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HISTORY - ? myopathy Weakness vs fatigue: – Proximal vs distal (DM1, sIBM, FSH, nemaline rod, distal myopathy (TCAP (telethonin), hIBM (GNE)). – Exercise related (MG, metabolic, pseudometabolic). – Daily “fatigue”, “trashed”, “tired all the time” are not mainfestations of ANY NMD except DM1. Pain: – Joint vs muscle. – Pain at rest is rarely neuromuscular disease (DM2, rare myotonia congenita, statin myopathy). – Most inflammatory myopathies are painless. HISTORY - family Multiple systems involved? – DM2, mitochondrial disease. Family history: – AD – DM2, OPMD, FSHD, LGMD, EDMD (lamin A/C). – AR – GSD-II, SMA-IV. – Maternal – mtDNA defects. – XLR – BMD, EDMD. Physical Exam Complete Neurological Exam. MSK exam – trochanteric bursitis may mimic proximal leg weakness/fatigue. – FSHD may get rotator cuff issues. – Contractures. Check the back (spinal stenosis with radiculopathy can mimic myopathy, lead to fatigue with activity, and elevate CK). Routine Bloodwork CK not aldolase. Remember that AST and ALT are in skeletal muscle. Cramps – Ca, Mg (cramps at rest are rarely significant BUT they can increase the CK). Make sure TSH is sent (commonly the CK will be elevated). Patients with motor neuropathy and motor radiculopathy can have elevated CK (< 1,000 U/L). Cause of HyperCKemia Sarcolemma leak/damage. All cytoplasmic proteins. Seen in many but not all muscle disorders . Huge variability between people (men>women; African > Caucasian). EXERCISE: ~ 4h post and up to 10 days. CK LDH AST ALT Aldolase Myoglobin When to send for further testing. No cause for the high CK. Neurological exam is abnormal (beyond radiculopathy or diabetic neuropathy). Any CK over 1,000 iU/L. Positive family history of high CK or NMD or arrhythmia/pacer or non-hypertensive cardiomyopathy (lamin A/C, BMD)(HOCM screen @ CHEO). SOBOE + weakness (Pompe, MG, LGMD, mito.). – Sitting/supine FVC - > 20 % drop = diaphragm weak. Needle EMG Fibs./PSW Myotonia Myopathic Potentials Muscle Biopsy Bourgeois and Tarnopolsky, Mitochondrion, 4:441-52, 2004. Tarnopolsky, et al, Muscle Nerve, 2011. Biopsy Patterns Central Core Ragged Red Inflammation Dennervation Dystrophic Pompe EM Changes Myopathies Muscle – – – – – – – INFLAMMATORY. DYSTROPHY. TOXIC/INFECTIOUS. METABOLIC. CONGENITAL MYOPATHY. ENDOCRINE. CHANNELOPATHY. Inflammatory Myopathies Polymyositis. Dermatomyositis. Inclusion Body Myositis. Myositis associated with connective tissue disorders (MCTD, RA, lupus) Rashes, etc. Gottron’s Papules Rash on knuckles – Gottron’s Sign Shawl Sign Heliotrope Rash Calcinosis Diagnosis – DM/PM. proximal weakness. CK activity. + EMG. + Biopsy. Rash. Definite PM all 4 DM 3 or 4 + R Probable 3/4 2+R Possible 2/4 1+R Diagnosis-IBM More common in older men. Quadriceps and finger flexor atrophy. CK is elevated but mild/moderate. EMG is often distinct from others. Swallowing affected in about 70 %. Biopsy shows rimmed vacuoles (+ αB crystallin, tau, APP) + COX – ve. Muscular Dystrophy Dystrophinopathy LGMD OPMD (AD, ptosis NOT ophthalmoplegia, dysphagia, onset 40 - 50 y) Congenital DM1/DM2 Distal (TCAP)/hIBM (GNE) FSHD Dx: ? Dystrophinopathy - gene first (MLPA - HSC = 66 %) > biopsy. BMD NORM Gene Seq. DMD WESTERN BLOTTING I.H.C. Dystrophinopathies Duchenne: – – – – – XLR, 1/3500 live male births. weakness age 3 – 4 y. CK – 10,000’s. W/C by teens. Death resp. failure in 20’s. Becker’s: – Less common. – Milder phenotype. – CLINICAL - ++ calf hypertrophy, quads affected (atrophy) with relative preservation of upper extremeties. Myotonic Dystrophy-1. AD trinucleotide disorder (CTG), ch. 19. ~1.4/10,000 live birth. Disease affects multiple systems (somnolent, cataracts, dysphagia, conduction blocks, GI issues, distal weakness). Rough correlation with size of CTG expansion. (CHEO). Anticipation (females). Myotonic Dystrophy-2. Chr. 3, AD. No congenital form. CCTG repeat in ZNF9 (Zn finger)(CHEO). Weakness is mainly proximal (“PROMM”). Usually not suspected until the EMG. Cataracts are very common, conduction block risk is similar to DM1 (~ 50 % will get at least a 1st degree). Muscle pain is common. LGMD Sarcoglycanopathies (α,β,γ,δ – sarcoglycan) – 60 % of kids; 10 % adults. Calpainopathy (Calpain 3) – 10 – 30 % of late-childhood/adult. Bethlem/Ullrich Myopathy – Early contractures (elbows, Achilles). – COL6A1,2,3 mutations. Dysferlinopathy – Very high CKs/inflammation on Bx. FSHD AD condition (variable). Type 1 = Chr. 4q33 deletion (CHEO). Early adult onset. FSH distribution. Dorsi-flexion and asymmetrical weakness are common. Usually normal lifespan. No significant cardiac Pompe Disease • First described in 1932 by Dutch pathologist J.C. Pompe • Also known as acid maltase deficiency (AMD) or GSD-II. • Characterised by the deficiency of a lysosomal enzyme, acid alpha-glucosidase (GAA) • Results in progressive intracellular accumulation of glycogen, primarily in muscle cells • Signs and symptoms begin anywhere from early infancy through adulthood Onset of Pompe Disease in Adults Age-specific distribution of events in a Dutch cohort of mean age 48.6 years Black line = mean age for event First complaints n=54 Running problems n=31 Diagnosis n=54 Problems going up and down staircase n=46 Problems rising from armchair n=45 Problems rising from lying position n=37 Walking problems n=41 Problems with dressing n=32 Problems going to toilet n=18 Start of walking aid use n=23 Start of wheelchair use n=26 Start use of artificial ventilation (n=54) n=20 0 10 20 30 40 50 60 Figure from Hagemans ML, Winkel LP, Van Doorn PA, et al. Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain 2005; 128:671-7, by permission of Oxford University Press. 70 yrs Pompe – diagnosis. form (AR) – shortness of breath, proximal weakness, contractures. CK usually up. EMG – fibs, PSW, myotonia – paraspinals. EM – membrane bound glycogen, autophagic vacuoles. LM – PAS increase (blebs), acid phosphatase +ve, vacuolar myopathy. Fibroblasts/muscle/blood spot – reduction of -glucosidase. Adult Biopsy Patterns ADULT INFANT Drugs associated with myopathy AZT – mitochondrial. Corticosteroids – type 2 atrophy; ICU – myosinolysis +/- NDMBAs. Ethanol – acute rhabdo. Hydroxychoroquine. Neuroleptics – NMS, CK. d-penicillamine (MG, inflammatory). Lithium ( K+, rhabdo). Retinoic acid (vitamin A). Interferon. Antibiotics (Macrolides) Cholesterol lowering agents: – HMG-CoA reductase inhibitors (fibrates, cholchicine, cyclosporine). – Fibric acid derivatives Statins and myopathy. 3 - 5 % of patients develop myalgias. 0.1 % = rhabdomyolysis (10 X ULN). ? direct toxicity (phrenylation, COQ10). Recently there is evidence of delayed onset necrotic myopathy responsive to immunomodulation (Amato, M and N; Mammen, AL, Arthritis and Rheum, 63:713-, 2011) = statins induce expression of anti-HMGCR autoanitbodies. Statin myositis. 100 % of patients had myonecrosis. 20 % showed “inflammation”. MOST of the patients in both studies responded to MTX and prednisone. 27/28 of our patient IDed in past 4 years responded to MTX and prednisone - one needed pulse solu-medrol and IgG. 50 % of our patients had inflammation in biopsy. Case # 1- Calf atrophy 26 y old male with difficulty getting up from squat age 19 y > progressive. Family history - parents are consanguinous (paternal great grandmother is sister to his maternal great grandmother), one sister with similar phenotype and brother sister no weakness. Examination: MS/CN = N; MOTOR = minimal proximal UE weakness, profound calf > anterior lower leg atrophy and weakness with hip flexors = 2/5 and hamstrings 3/5. Case # 1- Calf atrophy. Muscle biopsy = inflammation, N - dysferlin. CK > 3,000 iU. Dx: inflammatory myopathy - no response to corticosteroids. Rheumatologist wanted a second opinion. Patient wanted to know about Rx options. Case # 1= New mutation Whole DYS gene sequenced. Mutation analysis = c.4747 T>G transversion (homo); p.Tyr1583Asp. Athena = “Since these types of sequence variants are similar to those observed in both disease-associated mutations and benign polymorphisms, the nature of this variation precluded clear interpretation.” in silico evaluation: – SIFT = “not tolerated” – PolyPhen = “probably damaging”, score = 3.024. – Tyr = tyrosine is highly conserved 46/46 vertebrata. Case # 1 - Molecular issues claims that they can detect 99 % of DYS cases with a blood lyphocyte Western blot. We found that the immunohistochemistry was normal in this case and many others. We ran Western blotting and found none, reduced, normal and overexpression in 9 cases. Athena Muscle Nerve. 2013 May;47(5):740-7. Dysferlin aggregation in limb-girdle muscular dystrophy type 2B/myoshi myopathy necessitates mutational screen for diagnosis. Nilsson MI, Laureano ML, Saeed M, Tarnopolsky MA. Case # 2– Lumber Jack! 69 y RHD male. PMHx: Angioplasty – 1995 Meds: Simvastatin, ASA, atenolol, terazocin, vits B/C/E HPI: tree cutting x 2 ++ DOMS w/ CK to 4869 then dropping to 341 over 2 d Case # 3: Fibromyalgia? 59 y old female. Dx = fibromyalgia for 20 + y. Hx: non-specific pains and weakness for > 20 years and fatigue with exercise + more recent SOBOE - Dx = sleep apnea + obesity. O/E: MS - N; CN - N; MOTOR - ~ 4/5 prox. weakness; MSR - N; sensory -N. CK = 678 U/L; EMG = fibs, PSW, small, brief (incl. paraspinals). Spirometry: FVC = 2.1 L/ FEV1 = 1.9 L/s Case # 3- Testing DBS = low GAA activity Biopsy = Genetics = c.692+5G>T (known - alters splicing of mRNA in 3’ region of exon 3); c.1211A>G; p.Asn404Gly). The clinic: Ms. L. Brandt Ms. Erin Hatcher Ms. L. Brady Ms. D. Johnston Ms. H. Vey Ms. K. Scott The lab: Dr. M. Nilsson Dr. M. Akhtar Dr. L. MacNeill Mr. D. Ogborn Collaborators: Dr. B. Lach Dr. J. Provias Dr. J. Bourgeois Dr. T. Hawke Dr. J. Schertzer Thanks • Warren Lammert and Family • CIHR – Institute of aging. • McMaster Children’s Hospital and Hamilton Health Sciences Foundation.