1. Muscular Dystrophies

2. What is Muscular Dystrophy? (MD) MD is an inherited muscle disease with many different forms. In most cases muscle progressively become weaker. Some types of MD affect voluntary muscles such as the heart. Muscular Dystrophy: group of genetic disorders that are characterized by progressive loss of muscle integrity, wasting, and weakness. Characterized by degeneration and regeneration of muscle fibers (in contrast with static or structural myopathies) Muscular Dystrophy Association – Covers all muscular dystrophies and myopathies – Multisystem diseases : ALS or Friedreich Ataxia – Neuropathy : HSMN, CMTD

3. Muscular dystrophy refers to a group of genetic, hereditary muscle diseases that cause progressive muscle weakness. genetichereditarymuscle diseases Muscular dystrophies are characterized by progressive skeletal muscle weakness, defects in muscle proteins, and the death of muscle cells and tissueskeletal muscleproteinscellstissue

4. Symptoms Lack of coordination Muscle weakness Progressive crippling Loss of mobility

5. 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

6. 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 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

7. Genetic analysis – PCR for specific known defects – Southern blot for nucleotide repeats 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

8. CLASSIFICATION X-linked muscular dystrophy Duchenne muscular dystrophy Becker muscular dystrophy Emery-Dreifuss syndrome

9. CLASSIFICATION Autosomal recessive muscular dystrophy Limb-girdle muscular dystrophy Autosomal dominant muscular dystrophy Fascioscapulohumeral muscular dystrophy

10. Differential Patterns of Initial Muscle Weakness in MD Congenital MDDuchenne MD Limb Girdle MDFSHD Facio- Scapulo- humeral Emery Dreifuss MD OPMD Oculopharyngeal MD

11. Congenital Muscular Dystrophy Presentation: neonatal onset of severe weakness, delayed motor milestones, contractures Merosin negative/CMD A1 – White matter hypodensities on brain scan but normal mental capacity – Diagnosis by muscle biopsy immunohistochemistry showing loss of α2- laminin (AR-chromosome 6q22-23)

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

13. Duchenne Muscular Dystrophy

14. Clinical Manifestations – Onset : age 3-6 years – Progressive weakness – Pseudohypertrophy of calf muscles – Spinal deformity – Cardiomyopathy – Respiratory – 30% mild to moderate MR

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

16. Disappearance of lordosis while sitting

17. GOWER’S SIGN

18. Duchenne Muscular Dystrophy 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

19. 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

20. Becker Muscular Dystrophy 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

21. DMD / BMD

22. Emery-Dreifuss Muscular Dystrophy 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)

23. Limb Girdle Muscular Dystrophy 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

24. TypeProteinChromosomeInheritance 1AMyotilin5q22-34AD 1BLaminin A/C1q21AD/allelic to EDMD 1CCaveolin-33p25AD 1D7qAD 2ACalpain-315q15-21AR 2BDysferlin2p13AR/allelic to Myoshi Myopathy 2CGamma sarcoglycan 13q12AR 2DAlpha sarcoglycan17q12-21AR 2EBeta sarcoglycan4q12AR 2FDelta sarcoglycan5q33-34AR 2GTelethonin17q11-12AR 2H9Q33AR 2IFukutin-related protein 19q13AR/allelic to CMD 1C

25. FascioScapularHumeral Muscular Dystrophy (AD) 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

26. 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)

27. Myotonic Dystrophy 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

29. Huntington Disease 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 The earliest onset of Huntington’s ever documented was a two year old boy. The symptoms of HD can also develop at 55 or later, in which case it is harder to recognize.

30. 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

31. Summary ClinicalDMDLGMDFSMDDDCMD IncidencecommonlessNot common Rare Age of onset3-6 y2nd decade 20-77 yAt/ after birth SexMaleEither sexM = FEither sexBoth InheritanceSex-linked recessive AR, rare ADAD Unknown Muscle involve. Proximal to distal Face & shoulder to pelvic DistalGeneralized Muscle spread until late Leg, hand, arm, face, larynx,eye Upper ex, calf Back ext, hip abd, quad Proximal-

32. Summary ClinicalDMDLGMDFSMDDDCMD Pseudo hypertrophy 80% calf < 33%RarenoNo ContractureCommonLateMild, late Severe Scoliosis Kyphoscoliosis Common, late Late--? HeartHypertrophy tachycardia Very rare Not observed IntellectualdecreaseNormal ? CourseStead, rapidSlowInsidiousbenignSteady

33. 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