Myotonic dystrophy Flashcards
DM1 cause
DMPK gene
Trinucleotide repeat (CTG)
Expressed DMPK mRNA translated into myotonic dystrophy protein kinase - shuts off myosin phosphate (involved in muscle contraction)
DM2 cause
CNBP gene
Tetranucleotide repeat (CCTG)
Expressed CNBP mRNA translated into cellular nucleic acid binding protein
Pathophysiology of myotonic dystrophy
Repeat expansions (CTG and CCTG) caused by slipped mis-pairing (DNA polymerase repeats copy)
Anticipation phenomenon (>200 repeats per generation)
DMPK > 50
CNBP > 75
Repeated regions have widespread hydrogen bonds between C and G base pairs
RNA forms condensed clumps inside the nucleus, RNA clumps attract RNA binding proteins needed for processing other genes so other genes cannot be expressed normally
Genes include Six5 (eye), Insulin receptor gene, Cardiac troponin T gene - causes symptoms of myotonic dystrophy
Type 1 MD
Congenital form - symptoms start from birth, babies too weak to suck or breathe, don’t survive for long
Adult form - muscle weakness later in life, primarily facial muscles (hollow cheeks, drooping eyelids, distal hand muscles and lower leg/toe foot drop)
Type 2 MD
Only in adulthood, typically milder weakness and mostly proximal muscles of the thighs and hips - difficulty climbing stairs or rising from a seat. Shoulders and elbows weak (problems lifting/holding an object)
Classic presentation of myotonic dystrophy
Myotonia (sustained muscle contraction and difficulty relaxing muscles after use)
Cataracts
Muscle wasting
Ptosis
Facial muscle wasting
Respiratory and cardiac dysfunction
Insulin resistance (high blood glucose - hyperglycaemia)
Cardiac conduction defects
Diagnosis of myotonic dystrophy
Genetic testing (no. of repeats)
EMG - stratchy low-amplitude appearance
MUAPs - low amp shorter duration, phases increased
Interference pattern - full and early recruitment pattern in muscle weakness, fills screen, motor units fine but muscle cell fibres not, compensate by recruiting lots of motor units at low contraction
Spontanous activity - fibs/sharp waves, complex repeitive discharges
Myotonia - provoked by muscle activation or needle involvement, waxing and waning frequency/amplitude, dive bomber sound (congenital myotonias)
Muscle biopsy - to distinguish muscle problems from nerve problems
Counselling
Major affects of myotonic dystrophy
Cognitive function: (memory, executive function, intelligence, behavioural and psychological, daytime sleepiness)
Vision: premature cataracts with muscle symptoms <55, retinal damage
Endocrine: diabetes, low thyroid hormone levels, abnormal liver function, high cholesterol
Respiratory: aspiration, sleep apnoea, pneumonia
Skin: Pilomatrixomas (benign tumour of the hair follicle)
Bone anomalies
Reproductive system: erectile dysfunction, weakened uterine muscle, pregnancy complications
CVS: heart condition abnormalities, arrhythmias, heart failure (30% by age 70)
GI: swallowing issues, abdominal pain, IBS, weight loss
Muscle: wasting, myotonia, pain
Increased cancer risk
Balding
Treatment of myotonic dystrophy
Myotonia - anticonvulsants, mexiletine (sodium channel blocker)
Chronic pain - management follows the analgesic ladder (WHO)
Monitor - ECG, Glucose, lipids, cataracts (surgical removal), respiratory failure
Erectile dysfunction - viagra
Genetic counselling for families - 1/3,500 boys, female carriers, 50% chance of passing down gene to children, 2/3rd of cases explained by inheritance, 1/3rd spontaneous mutation
Anaesthetic counselling - alert cards condition specific alert cards for different muscle wasting conditions - given to non-specialised clinician during worsening health to say recommendations/precautions
Future therapies: genetic strategies - Antisense oligonucleotides - short segments of genetic material activate enzymes to destroy toxic RNA, target specific areas of gene chromosome
Up-regulate MBNL (increase production of)
Prevent binding of MBNL to expansion
Target specific splicing events
