DM1 Flashcards
DM1
1. def
2. prevalence
3. treatment
- progressive muscle degen leading to weakness and wasting in multiple sys; progeroid disease (fast track aging) with multiple phenotypes assoc with mutational load
- prevalence 1 in 8000, but highly prevalent in Charlevoix and Saguenay-Lac St-Jean regions in Quebec as 1 in 600
- no current treatment options
DM1 phenotypes
non linear assoc with number of CTG repeats
1. congenital: onset at birth, most severe with hypotonia, resp failure, feeding difficulties, cardioresp complications, >1000 repeats
2. childhood/junvenile onset: 1-20 yrs, facial weakness, myotonia, heart conduction defect, 50-1000 repeats
3. adult onset: weakness, myotonia, conduction defect, cataracts, insulin res, resp failure, 50-1000
4. late onset: mild myotonia, cataracts, 50-100, <50 asymptomatic
physical manifestation of DM1
- myalgia (pain and poor Ca2+ handling),
- muscle atrophy and weakness in distal and facial muscles, long faces
- male pattern baldness linked to poor distribution of sex hormones and receptors, 4. poor vision and insulin res
atrophy in DM1
- overall size of muscle stays the same since muscle is replaced by adipose tissue, can go unnoticed
- connected with weakness, unknown cause since pop is highly sedentary
- distal muscle more affected (either v. large or small with uneven muscle fibres distribute), atrophy of (exclusive) type 1 muscle fibres, nuclear clumping, centrally located nuclei (hard to clear out dmg tissue or inflammation, constant repairing of muscle), poor mitochondria
manifestations of fatigue in DM1
- visible signs such as ptosis (fatigue of facial muscle results in droopy eyes),
- excessive daytime sleepiness, fatigue, and concentration diffculties due to reduced ATP, ECC, and Ca2+ handling, leads to excessive sleep or hypersomnolence
clinical manifestations of DM1:
1. myotonia
2. testing for myotonia
- inabilty to relax muscle immediately after vol contraction due to poor Ca2+ handling during ECC (slow repolarizationi of sarcolemic membrane offsets Ca2+ homeostasis) leading to irregular muscle movement
- test visually for slow relaxation using percussion myotonia test (initate reflex and wait for relaxation)
- grip release myotonia (ask patient to grip hand and wait for relaxation) and using EMG (myotonia will have signal during relaxation)
genetic factor of DM1 inheritance
DM1 is an autosomal (non-sex chromosome) dominant condiiton affecting chromosome 19 on DMPK locus as CTGn repeats in 3’ untranslated region; each child of affected parent has 50% chance of inheriting DM1
genetic anticipation in DM1
worsens in each subsequent generation (genetic anticipation); parent with over 50 repeats since CTGn becomes unstable and mutation passed increases disease severity and increases age of onset for child; higher chance of increased repeat number when mother passes DM1 due to greater DNA instability during oogenesis
genetic cause of DM1: repeated expansion
CTG repeat in 3’ untranslated region in DMPK gene of chromosome 19 causes accumulation of the noncoding exon CUGn DMPK mRNA transcripts, CTGn length predictivee of clinical severy and onset age but not always linear relation
somatic repeat instability in DM1
1. fluxation CTGn
2. age
3. SRI in muscle
variations in CTGn between tissues can occur during dev and in mature tissue, can have different repeat numbers in different cells in a single tissue causing somatic mosaicism, thus diease can shift in serveritiy over time so mutational load is always in flux
2. increases with age but not always by same amount making it challenging to know the stability of DM1
3. more repeats there are the more unstable CTGn becomes and is worse in muscle since it naturally has high CTGn (why muscle degrades faster)
pathophysiology of DM1
1. nuclear foci
2. RNA toxicity
3. DM1 as spliceopathy
- expanded CUGn form hairpin shaped nuclear foci and sequesters muscle blind like pro (RNA binding pro responsible for promoting adult isoforms) preventing them from functioning and abnormally activate RNA dependent pro kinase R which hyperphosphorylates CUG-BP/CELF1 pro which promotes fetal isoforms in adult tissues
- FISH shows normal motor neurons MBN1 is localized throughout cytoplasm and nucleus but in DM1 foci is sequested at CUGn RNA in centre
- due to accumation of fetal isoforms promotes missplicing of insulin receptor, chloride channel, SERCA, troponin T as fetal forms which get degraded and therefore the proteins are not present, leading to insulin res, myotonia, cardiac arrhythmia, and cataracts
treatment for DM1
1. overview
2. therapeutic strategies
3. current therapeutic landscape
- no cure, cannot change with gene editing bc error is in RNA translation
- can inhibit transcript and edit at level of gene, inactivate toxic RNA, can modulate MBNL and CELF expression, and modulate downstream signalling pathways involved in splicing
- not many drugs or tech have passed clinical trial stages to target root cause but many different drugs to target specific disease symptoms such as insulin res, myotonia, CNS issues, etc. but exercise holistically fixes symptoms and alt splicing
exercise on preclinical DM1 outcomes in murine model
1. functional outcomes
2. inactivation of toxic transcript and modulation of RNABP
3. missplicing and downstream events
- DM1-like HSALR mice did 7 weeks of vol running, exercise improves functional outcomes (time to failure and all grip strength) and decreases EMG signal myotonia compared to sedentary HSALR mice
- decreases CUG transcript repeats (less fluorescent hairpins) and dispersed MBNL1 (less clumping in FISH) to allow for inactivation of tic transcript
- corrects missplicing with similar splicing as sedentary wildtype than DM1sedentary and enhances CLC-1 expression for Ca2+ regulation for downstream modulation
clinical trial investigating aerobic exercise in DM1 patients
1. clinical outcomes
2. molecular pathology
3. type I fibre atrophy
4. mitochondrial biology
- 12 weeks of cycling increase in VO2peak and max workload for greater muscular function, global improvement of clinical outcomes
- improves splicing for all people but high interindividual variability in amount of improvement in splicing allowing for regulation in downstream pathways
- cycling recruits type I (SO) fibres, fibre type shift from IIB (FG) to IIA (FOG) to buffer loss of smaller type I fibres from DM1
- DM1 losses mitochondria and decrease mitochondrial function (shown as increase in ragged red fibres showing abnormal mitochondria when stained), exercise in DM1 muscle increase mitchondrial PRO and mitochondrial function
clinical trial investigating resistance exercise in DM1 patients
1. muscle fibres and strength
2. molecular pathology
- 12 weeks of resistance exercise improves muscle strength even at 6 weeks, improves clinical outcomes at 12 weeks, and augments type I and II SM fibres size at same rate in DM1 patients but with high interindividual variability
- improve missplicing for all but with high interindividual variability with amount of improvement in missplicing, allowing for regulation in downstream pathways
