POST-SURGERY RECOVERY

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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.

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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.

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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).

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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 (lt 1,000 U/L).

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Cause of HyperCKemia

• Sarcolemma leak/damage.
• All cytoplasmic proteins.
• Seen in many but not all muscle disorders .
• Huge variability between people (mengtwomen
  African gt Caucasian).
• EXERCISE 4h post and up to 10 days.

CK LDH AST ALT Aldolase Myoglobin
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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 _at_
  CHEO).
• SOBOE weakness (Pompe, MG, LGMD, mito.).
• Sitting/supine FVC - gt 20 drop diaphragm weak.

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Needle EMG
Fibs./PSW
Myotonia
Myopathic Potentials
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Muscle Biopsy
Bourgeois and Tarnopolsky, Mitochondrion,
4441-52, 2004. Tarnopolsky, et al, Muscle Nerve,
2011.
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Biopsy Patterns
Ragged Red
Central Core
Dystrophic
Pompe
Inflammation
Dennervation
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EM Changes
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Myopathies

• Muscle
• INFLAMMATORY.
• DYSTROPHY.
• TOXIC/INFECTIOUS.
• METABOLIC.
• CONGENITAL MYOPATHY.
• ENDOCRINE.
• CHANNELOPATHY.

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Inflammatory Myopathies

• Polymyositis.
• Dermatomyositis.
• Inclusion Body Myositis.
• Myositis associated with connective tissue
  disorders (MCTD, RA, lupus)

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Rashes, etc.
Gottrons Papules
Rash on knuckles Gottrons Sign
Shawl Sign
Heliotrope Rash
Calcinosis
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Diagnosis DM/PM.

• proximal weakness.
• CK activity.
• EMG.
• Biopsy.
• Rash.
• Definite Probable Possible
• PM all 4 3/4 2/4
• DM 3 or 4 R 2 R 1 R

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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 ( aB crystallin,
  tau, APP) COX ve.

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Muscular Dystrophy

• Dystrophinopathy
• LGMD
• OPMD (AD, ptosis NOT ophthalmoplegia, dysphagia,
  onset 40 - 50 y)
• Congenital
• DM1/DM2
• Distal (TCAP)/hIBM (GNE)
• FSHD

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Dx ? Dystrophinopathy - gene first (MLPA - HSC
66 ) gt biopsy.
BMD
NORM
Gene Seq.
DMD
WESTERN BLOTTING
I.H.C.
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Dystrophinopathies

• Duchenne
• XLR, 1/3500 live male births.
• weakness age 3 4 y.
• CK 10,000s.
• W/C by teens.
• Death resp. failure in 20s.
• Beckers
• Less common.
• Milder phenotype.
• CLINICAL - calf hypertrophy, quads affected
  (atrophy) with relative preservation of upper
  extremeties.

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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).

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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.

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LGMD

• Sarcoglycanopathies (a,ß,?,d 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.

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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.

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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

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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
Running problems
Diagnosis
Problems going up and down staircase
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
(n54)
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 128671-7, by permission of
Oxford University Press.
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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 a-glucosidase.

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Biopsy Patterns
INFANT
ADULT
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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

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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, 63713-, 2011) statins induce expression
  of anti-HMGCR autoanitbodies.

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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.

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Case 1- Calf atrophy

• 26 y old male with difficulty getting up from
  squat age 19 y gt 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 gt anterior lower leg
  atrophy and weakness with hip flexors 2/5 and
  hamstrings 3/5.

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Case 1- Calf atrophy.

• Muscle biopsy inflammation, N - dysferlin.
• CK gt 3,000 iU.
• Dx inflammatory myopathy - no response to
  corticosteroids.
• Rheumatologist wanted a second opinion.
• Patient wanted to know about Rx options.

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Case 1 New mutation

• Whole DYS gene sequenced.
• Mutation analysis c.4747 TgtG 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/Ltestosterone N.
• Creatine monohydrate (0.1 g/kg/d).

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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 May47(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.

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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

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Case 3 Fibromyalgia?

• 59 y old female.
• Dx fibromyalgia for 20 y.
• Hx non-specific pains and weakness for gt 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

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Case 3- Testing

• DBS low GAA activity
• Biopsy
• Genetics c.6925GgtT (known - alters splicing of
  mRNA in 3 region of exon 3) c.1211AgtG
  p.Asn404Gly).

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Thanks

• 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

• Warren Lammert and Family
• CIHR Institute of aging.
• McMaster Childrens Hospital and Hamilton
  Health Sciences Foundation.