dystrophy肌营养不良症（ppt46）课件

Muscular Dystrophy,Beyond Duchenne Ann Bubenzer,Objectives,Recognize patients that require referral for diagnosis and management of muscular disorders. Perform the history and physical exam to screen for neuromuscular disorder for patients of all ages. Describe current methods of diagnostic testing for neuromuscular disorders. Discuss current therapy and treatment options available and the affect on prognosis,Presentations of patients with neuromuscular disorders,Case 1 Called to evaluate newborn infant with hypotonia. Pregnancy complicated only by flu-like illness in 2nd trimester and question of decreased strength of fetal movements compared to first pregnancy. Labor and delivery complicated by precipitous delivery.,Case 1 cont Physical exam reveals hypotonic infant with high arched palate. Physical exam is otherwise normal. Laboratory such as CBC and electrolytes are normal.,Case 2 4 year old presents to clinic with chief complaint of toe walking and falling. The parents also state that he has trouble with stairs and running. Sat alone at 8 months, walking by 15 months. On physical exam he demonstrates walking up legs with hands in order to rise from seated position on floor. Calves are prominent.,Case 3 14 y/o with difficulty lifting arms above head. On review of symptoms, this adolescent states he has never been able to blow up a balloon. On physical exam, scapular winging is noted.,Case 4 Infant presents with narrow facies, shaped upper lip, and respiratory distress after birth. Poor feeder requiring OG tube assistance. Mother has similar facial features. When you shake her hand, she cant let go easily.,History and Physical Exam in the Newborn and Office,History Newborn floppy infant, term or preterm, poor head control, poor feeding, prolonged labor, maternal complications Childhood development delay in sitting, standing, walking, toe walking, difficulty stair climbing or running Teen or adult difficulty in self-care, swallowing, athletic/endurance activity,Family History Include enough of family tree to pick up autosomal recessive disorders and X-linked or AD disorders with variable penetrance Many x-linked or AD represent new mutations Past diagnoses in older family members may not be accurate Review of Systems School functioning/cognitive development Cardiac function/arrhythmias/syncope Respiratory,Physical exam findings Muscle mass: signs of wasting or hypertrophy/pseudohypertrophy Muscle strength: power generation of force against resistance or gravity Observe reaching, getting up from floor Observe trunk and head/neck control Test specific proximal groups position so against gravity Tone: resistance to passive movement Note hyper vs. hypotonia in weak areas Deep tendon reflexes: normal or decreased Normal sensation: remember proprioception Joint contracture: reduced passive range of motion not due to tone,What is Muscular Dystrophy? (MD),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,Dystrophinopathy: disorders involving dystrophin Duchenne MD and Becker MD are the muscular disorders the two most common and severe dystrophies Dystrophin is a very large gene on the X-chromosome, ubiquitous in the human body Dystrophin-Associated Protein (DAP) Complex composed of the extracellular, transmembrane, and intracellular components,The Lancet Neurology Volume 2 Number 5 May 2003 Copyright 2003 Elsevier,General Diagnostic Testing,Creatine kinase : Aids in narrowing the differential diagnosis if 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,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,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,Duchenne Muscular Dystrophy,Presentation: 3-5 y/o with pseudohypertrophy of calf muscles, frequent falls, slow running, and waddling gait Prevalence of 1:3500 Other organs affected Heart cardiomyopathy Respiratory Intellect - 30 % with impairment IQ 75 Testing Immunostaining with absence of dystrophin PCR testing available for common mutations (X21.2),Becker Muscular Dystrophy,Slowly progressive form with same gene affected as Duchenne MD Muscle biopsy immunostaining for dystrophin with patchy staining Disorder of function or decreased amount of dystrophin rather than absence of the protein,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 2-laminin (AR-chromosome 6q22-23),Neuronal Migration Disorders,With neuronal migration disorders get mental retardation, brain malformations, and clinical eye involvement Fukuyamas muscular dystrophy affects fukutin protein (AR chromosome 9q31) Muscle-eye-brain disease affects POMGnT1, (AR chromosome 1p32-34) Walker Warburg affects POMT1 (AR) Glycosyltransferases are also important in neuronal development,Other Merosin Positive CMD,Myotonic Muscular Dystrophy or Steinerts disease,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,Genetics: Mothers can have adult or congenital onset offspring; fathers can have adult onset offspring Parents may not be aware of own diagnosis Myotonin gene is affected as well as adjacent transcription factor gene SIX 5 by CTG repeat in noncoding region of chromosome 19q13.3, and anticipation seen with increased repeats Muscle biopsy with internalized nuclei, type 1 fiber atrophy, ring fibers, and sarcoplasmic masses Congenital: severe form, initial respiratory distress after birth with ventilatory requirement or apnea, feeding difficulty, mental retardation, club feet, scoliosis, strabismus,FascioScapularHumeral Muscular Dystrophy,Presentation: Facial weakness with trouble blowing up a balloon, sipping through a straw, whistling, trouble closing the eyes at night, scapular winging that may be asymmetric, pain May have absence of pectoralis, biceps, or brachioradialis Also affected: 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,Limb Girdle Muscular Dystrophy,Presentation: variable age of onset with weakness and wasting of the limb-girdle May have calf hypertrophy, involvement of scapular muscle and deltoid in sarcoglycanopathies Many types involve dysfunctional sarcoglycans transmembrane proteins of the DAP that interact with cytoplasmic proteins Table 2 types of LGMD,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 Muscle biopsy shows filamentous nuclear inclusions and ubiquitin containing vacuoles Affects poly A binding protein 2 (PABP2) by expansion of a GCG repeat without anticipation seen Southern blot (chromosome 14q11-13),Emery-Dreifuss Muscular Dystrophy Scapuloperoneal MD,Presentation: stiff joints, shoulder and upper arm weakness, calf weakness, cardiac conduction defects and arrhythmias, contractures Genetics X-linked type affects emerin Diagnose by protein analysis of leukocytes or skin fibroblasts DNA testing available (chromosome Xq28) AD affects lamin A or lamin C (chromosome 1q21) Nuclear membrane proteins,Distal Muscular Dystrophy,Presentation: weakness in forearms, hands, and lower legs clinically similar to a neuropathy but NCV normal Muscle biopsy with autophagocytic vacuoles/ inclusion bodies Table 3 Types of DMD,Myopathies,Central core disease: Ryanodine receptor, Ca channel that mediates excitation/contraction coupling, (AD chromosome 19q13) Associated with Malignant Hyperthermia Myotubular myopathy Myotubularin, important in myogenesis (Xq28) Nemaline Myopathy Caused by many defects, disorder of thin filaments Rod-like stuctures on muscle biopsy Inflammatory Juvenile Dermatomyositis Inclusion Body Myositis (usually distal) Adult Polymyositis (associated with malignancy),Treatment - Medications,Steroids Briefly increase strength, slow progression in dystrophinopathy for walking, arm use, and respiratory function Weekend or 15-20/month as well as prednisolone/deflazacort may minimize SE Dilantin and Tegretol raise the repolarization threshold and improve myotonia Methylphenidate improves daytime somnolence in DM Albuterol may help in FSH MD Creatine and glutamine may help delay progression/improve energy in youngest with DMD,Treatment future therapies,Genetic therapies Repairing the mutated sequences Using cells own repair mechanisms but adding template Gentamicin trial for relaxation in stop codon recognition for DMD has not worked Replacing the mutated sequences Inserting truncated genes or whole gene with vector Upregulation of similar functioning proteins Utrophin in DMD,Therapy,Contracture prevention Stretching exercises and postural changing Stretch the most contracture prone groups (gastrocnemius, hip flexors, iliotibial bands, hamstrings) AFO at night to supplement,Strengthening/conditioning/endurance Goal is to maintain or improve muscle strength and maximize functional ability slight improvement is possible Additional goal is to avoid muscular damage by overwork or injury No eccentric contraction or delayed soreness Voluntary active exercise such as swimming/hydrotherapy or cycling in ambulatory children currently recommended,Mobility aids Walking orthoses KAFO Standing frames, standing wheelchairs, swivel walker occasionally used Walkers where arm strength less affected Transfer board Wheelchair power needed for independence Plan for indoor lift, van with lift, roll in shower Improving daily activities of daily living Physical and Occupational Therapy teaching modified techniques Antigravity orthoses are being developed to assist in daily living activities Splinting and therapy to prevent hand contractures,,Surgery note the risk inherent to surgery malignant hyperthermia Palliative vs. rehabilitative Tendon releases Achilles Need KAFO to walk post-op Relieves pain and allow shoe wear Hamstring and iliotibial band Relieves hip and knee pain or contracture Allows better gait compensation,Scoliosis spine stabilization Bracing is not effective with progressive neuromuscular disease Timely correction of scoliosis is important for patient comfort and respiratory ability Spine and scapular stabilization may aid function of arms Ophthalmology Deficient eye closure oculomaxillofacial MD and FSH MD may require artificial tears or tarsorrhaphy Treatment for cataracts in Myotonic MD,Respiratory Patients with morning headache, nightmares, excessive daytime somnolence