MDT1

Question 1

Muscular dystrophies

Answer 1

Encompass a range of disorders involving muscle weakness

Question 2

Myotonic dystrophy type 1 (DM1)

Answer 2

Also known as Steinert’s disease
Progressive
Multisystemic disease

Question 3

Systems affected in DM1

Answer 3

Muscle
Nervous system
Endocrine
Respiratory
Immune
Skeletal muscle
Reproductive systems
GIT

Question 4

Autosomal dominant disorder characterised by…..

Answer 4

Myotonia
Inability to relax muscles following contraction
Uncontrolled muscle contraction including cardiac muscle
Respiratory changes

Question 5

Early death caused by

Answer 5

Cardiorespiratory failure

Question 6

Cognitive changes associated with DM1

Answer 6

Apathy, OCD, autistic-like traits

Question 7

DM1 affects…

Answer 7

1 in 8000 people
Most common adult form of muscular dystrophy

Question 8

Common symptoms

Answer 8

Drooping face and neck muscles
Difficulty swallowing
Cataracts
Weight loss
Symptoms vary throughout disease progression

Question 9

DM1 occurs as a result of

Answer 9

CTG repeat length expansion in the DMPK gene

Question 10

Meola and Cardani

Answer 10

Devised ranking system based on number of DMPK repeat lengths and age of onset in order to predict disease severity

Question 11

Congential DM1

Answer 11

Typically results in repeat lengths of more than 1000 trinucleotides
Not considered most severe
CTG repeats increase during life in correlation with DM1 symptoms

Question 12

Childhood onset (1-10 yo)

Answer 12

50-1000 repeats
Often not diagnosed with DM1

Question 13

Common age of diagnosis

Answer 13

10-30 yo

Question 14

Late onset (20-70 yo)

Answer 14

Mild dystonia
50-100 repeat lengths

Question 15

Full length (85kDa) DMPK

Answer 15

Nuclear envelope stability
Lipid bilayer enclosing eukaryotic nucleus

Question 16

Nuclear pores

Answer 16

Allow genetic material to pass from one side to other

Question 17

Role of nuclear envelope

Answer 17

Important for nuclear structure
Gene regulation
Muscle function

Question 18

Disturbances in nuclear envelope caused by

Answer 18

Depletion or overexpression of DMPK

Question 19

Instability in nuclear envelope may contribute to

Answer 19

Skeletal muscle wasting in DM1

Question 20

Epigenetic changes in DMPK DNA locus

Answer 20

Methylation of CTCF1 region linked to repeat length and disease severity

Question 21

Repeat length expansion of DMPK gene in DM1 results in

Answer 21

Splicing defects which may be central to disease progression

Question 22

In healthy individuals, RNA binding proteins (RBPs) involved in:

Answer 22

DNA repair
Transcription regulation
Cellular processes (apoptosis)

Question 23

In DM, RBPs such as MBNL and CELF proteins

Answer 23

Participate in pre mRNA transcription and maturation

Question 24

mRNA length expansion copies in DM1

Answer 24

Block nuclear pores of membrane leading to accumulation and trapping of proteins preventing optimal protein synthesis and expression

Question 25

Consequence of nuclear pore blocking

Answer 25

Negative effects on communication between muscle cells (myocytes) with DM1 patients demonstrating 50% reduction in protein expression during muscle biopsies compared to healthy individuals

Question 26

Severity of DM1 in each tissue...

Answer 26

Dependent on number of CTG repeats with suggestions that the extent of CTG repeats isolated from peripheral blood of DM1 patients is indicative of disease severity as a whole

Question 27

DM1 patients commonly present with

Answer 27

insulin resistance in the ABSENCE of diabetes

Question 28

Proposed mechanisms associated with insulin resistance in DM1 include

Answer 28

splice variation in insulin receptor (IR) and IGF1R

Question 29

AKT1/GSK3 beta signalling

Answer 29

associated with decreased glucose uptake and fatigue common symptom in DM1

Question 30

AMPK and mTOR pathways

Answer 30

protein degradation flagged as possible mechanisms in DM1-related insulin resistance

Question 31

Transcriptome analysis of OPTIMISTIC DM1 patient cohort

Answer 31

Key immune pathways NFAT OX40

Question 32

Immune pathways suggest muscle wasting in DM1 promotes disease severity

Answer 32

Due to ability of skeletal muscle to act as antigen presentation cells

Question 33

Increased muscle loss may play a role in

Answer 33

immune alterations associated with disease progression (increased MIRS scores)

Question 34

The DMSXL mouse model of DM1

Answer 34

has provided valuable insights into mechanisms underlying DM1

Question 35

Impaired protein synthesis in DMSXL mice causes

Answer 35

misplicing and expression of embryonic protein isoforms in adult muscle and heart leading to myotonia, synaptic dysfunction and insulin resistance

Question 36

How many repeats and what symptoms in DMSXL mouse

Answer 36

1000-1800 CTG repeats Multisystemic DM1 feature Severe growth retardation

Question 37

Motor dysfunction Increased lipid content Decreased serum insulin prompted...

Answer 37

Behavioural analysis for compulsivity

Question 38

Late phase reversal learning differences coupled to...

Answer 38

increased correction errors identified compulsive behaviour in the DM1 mouse mdoel

Question 39

DMSXL mice also demonstrated.....

Answer 39

Enhanced distinction behaviour with executive control similar to OCD