Contents

Hereditary Myopathies. 1

Summary table. 1

Myotonic Dystrophy. 2

Epidemiology. 2

Pathogenesis. 2

Clinical 2

Diagnosis. 3

Prognosis. 3

Treatment 3

Muscular Dystrophies (Hereditary myopathies)

Definition

· A group of inherited disorders that are manifest by progressive muscle weakness

· Most of which are associated with defects in the dystrophin associated membrane complex.

Summary table

Disease	Epi	Clinical	Aetiology	Rx
Duchenne MD	XR 30/100,000 Dystrophin gene	Onset 3-5yrs Proximal b/f distal Girdle weakness Kyphoscoliosis Death from pulmonary causes (~20y) Cardiac involvement but not often serious	CK always very high Dystrophin protein abnormalities or absence on muscle biopsy	Steroids slow progression for up to 3 years
Becker MD	XR 3/100,000 Dystrophin gene	Similar to Duchenne but later onset (>15) Calf hypertrophy common	As for Duchenne Less severe dystrophin abnormalities	Effect of steroid unknown
Limb-Girdle MD	AD or AR	Range of disorders with pelvic and shoulder muscle weakness Onset in 20’s	Variable. Defects in a number of different proteins.
Myotonic Dystrophy	AD P 1/8000 CTG expansion	Two types DM1 and DM2 Affects facial muscles Fontal baldness Head and neck involved early Distal > proximal Myotonia		Symptomatic Rx for myotonia Cardiac disease
Facioscapulo-humeral	AD Repeat disease	Infant or adult onset Face first – general weakness Shoulder and upper arm involvement – biceps, triceps, preserved deltoid Scapular winging, riding up of scapula Foot drop may occur Cardiac involvement can occur	CK mild elevation Genetic tests	Supportive Surgical fixation of scapula may help
Other: Emery-Dreifuss Congenital MD Oculopharyngeal

Myotonic Dystrophy

• Also called Dystrophia myotonica

Epidemiology

• 1 in 8000
• The proportion of the disease that is type 1 vs type 2 is not well characterised, type 1 is probably more common.
• Onset 20-40 for DM1 and a bit later 30-60 for DM2
• Occasional juvenile and late onset
• AD

Pathogenesis

• DM1
• CTG repeat expansion in DMPK gene
• Normal – 5-35 repeats, disease hundred or thousands
• Gene transcribed but not translated
• Severity of disease generally correlates with size of repeats
• Anticipation – worsening with generations due to increased repeat size.
• DM2
• CCTG expansion in intron 1 of ZNF9 gene
• Correlation of expansion size with severity not documented
• Mechanism for disease is not completely known
• However it is suspected that abnormal RNA interferes with a number of different genes
• DMPK and ZNF9 gene products are not thought to be central to disease process

Clinical – Type 1 (see below for type 2)

Muscle and nerve

• Overall pattern
• Often onset with hand or foot weakness
• Often distal >proximal weakness (in contrast to most other dystrophies)
• Neck often significantly affected
• Facial muscles
• Characteristic facial appearance – long narrow, high arched palate, frontal baldness
• Cheeks hollow (Masseter wasting) and jaw sags
• Temporalis atropy with hollowing of temples
• Wasting of SCM
• Ptosis
• Palatal, pharyngeal and extra-ocular weakness can occur rarely
• Palatal weakness can cause hollow/echoing voice.

• Neck – weak flexion, normal extension
• Distal forearms and hand muscles most affected
• Ankle dorsiflexors (bilateral foot drop)
• Usually unaffected - Pelvic girdle, hamstrings and ankle plantar flexion.
• Muscle pain common
• Myotonia
• Slowed relaxation following normal muscle contraction – test by handshake and rapid hand opening.
• Percussion myotonia – tapping thenar eminence causes slow relaxation after contraction
• Prominent in early stages of disease – reduces as muscle weakness progresses
• Sensory changes
• Axonal, sensorimotor polyneuropathy may occur – exact incidence is debateable
• DM2
• Facial involvement less common and later
• Proximal weakness common
• Elbow extension affected

GIT

• Involves smooth muscle
• Lower GI - Colickly abdominal pain, constipation, diarrhoea, pseudo-obstruction , cholecyctitis
• Upper GI
• Dysphagia and aspiration

Cardiac

• Conduction disturbances
• First degree block 20-30%
• Bundle branch block in 10-15%
• AF and Atrial flutter common
• Structural abnormalities
• LVH and/or systolic dysfunction in 10-20%

Respiratory

• Weakness of respiratory muscles
• Problems with respiratory drive
• Excessive daytime sleepiness

Endocrine

• Primary hypogonadism
• Testicular atrophy
• Male-pattern frontal balding
• Insulin resistance

Cognitive impairment

• Variable
• Can be severe in early onset disease
• IQ on average 1SD below the mean

Ocular

• Cataracts (occur in most patients)
• Posterior subcapsular (Characteristically iridescent)

Diagnosis

• Characteristic features and positive family history is probably sufficient to make the diagnosis
• Genetic testing
• Measurement of CTG repeats – gold standard for diagnosis
• Can be done antenatal with chorionic villus biopsy
• EMG
• Changes of myotonia – waxing and waning action potentials (both in amplitude and frequency)
• Muscle biopsy
• Usually not necessary
• Will show typical myopathic changes
• Type I fiber atrophy
• CK
• Mild to moderate elevation

• Hypogonadism
• FSH elevated, testosterone low

• ECG to screen for cardiac abnormalities
• Eye examination for cataracts
• Neuroimaging- MRI brain
• Cerebral atrophy
• Increased frequency of T2 white matter hyperintensities
• Thickening of the cranial vault

Prognosis

• Reduced life expectancy
• Mortality ratio up to 7x higher
• Main causes of death
• Pneumonia
• Cardiovascular disease
• Neoplasia

• Congenital form hold poor prognosis – 50% survival to 30years

Myotonic Dystrophy Type 2

· Previously called proximal myotonic myopathy

· Shares many features with type 1

· Later onset

· More prominent muscle pain, stiffness and fatigue

· More early proximal weakness

· Diabetes more common

• Cardiac abnormalities less frequent
• Prognosis
• Lack of data
• Less frequently need assistance to walk etc.
• Life expectancy probably not much worse than baseline.

Treatment

• Muscle weakness
• Splints
• Physio
• Exercise training felt to be beneficial
• Statins best avoided?
• Muscle pain/myotonia
• TCAs (Cloipramine and imipramine)
• Taurine
• Quinine, Phenytoin, procainamide, mexiletine, acetazolamide
• Prednisolone
• Benzodiazepines
• Sleep
• CPAP
• Breathing exercises
• Excessive daytime sleepiness - modafinil
• Dysphagia
• Change in meal consistency and size etc.
• Speech R/V
• Cardiac
• Monitor
• PPM may be indicated early
• No data on ICDs
• Genetic counselling
• Family members

Suggested Screening Plan:

· Yearly ECG – refer to cardiology if prolonged PR, QRS, conduction block or palpitations

· Sleep study

· Fasting glucose yearly

· Yearly eye review for cataracts

Duchenne Muscular Dystrophy

Pathogenesis

· Dystrophin gene nutations

· Multiple types of mutations – deletions, splice, etc.

Clinical

• Onset usually evident by 2-3years age
• Usually wheelchair bound by 12 years
• Death usu <20yrs

Muscle

• Proximal before distal
• Lower limbs before upper limbs
• Gait – waddling,
• Defromities – often severe kyphoscoliosis, lumbar lordosis,
• Difficulty rising – may push up with hands (Gower;s sign)
• Calf hypertrophy to compensate for proximal weakness – this later becomes atrophic. May be ‘pseudohypertrophy due to relative proximal wasting.
• Falls and subsequent fractures are common

Cognition

• Often mild cognitive impairment
• ?Autistic type traits

Cardiac

• Dilated cardiomyopathy (with characteristic features)
• Fibrosis of posterobasal LV wall
• ECG – left atrial hypertrophy, tall R in V1 and inferolateral Q-waves
• Increases in frequency with age such that nearly all patients are affected by age 18yrs.
• Supraventricular conduction defects

Limb-Girdle Muscle Dystrophy

Management

· Corticosteroids

· Deflazacort – synthetic corticosteroid

o Slight benefits relative to corticosteroids, and some drawbacks

· Rehabilitation

· Vamorolone

o In trials

o Synthetic steroid with much less side effects

· Antisense oligonucleotide

o Ongoing research

o Need to have a specific one designed for each different gene mutation

o

Patient Resources

· Muscular dystrophy Australia – www.mdaustralia.org.au

· Myotonic dystrophy – www.myotonic.org