Muscle disease for physios

May 2014

Categories of muscle disease• Congenital

– muscular dystrophy, congenital myopathy– Mitochondrial– Metabolic– Channelopathy

• Inflammatory– polymyositis– Degenerative eg inclusion body myopathy– Iatrogenic eg drugs, statins

• Function – watch how they walk into clinic/get out of their seat etc before actual assessment– Limb girdle type of pattern? (waddling gait; lordosis)– Facial weakness? Droopy eyelid?– Foot drop?– Odd shoulders?– Scoliosis/other spinal deformity?– Small stature? Dysmorphic? Hearing aids?– Walking aids, Wheelchair?

• Alteration in function– Difficulty getting up and out of chairs/sofas/cars– Difficulty rising from a squat– Climbing stairs/holding onto bannisters– Reaching out for shelves; raising arms; hairdrying;

shaving– Difficulty opening jars; picking objects; doing

buttons– Slapping feet

Muscle pain

• Myalgia (flu-like) – myositis, Vitamin D def, fibromyalgia/PMR

• Cramp• Contracture (cramp but muscle goes rock hard)• Myotonia (muscle stiffness) look for grip and

percussion myotonia• Muscle pain with focal swelling

(myositis/metabolic)

Contractures

• Progressive fibrosis of muscle + weakness of antagonistic muscles = muscle shortening and inability to passively stretch to normal length

• Sometimes pathognomic of certain disease

Contractures are typical especially in Lamin A/C mutations (LGMD) and Bethlem myopathy (congenital myopathy with collagen 6 mutations)

Emery-Dreifuss

Selenoprotein

Skeleton – look for rigid spine

Scapular winging in FSH muscular dystrophy

But other LGMDs can give you scapular winging

Muscle weakness

• Distribution– Axial (do they have a dropped head? Do they have

a bent spine – camptocormia?)– Limbs– Face– Eyes – Bulbar

Anaesthetic complications

• Patient should wear Medic-Alert bracelet

• Anaesthetist should be informed of condition and long-acting neuromuscular blocking agents should be avoided

Dystrophinopathies

• Duchenne (DMD): Commonest childhood muscular dystrophy

• 1:3500 male births• Becker (BMD): 1:18,000 male births• X-linked recessive• Females not generally affected, but some may

have abnormalities on clinical exam, or nonprogressive myopathy, or manifesting carriers (skewed inactivation of X chromosome and higher proportion of defective gene producing mutant protein)

Origin of DMD

• 1/3 previous family history• 2/3 no family history• In the latter, mother is an undiagnosed carrier

(33%)• Or mutation occurred in ovum producing the son

with DMD (germ line mutation) (66%)• Once the diagnosis is made, genetic counselling

should be offered to the family especially maternal female relatives who are likely to be carriers

Molecular genetics

• Dystrophin is a large protein• Gives structural integrity to the

sarcolemma and prevents contraction-induced damage

• Links intracellular cytoskeleton to the extracellular matrix

• Gene lies on X chromosome, at Xp21• Large gene – 2500 kb long, >70 exons

Clinical manifestations

• Progressive weakness and wasting of mainly proximal muscles first, distal muscles later

• Girdle muscles affected first• Calf pseudohypertrophy (fat replacement)• Abnormal gait in the child, frequent falls• Waddling gait because of involvement of hip

abductors and more lordotic because of weakness of hip extensors

Calf pseudohypertrophy Increasing lordosis

Course of disease

• Progressive weakness and wasting• Worse after period of inactivity/bedrest• Kyphoscoliosis (spinal surgery and bracing)• Wheelchair bound• Frequent respiratory infections• Respiratory muscle weakness (non-invasive

ventilation)• Contractures (may need releasing)

Cardiac manifestations

• Conduction defects• Congestive heart failure often in terminal

stages when respiratory failure develops• Beta-blockers and ACEI• Important to monitor female carriers (even in

absence of limb muscle involvement)

Intellectual impairment

• Not progressive

• IQ at least one SD below normal

• Minor cerebral atrophy

Becker MD

• Milder version of DMD• Phenotype more variable• Onset between 5 and 15 years but may present

in their 30s or 40s• Similar distribution of muscle weakness• Contractures and spinal deformity almost never• Dilated cardiomyopathy even when weakness is

mild• Intellectual impairment less common

Diagnosis

• Clinical features + High CK

• Muscle biopsy – frequently not required/done

• Genetic analysis (detects deletions/duplications in 70% of DMD and 80% of BMD)

Treatment options and trials

• Corticosteroids: improvement in muscle strength in 11% and improved functional activity (climb stairs faster)

• Viral vector delivery of dystrophin cDNA (AAV safer)

• Exon skipping

Females • Females not generally affected, but some may

have abnormalities on clinical exam, or nonprogressive myopathy

• Can be manifesting carriers (skewed inactivation of X chromosome and higher proportion of defective gene producing mutant protein)

• Large calves • May have proximal muscle weakness• May have cardiomyopathy

Facioscapulohumeral MD

• Age of onset of symptoms: 7 to 30 years• Can present much later• Autosomal dominant inheritance• Signs can be subtle and asymmetric• Facial weakness often detected first• Unable to close eyes tightly/bury eyelashes• Transverse smile• Unable to whistle

Progression

• Facial weakness first• Foot dorsiflexors• Abdominal muscles• Shoulder girdle and humeral muscles• Pelvic girdle and proximal lower limb muscles

later• 20% are wheelchair dependent by age 40

Odd shoulder contourHigh-riding scapulae

Scapular wingingWeakness of shoulder girdle develops first.Weakness of triceps/biceps and supraspinatus develops later

• Cardiac muscle not affected• But respiratory muscle involvement is

common and respiratory muscle function needs to be regularly monitored

• Sensorineural hearing loss (75%)• Patients need to be asked specifically

about this• Commoner in those who present earlier in

life• Retinal vasculopathy (50%) (Coat’s

disease)

Pain

• Beyond the deformity from their periscapular and pelvic muscle weakness

• Often difficult to control

Limb-girdle MD

• Marked genetic heterogeneity• Clinically diverse with wide range of phenotypes• Different ages of presentation, different muscle

group involvement, different grades of severity with different rate of progression

• LGMD 1 = autosomal dominant• LGMD 2 = autosomal recessive• Diagnosis mostly made by protein

immunoblotting from muscle biopsies

LGMD

• Autosomal dominant• LGMD1A: Myotilin

• LGMD1B: Lamin A/C (+cardiac involvement)

• LGMD1C: Caveolin 3

• LGMD1D: ? Gene product (+cardiac involvement)

• LGMD1E: ? Gene product

• Autosomal recessive• LGMD 2A:Calpain 3• LGMD 2B: Dysferlin• LGMD 2C: Gamma-sarcoglycan• LGMD 2D: Alpha-sarcoglycan• LGMD 2E: Beta-sarcoglycan• LGMD 2F: Delta-sarcoglycan• LGMD 2G: Telethonin• LGMD 2H: TRIM32• LGMD 2I: FKRP• LGMD 2J: Titin• LGMD 2K: POMT1• LGMD 2L: ANO5

LGMD 1B

• Contractures• Rigid spine• Some patients have lipodystrophy• Cardiac involvement requiring

pacemakers/ICDs• Proximal and distal muscle weakness

Rigid spine

Emery-dreifuss: typical contractures at theelbows

LGMD 2A

• Contractures esp around calf, elbows, fingers• Waddling gait• Toe-walking as a child• Leg>arms• Periscapular and quadriceps• Respiratory failure

LGMD 2L FKRP

• Proximal>distal• Legs and arms• Legs affecting thigh adductors, psoas and quads• Arms – periscapular, deltoid, biceps and triceps• Type 2 respiratory failure even when ambulant• Can have calf, thigh and tongue hypertrophy

LGMD 2L ANO5

• Progressive proximal muscle weakness• Previously can be very strong individuals

including marathon runners etc• Can have focal atrophy of biceps and focal

hypertrophy of lateral gastrocnemius• Can have mild distal lower limb weakness

Oculopharyngeal muscular dystrophy

• Men>women• Autosomal dominant• Ptosis• Bulbar problems – may require gastrostomy for feeding• Progressive myopathy• May develop respiratory muscle involvement

Metabolic myopathies

• Lipid storage myopathies– CPT2 deficiency

• Glycogen storage disorders– McArdle’s

• Mitochondrial myopathies– Syndromes– Defects in fatty acid oxidation pathways– Complex

• Cramps• Exercise intolerance• Rhabdomyolysis• Progressive myopathy

Mitochondrial disorders

• Multi-system disorders• Myopathy• Complex eye problems• Endocrinological problems• Hearing loss• Gastrointestinal problems• CNS problems including migraine and seizures• Learning disabilities• Short stature etc

Pompe’s disease

• Infantile onset – severe and fatal• In infants with cardiac involvement and

hepatosplenomegaly• Adult-onset • Progressive myopathy• Respiratory involvement• Enzyme replacement therapy

Inclusion body myopathy

• An acquired degenerative muscle condition• Slow, insiduous and progressive• Usually affects >4th decade• Fine motor tasks (eg opening bottle jars, buttons) • Early falls in IBM due to involvement of quadriceps

(with wasting often by time of presentation)• Also wasting of flexor muscle compartment of

forearm with finger flexion weakness in IBM• Patients with IBM do not respond to

immunomodulatory treatments eg steroids

Quadriceps wasting in IBM

Wasting of forearm flexor compartment in IBM

Prognosis

• Poor• Develop facial weakness and problems

swallowing• Can have neck weakness• Often end up in wheelchair• No cardiac complications but may require NIV

and PEG feeding