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.

CKLDHASTALTAldolaseMyoglobin

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 Needle EMG

Myopathic

Potentials

Fibs./PSW

Myotonia

Muscle BiopsyBourgeois and Tarnopolsky, Mitochondrion, 4:441-52, 2004.Tarnopolsky, et al, Muscle Nerve, 2011.

Biopsy Patterns

Inflammation

Dystrophic

Dennervation Pompe

Ragged RedCentral Core

EM Changes

Myopathies

Muscle– INFLAMMATORY.

– DYSTROPHY.

– TOXIC/INFECTIOUS.

– METABOLIC.

– CONGENITAL MYOPATHY.

– ENDOCRINE.

– CHANNELOPATHY.

Inflammatory MyopathiesInflammatory Myopathies

Polymyositis. Dermatomyositis. Inclusion Body

Myositis. Myositis associated

with connective tissue disorders (MCTD, RA, lupus)

Rashes, etc.Rashes, etc.

Rash on knuckles – Gottron’s Sign

Shawl Sign

Gottron’s Papules

Heliotrope Rash

Calcinosis

Diagnosis – DM/PM.Diagnosis – DM/PM.

proximal weakness. CK activity. + EMG. + Biopsy. Rash.

Definite Probable PossiblePM all 4 3/4 2/4

DM 3 or 4 + R 2 + R 1 + R

Diagnosis-IBM More common in older men.More common in older men. Quadriceps and finger flexor Quadriceps and finger flexor

atrophy.atrophy. CK is elevated but mild/moderate.CK is elevated but mild/moderate. EMG is often distinct from others.EMG is often distinct from others. Swallowing affected in about 70 %.Swallowing affected in about 70 %. Biopsy shows rimmed vacuoles (+ Biopsy shows rimmed vacuoles (+

ααB crystallin, tau, APP) + COX –B crystallin, tau, APP) + COX –ve.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 Dx: ? Dystrophinopathy - gene first (MLPA - HSC = 66 %) > biopsy.(MLPA - HSC = 66 %) > biopsy.

WESTERN BLOTTINGI.H.C.

BMD

DMD

NORM

Gene Seq.

DystrophinopathiesDystrophinopathies Duchenne: Duchenne:

– XLR, 1/3500 live male births.XLR, 1/3500 live male births.

– weakness age 3 – 4 y.weakness age 3 – 4 y.

– CK – 10,000’s.CK – 10,000’s.

– W/C by teens.W/C by teens.

– Death resp. failure in 20’s.Death resp. failure in 20’s.

Becker’s:Becker’s:– Less common.Less common.

– Milder phenotype.Milder phenotype.

– CLINICAL - ++ calf hypertrophy, quads affected (atrophy) CLINICAL - ++ calf hypertrophy, quads affected (atrophy) with relative preservation of upper extremeties.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.– Miyoshi or LGMD.

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

issues.

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

Problems going up and down staircase

Running problems

Diagnosis

Problems rising from armchair

Problems rising from lying position

Walking problems

Problems with dressing

Problems going to toilet

Start of walking aid use

Start of wheelchair use

Start use of artificial ventilation

0 10 20 30 40 50 60 70 yrs

First complaints n=54

n=31

n=54

n=46

n=45

n=37

n=41

n=32

n=18

n=23

n=26

n=20

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.

(n=54)

Pompe – diagnosis.

Adult 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 α-glucosidase.

Biopsy Patterns

INFANTADULT

Drugs associated with myopathyDrugs 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.

Treatment: – Vitamin D = 30 nmol/L;testosterone = N.– Creatine monohydrate (0.1 g/kg/d).

Case # 1 - Molecular issues

Athena 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.

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!Case # 2– Lumber Jack! 69 y RHD male.69 y RHD male. PMHxPMHx::

Angioplasty – 1995Angioplasty – 1995 MedsMeds: : SimvastatinSimvastatin, ASA, , ASA,

atenolol, terazocin, vits atenolol, terazocin, vits B/C/EB/C/E

HPIHPI: tree cutting x 2 ++ : tree cutting x 2 ++ DOMS w/ CK to 4869 then DOMS w/ CK to 4869 then dropping to 341 over 2 ddropping 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).

Thanks The clinic:

Ms. L. BrandtMs. Erin HatcherMs. L. BradyMs. D. JohnstonMs. H. VeyMs. K. Scott The lab:

Dr. M. NilssonDr. M. AkhtarDr. L. MacNeillMr. D. Ogborn Collaborators:

Dr. B. LachDr. J. ProviasDr. J. BourgeoisDr. T. HawkeDr. J. Schertzer

• Warren Lammert and Family

• CIHR – Institute of aging.

• McMaster Children’s Hospital and Hamilton Health Sciences Foundation.