Molecular Aspects of Myotonic Dystrophy Part 1

Question 1

What is DM2 also known as?

Answer 1

DM1 is also known as Proximal Myotonic Myopathy (PROMM).

Question 2

What is the incidence of DM1?

Answer 2

1 in 8000.

Question 3

Approximately what % of DM is DM1?

Answer 3

Approximately 98% of DM is DM1.

Question 4

Describe the phenotype of DM.

Answer 4

Both DM1 and DM2 have adult onset (classic) and late onset forms. Adult onset usually involves symptoms stating in the 30s or 40s but onset can be any time in adulthood with the severity and number of symptoms usually associated with an earlier onset.

Symptoms include myotonia, cardiac conduction defects, cataracts, muscle weakness, insulin insensitivity, insomnia and lethargy.

Male patients can show atrophy and male pattern baldness.

There is incomplete penetrance of symptoms and late onset cases are milder than adult onset.

DM1 also has a congenital form. Babies are born with hypotonia and show delayed mental and physical development. Other symptoms develop later in life.

Rare juvenile onset forms have also been described.

The most common cause of death for DM patients is heart failure, although the use of a pacemaker can help prevent premature death.

Question 5

Which type of DM also has a congenital form?

Answer 5

DM1 also has a congenital form. Babies are born with hypotonia and show delayed mental and physical development. Other symptoms develop later in life.

Question 6

What is the most common form of death for DM patients.

Answer 6

The most common cause of death for DM patients is heart failure, although the use of a pacemaker can help prevent premature death.

Question 7

Describe the DM1 mutation.

Answer 7

DM1 is associated with an expanded CTG trinucleotide tract in the 3’ UTR of the DMPK gene on chromosome 19.

DMPK is mainly expressed in the heart and skeletal muscle and codes for a kinase involved in the development of muscle fibres.

The number of CTG repeats positively correlates to the severity of the phenotype and negatively with the age of onset.

A larger number or repeats will lead to an earlier onset of symptoms and the symptoms are likely to be more severe.

Question 8

What does DMPK encode?

Answer 8

DMPK is mainly expressed in the heart and skeletal muscle and codes for a kinase involved in the development of muscle fibres.

Question 9

What does the length of the CTG repeat in the 3’ UTR of the DMPK gene correlate with?

Answer 9

The number of CTG repeats positively correlates to the severity of the phenotype and negatively with the age of onset.

A larger number or repeats will lead to an earlier onset of symptoms and the symptoms are likely to be more severe.

Question 10

What is the most common CTG repeat length?

Answer 10

5 CTGs, with 11, 12 and 13 CTGs also being very common.

Question 11

Outline the classifications of DM1 CTG repeat lengths.

Answer 11

Normal = 5-35 repeats - no phenotype, low probability of expansion on transmission.

Intermediate = 36-50 repeats - No phenotype nut may be unstable on transmission and potentially expand into the affected range.

Affected range >51 repeats - smaller repeat sixes may still not give a recognisable phenotype or mild symptoms may only arise later in life.
Repeat numbers between approximately 100 and 1000 are most likely to be associated with classic DM.
Repeat sizes of more than 1000 CTGs are very likely to give rise to congenital DM1.
All repeats in this range can be unstable on transmission to offspring.

Question 12

What is the normal DMPK CTG repeat range?

Answer 12

Normal = 5-35 repeats - no phenotype, low probability of expansion on transmission.

Question 13

What is the intermediate DMPK CTG repeat range?

Answer 13

Intermediate = 36-50 repeats - No phenotype nut may be unstable on transmission and potentially expand into the affected range.

Question 14

What is the affected DMPK CTG repeat range?

Answer 14

Affected range >51 repeats - smaller repeat sixes may still not give a recognisable phenotype or mild symptoms may only arise later in life.
Repeat numbers between approximately 100 and 1000 are most likely to be associated with classic DM.
Repeat sizes of more than 1000 CTGs are very likely to give rise to congenital DM1.
All repeats in this range can be unstable on transmission to offspring.

Question 15

Describe the DM2 mutation.

Answer 15

DM2 is linked to a CCTG repeat tract in the first intron of the CNBP gene (previously named ZNF9).

Normal alleles of the CNBP gene will have up to 26 repeats whereas affected alleles will have between 75 and 11000 repeats.

The length of the CCTG repeat does not have a strong correlation with the severity of symptoms.

The age of the patient at the time of testing is more likely to correlate with the repeat length as mitotic instability often leads to increasing repeat length over time in the DNA extracted from the blood.

Question 16

What mutation is associated with DM2?

Answer 16

DM2 is linked to a CCTG repeat tract in the first intron of the CNBP gene.

Question 17

Outline the normal and affected expansion ranges in the CCTG repeat region in the CNBP gene associated with DM2.

Answer 17

Normal alleles of the CNBP gene will have up to 26 repeats whereas affected alleles will have between 75 and 11000 repeats.

Question 18

True or false - The length of the CCTG repeat in the CNP gene associated with DM2 has a strong correlation with the severity of symptoms.

Answer 18

False - The length of the CCTG repeat does not have a strong correlation with the severity of symptoms.

Question 19

Describe the inheritance of myotonic dystrophy.

Answer 19

Both DM1 and DM2 are inherited with an autosomal dominant pattern.

The length of the repeat can change when transmitted to the offspring.

The stability of the repeat decreases as the number of repeats increases.

Longer repeats are more likely to change size when passed on and there is a greater chance of a big size change.

The instability is probably due to the formation of secondary structures within the DNA that interfere with DNA replication causing slippage and increased recombination.

Question 20

What is the correlation between repeat length and transmission stability in myotonic dystrophy?

Answer 20

The length of the repeat can change when transmitted to the offspring.

The stability of the repeat decreases as the number of repeats increases.

Longer repeats are more likely to change size when passed on and there is a greater chance of a big size change.

The instability is probably due to the formation of secondary structures within the DNA that interfere with DNA replication causing slippage and increased recombination.

Question 21

In myotonic dystrophy what is thought to account for the greater transmission instability seen in the transmission of larger repeats?

Answer 21

Longer repeats are more likely to change size when passed on and there is a greater chance of a big size change.

The instability is probably due to the formation of secondary structures within the DNA that interfere with DNA replication causing slippage and increased recombination.

Question 22

Describe repeat expansion in myotonic dystrophy.

Answer 22

Both DM1 and DM2 are inherited with an autosomal dominant pattern.

The length of the repeat can change when transmitted to the offspring.

The stability of the repeat decreases as the number of repeats increases.

Longer repeats are more likely to change size when passed on and there is a greater chance of a big size change.

The instability is probably due to the formation of secondary structures within the DNA that interfere with DNA replication causing slippage and increased recombination.

In DM1 an allele of 50-70 repeats will be transmitted stably in approximately 25% of cases and the majority of expansion will be to alleles less than 200 repeats.

Alleles of 70-90 repeats are very unlikely to be transmitted stably and approximately 60% will expand above 200 repeats.

Mutations with 100 or more repeats have a high risk of expanding into the congenitally affected range.

If the parental allele is relatively small (<100) the sex of the parent does not affect the risk of expansion.

Larger expansions are predominantly of maternal origin.

Males with adult onset DM1 will rarely have congenitally affected children.

Question 23

How stable is a DM1 allele of 50-70 repeats on transmission?

Answer 23

In DM1 an allele of 50-70 repeats will be transmitted stably in approximately 25% of cases and the majority of expansion will be to alleles less than 200 repeats.

Question 24

How stable is a DM1 allele of 70-90 repeats on transmission?

Answer 24

Alleles of 70-90 repeats are very unlikely to be transmitted stably and approximately 60% will expand above 200 repeats.

Question 25

How stable is a DM1 allele of >100 repeats on transmission?

Answer 25

Mutations with 100 or more repeats have a high risk of expanding into the congenitally affected range.

Question 26

Does the sex of the parent affect the risk of expansion of the DM1 allele?

Answer 26

If the parental allele is relatively small (<100) the sex of the parent does not affect the risk of expansion

Due to the increased number of cell divisions the risk of expansions in higher in males if the repeat length is very small.

Larger expansions are predominantly of maternal origin.

Males with adult onset DM1 will rarely have congenitally affected children.

Question 27

Are males with adult onset DM1 likely to have congenitally affected children?

Answer 27

Males with adult onset DM1 will rarely have congenitally affected children.

Question 28

Are larger DM1 expansions primarily of maternal or paternal origin?

Answer 28

Larger expansions are predominantly of maternal origin.

Question 29

What factors affect the likelihood of DM allele expansion on transmission?

Answer 29

1) . Size of allele

2) . Sex of transmitting parent

Question 30

Describe anticipation for myotonic dystrophy.

Answer 30

The expansion of the repeat through generations of a family gives rise to anticipation.

Anticipation is a term used to describe the pattern of increasing severity of symptoms and/or decreasing age of onset down the generations of a pedigree. This pattern is often seen particularly strongly in DM1 families.

e. g.
- Grandfather age 65 with cataracts and some mild facial muscle weakness.
- Mother age 30 with some muscle weakness, mild myotonia and a cardiac conduction defect.
- Child born with hypotonia, delayed development and wide range of other DM symptoms.

The anticipation seen in DM1 is due to the expansion of the repeat upon transmission.