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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.