene defect (65% deletions in hot spot regions , 7-10% duplications, 25% point mutations, small deletions or insertions) 1/3 new mutation 2/3 family history Xp21.2 region absent dystrophin

Duchenne Muscular Dystrophy (DMD)

Duchenne Muscular Dystrophy (DMD) Clinical Manifestations Onset : age 3-6 years Progressive weakness Pseudohypertrophy of calf muscles Spinal deformity Cardiomyopathy Respiratory 30% mild to moderate MR

Pseudohypertrhophy of calf muscle, Tip toe gait forward tilt of pelvis, compensatory lordosis

Disappearance of lordosis while sitting

GOWER’S SIGN

Duchenne Muscular Dystrophy (DMD) Natural History Progress slowly and continuously muscle weakness lower --> upper extremities unable to ambulate: 10 year (7-12) death from pulmonary/ cardiac failure: 2-3rd decade

Duchenne Muscular Dystrophy Diagnosis Clinical Signs (Gower’s Sign) Family history (pedigree analysis) Increase CPK (200x) DNA mutation analysis (65%) or haplotype analysis) Myopathic change in EMG Bx: m. degeneration Muscle biopsy and Immunoblotting: Absence dystrophin (if geneticist can’t find the mutation !!) Prenatal diagnosis is available

Becker Muscular Dystrophy (BMD) Slowly progressive form with same gene affected as Duchenne MD Etiology single gene defect short arm X chromosome altered size & decreased amount of dystrophin Muscle biopsy immunostaining for dystrophin with patchy staining Disorder of function or decreased amount of dystrophin rather than absence of the protein

DMD / BMD

Emery-Dreifuss Muscular Dystrophy (EDMD) Presentation: This disorder is characterized by a triad Early contractures of the Achilles tendon, elbows and posterior cervical muscles Slowly progressive muscle wasting and weakness with a humeroperoneal distribution Cardiomyopathy arises , which usually presents as cardiac conduction defects. Genetics X-linked type affects emerin (STA gene at chromosome Xq28) Diagnose by protein analysis of leukocytes or skin fibroblasts DNA testing available AD affects lamin A or lamin C (chromosome 1q21)

Congenital Muscular Dystrophy (CMD) Presentation: neonatal onset of severe weakness, delayed motor milestones, contractures Classification Merosin-negative Merosin-positive Neuronal migration Fukuyama Muscle eye-brain Wlaker-Warburg

Limb Girdle Muscular Dystrophy (LGMD) Presentation: variable age of onset with weakness and wasting of the limb-girdle 15 genetically different types (genetical and clinical heterogenic) AD forms are rare but more less severe than AR forms Several of these disorders are associated with clinically significant cardiac involvment

Type Protein Chromosome Inheritance 1A Myotilin 5q22-34 AD 1B Laminin A/C 1q21 AD/allelic to EDMD 1C Caveolin-3 3p25 1D 7q 2A Calpain-3 15q15-21 AR 2B Dysferlin 2p13 AR/allelic to Myoshi Myopathy 2C Gamma sarcoglycan 13q12 2D Alpha sarcoglycan 17q12-21 2E Beta sarcoglycan 4q12 2F Delta sarcoglycan 5q33-34 2G Telethonin 17q11-12 2H 9Q33 2I Fukutin-related protein 19q13 AR/allelic to CMD 1C

FascioScapuloHumeral Muscular Dystrophy (FSMD) Presentation: Facial and shoulder girdle are first affected muscle group Later foot extensors and pelvic girdle muscles become involved The heart is not implicated in most cases. mild high pitched hearing loss, retinal abnormalities, mental retardation in early onset Genetics/Testing Southern blot testing available (chromosome 4q35) for decrease in repeats normally present Muscle biopsy may show lymphocytic infiltrates

Oculopharyngeal Muscular Dystrophy Presentation: mid-adult with ptosis, facial muscle weakness with difficulty swallowing, proximal muscle weakness, may have extraocular muscle weakness, more common in French-Canadian and Hispanic population Genetics Affects poly A binding protein 2 (PABP2) by expansion of a GCG repeat without anticipation seen – Southern blot (chromosome 14q11-13)

Myotonic Dystrophy (DM) Presentation – adult with multiple systems affected Primarily distal and facial weakness Facial features: frontal balding in men, ptosis, low-set ears, hatchet jaw, dysarthria, swan neck, ^ shaped upper lip Myotonia: worse in cold weather, after age 20 Heart: conduction block – evaluate syncope

Smooth muscle: constipation, care with swallowing, gallstones, problems with childbirth, BP lability Brain: learning disabilities, increased sleep requirement Ophthalmology: cataracts Endocrine: insulin resistance, hypothyroidism, testicular atrophy

Myotonic Dystrophy Genetics 4-37 repeats Normal Myotonic dystrophy is caused by a triple nucleotide (triplet) expansion (CTG) in the noncoding region of the myotonin gene at chromosome 19q13.3. The condition is characterized by extreme variability, anticipation and differential expansion in the maternal and paternal germline. 4-37 repeats Normal >50 repeats Affected

Myotonic Dystrophy (DM) Congenital: severe form initial respiratory distress after birth with ventilatory requirement or apnea, feeding difficulty, mental retardation, club feet, scoliosis, strabismus

Huntington Disease (HD) Presentation Mood Swings Impaired cognitive functions Chorea Huntington’s Disease is an Autosomal Dominant “Tri-nucleotide Repeat” Disorder caused by a mutation of a gene on the 4th chromosome which is responsible for producing the protein Huntingtin, that creates excess copies of the CAG codon which genetically program the degeneration of the neurons of the brain. Age of onset is found generally in adults around the age of 40 but varies based on the number of repeats. The earliest onset of Huntington’s ever documented was a two year old boy who was found to have nearly 100 CAG repeats. The symptoms of HD can also develop at 55 or later, in which case it is harder to recognize.

Huntington Disease (HD) The number of CAG codons varies and so does the severity of the disease >40 repeats you develop HD, children 50% chance of developing disease 36-39 repeats “Grey Zone” May develop HD, children may or may not develop HD 29-35 repeats the individual will not develop HD, children may <29 repeats, the individual will not develop HD, children will not develop HD

Summary Clinical DMD LGMD FSMD CMD Incidence common less Not common Rare Age of onset 3-6 y 2nd decade At/ after birth Sex Male Either sex M = F Both Inheritance Sex-linked recessive AR, rare AD AD Unknown Muscle involve. Proximal to distal Face & shoulder to pelvic Generalized Muscle spread until late Leg, hand, arm, face, larynx,eye Upper ex, calf Back ext, hip abd, quad -

Summary Clinical DMD LGMD FSMD CMD Pseudo hypertrophy 80% calf < 33% Rare No Contracture Common Late Mild, late Severe Scoliosis Kyphoscoliosis Common, late - ? Heart Hypertrophytachycardia Very rare Not observed Intellectual decrease Normal Course Stead, rapid Slow Insidious Steady

Treatment There is no cure for MD Medications that are prescribed for MD patients Steroids Braces for support Mobility chairs Surgery is also an option to release contractures STEM CELL THERAPY !!!!?