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Dr Neha
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
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
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 School functioning/cognitive development Cardiac function/arrhythmias/syncope Respiratory
Review of Systems
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
Deep tendon reflexes: normal or decreased Normal sensation: remember proprioception Joint contracture: reduced passive range of motion not due to tone
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 Xchromosome, 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
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 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 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
Electromyography
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)
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
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 2laminin (AR-chromosome 6q22-23)
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
Ullrich CMD
COL6A2
21q22
AR
12q13 19q13
Presentation adult with multiple systems affected Primarily distal and facial weakness Facial features: frontal balding in men, ptosis, lowset 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
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
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
Type 1A 1B 1C 1D 2A 2B 2C 2D 2E 2F 2G 2H 2I
Gamma sarcoglycan 13q12 Alpha sarcoglycan Beta sarcoglycan Delta sarcoglycan Telethonin Fukutin-related protein 17q12-21 4q12 5q33-34 17q11-12 9Q33 19q13
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)
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)
Muscle biopsy with autophagocytic vacuoles/ inclusion bodies Table 3 Types of DMD
AD/2p13 hands first
Anterior tibial/Markesbery-Griggs/Udd AD/2q31-33 Nonaka/Inclusion body myopathy 2 Gowers/Laing distal myopathy Miyoshi myopathy Distal myopathy with vocal cord and pharyngeal weakness AR/9p13 AD/14q11 AR/2p13 AD/5 Affects dysferlin Rimmed vacuoles, inclusion bodies, affects GNE
Myopathies
Myotubular myopathy
Ryanodine receptor, Ca channel that mediates excitation/contraction coupling, (AD chromosome 19q13) Associated with Malignant Hyperthermia Myotubularin, important in myogenesis (Xq28) Caused by many defects, disorder of thin filaments Rod-like stuctures on muscle biopsy Juvenile Dermatomyositis Inclusion Body Myositis (usually distal) Adult Polymyositis (associated with malignancy)
Nemaline Myopathy
Inflammatory
Treatment - Medications
Steroids
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
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
Genetic therapies
Using cells own repair mechanisms but adding template Gentamicin trial for relaxation in stop codon recognition for DMD has not worked Inserting truncated genes or whole gene with vector
Utrophin in DMD
Therapy
Contracture prevention
Stretching exercises and postural changing
Stretch the most contracture prone groups (gastrocnemius, hip flexors, iliotibial bands, hamstrings)
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
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
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Surgery
Achilles
Need KAFO to walk post-op Relieves pain and allow shoe wear Relieves hip and knee pain or contracture Allows better gait compensation
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, mental dullness, difficulty concentrating, increased colds, coughing, or pneumonia should undergo evaluation Influenza vaccine and pneumococcal vaccine In-exsufflator for airway clearance, cough assist Pulmonologist, pulmonary function testing
Cardiology
EKG pacemaker for conduction defects and arrhythmias Echocardiogram afterload reduction, digoxin for cardiomyopathy
Nutrition/GI
Protein and calorie supplements Assess for dysphagia Intestinal hypomotility in DMD, CMD, and myotonic dystrophy can require a bowel regimen to prevent constipation
Osteopenia/Osteoporosis
Begins before walking stops, fractures may end walking Worsened by steroids Calcium supplements, Miacalcin may help Education aid in planning Special education may not be needed with accomodation and modifications Progressive loss of function affects patient and family
Psychology/Neuropsychological
Thank you