Clinical Aspects of Myotonic Dystrophy

Question 1

Describe myotonic dystrophy?

Answer 1

Myotonic Dystrophy (DM) is the commonest adult form of muscular dystrophy.

DM is a multi-system disorder that affects the skeletal muscle and smooth muscle, as well as the eye, heart, and endocrine system.

DM is characterised by muscle weakness and wasting, myotonia, cataract and often cardiac conduction abnormalities.

Age of onset usually 20-50yrs and mean age of death is 60yrs.

Common symptoms include daytime sleepiness, fatigue, hands locking up, choking on food. May also have chest infections, IBS and palpitations. React very badly to certain muscle relaxants.

DM is inherited in an autosomal dominant (AD) fashion.

Additional feature of anticipation. The occurrence of increasing disease severity and decreasing age of onset in successive generations.

DM is due to an expansion of the CTG trinucleotide repeat in the DMPK (myotin-protein kinase) gene on chromosome 19.

The number of CTG repeats ranges from 5-37 in normal alleles. Symptomatic individuals have >50 repeats. Infants with congenital DM have CTG repeat lengths >100.

Question 2

What is the prevalence of myotonic dystrophy?

Answer 2

Prevalence of 1 in 8,000

Question 3

What systems of the body does myotonic dystrophy affect?

Answer 3

DM is a multi-system disorder that affects the skeletal muscle and smooth muscle, as well as the eye, heart, and endocrine system.

Question 4

What is the age of onset of myotonic dystrophy?

Answer 4

Age of onset usually 20-50yrs and mean age of death is 60yrs.

Question 5

What are the common symptoms of myotonic dystrophy?

Answer 5

Common symptoms include daytime sleepiness, fatigue, hands locking up, choking on food. May also have chest infections, IBS and palpitations. React very badly to certain muscle relaxants.

Also have increased risk of cataracts, may have gynaecomastia, frontal balding, temporal indentations, drooping of facial muscles, problems relaxing grip, may see a myotonic contraction of the thumb when you percuss on the thenar eminence on the hands. Over time you will see some wasting of the muscles. Atrophy of the temporal muscles is what gives indentation on each side of the forehead.

Question 6

How is myotonic dystrophy inherited?

Answer 6

DM is inherited in an autosomal dominant (AD) fashion.

Question 7

What is the molecular cause of myotonic dystrophy?

Answer 7

DM is due to an expansion of the CTG trinucleotide repeat in the DMPK (myotin-protein kinase) gene on chromosome 19.

The number of CTG repeats ranges from 5-37 in normal alleles. Symptomatic individuals have >50 repeats. Infants with congenital DM have CTG repeat lengths >1000.

Question 8

What chromosome is the DMPK (myotin-protein kinase) gene found on?

Answer 8

Chromosome 19.

Question 9

What is considered to be a normal CTG repeat length in the DMPK gene?

Answer 9

The CTG repeat length is between 5 and 37 repeats in normal alleles.

Question 10

What DMPK CTG repeat length is seen in individuals who are symptomatic for myotonic dystrophy?

Answer 10

Symptomatic individuals have >50 repeats.

Question 11

What DMPK CTG repeat length is seen in infants with congenital myotonic dystrophy?

Answer 11

Infants with congenital DM have CTG repeat lengths >1000.

Question 12

What may cataracts look like in DM patients?

Answer 12

May have a christmas tree like appearance and have a younger age of onset than standard cataracts.

Question 13

Why might the grip release test be used?

Answer 13

DM patients often have trouble letting go of objects - e.g. may be slow to release from a handshake. Reported to be worse in cold weather.

Question 14

What investigations are conducted in myotonic dystrophy patients once the clinical diagnosis of DM has been confirmed?

Answer 14

Once the diagnosis is confirmed on genetic testing (muscle biopsy and nerve conduction rarely used) you would go on to carry out an ECG to look for heart block, a fasting blood glucose test to look for diabetes, and ophthalmology tests if cataracts are suspected.

If the genetic testing is normal then you should consider proximal myotonic dystrophy of DM2. The weakness in DM2 is mostly proximal and they have quite mild myotonia and they particularly have muscle pain which you don’t usually see in standard MD. DM2 is rare. It is due to a CCTG expansion in ZNF9.

Question 15

What should be considered as a possible diagnosis if genetic testing for myotonic dystrophy is normal?

Answer 15

If the genetic testing is normal then you should consider proximal myotonic dystrophy of DM2. The weakness in DM2 is mostly proximal and they have quite mild myotonia and they particularly have muscle pain which you don’t usually see in standard MD. DM2 is rare. It is due to a CCTG expansion in ZNF9.

Question 16

What is the molecular cause of DM2?

Answer 16

DM2 is due to a CCTG expansion in ZNF9.

Question 17

How should myotonic dystrophy be managed?

Answer 17

Patients need to be advised that they need to be careful with anaesthetics - they can have general anaesthetics but they need to avoid certain types of muscle relaxants.

Need to have an ECG every year at GP to check for conduction problems.

Ideally should have a yearly fasting glucose at GP to check for diabetes.

Yearly eye test to look for cataracts.

Advice relating to reproduction (RR, anticipation, PND and PGD options) and reduced fertility.

Sleep study to exclude sleep apnoea as a cause of daytime sleepiness.

Question 18

Describe congenital myotonic dystrophy.

Answer 18

Congenital DM is characterised at birth by hypotonia, severe generalised weakness at birth, often with respiratory compromise and early death.

Survivors often have significant developmental delay and go on to develop a progressive myopathy.

May present antenatally with polyhydramnios. reduced foetal movements and talipes.

Congenital DM is only seen when the condition is transmitted by the mother. There are only a few reports of it being inherited from the father in the literature. Very strong sex bias. It is thought that there is a selection against sperm with large repeat sizes.

Risk with minimal neuromuscular disease in mother = 3-5%.

The risk is higher if the mother has established neuromuscular disease (40%) or has a child who is affected (40%).

Prenatal diagnostic testing is available, as is PGD. Often the diagnosis of myotonic dystrophy is made in the family after the birth of a child with congenital myotonic dystrophy.

Question 19

How is congenital myotonic dystrophy characterised at birth?

Answer 19

Congenital DM is characterised at birth by hypotonia, severe generalised weakness at birth, often with respiratory compromise and early death.

Question 20

How may congenital myotonic dystrophy present antenatally?

Answer 20

May present antenatally with polyhydramnios. reduced foetal movements and talipes.

Question 21

How is congenital myotonic dystrophy usually transmitted?

Answer 21

Congenital DM is only seen when the condition is transmitted by the mother. There are only a few reports of it being inherited from the father in the literature. Very strong sex bias. It is thought that there is a selection against sperm with large repeat sizes.

Question 22

What is the risk of having a child with congenital myotonic dystrophy if the mother has minimal neuromuscular disease?

Answer 22

Risk with minimal neuromuscular disease in mother = 3-5%.

Question 23

What is the risk of having a child with congenital myotonic dystrophy if the mother has established neuromuscular disease?

Answer 23

The risk is higher if the mother has established neuromuscular disease (40%) or has a child who is affected (40%).

Question 24

What is the risk of having a child with congenital myotonic dystrophy if the mother has previously had an affected child?

Answer 24

The risk is higher if the mother has established neuromuscular disease (40%) or has a child who is affected (40%).

Question 25

What are the psycho-social implications to consider when considering a pre-symptomatic test for myotonic dystrophy?

Answer 25

There are similar psycho-social considerations to a PST for HD but there are interventions in myotonic dystrophy to prevent complications and the condition does not lead to dementia or the psychiatric problems seen in HD. Family experience is not seen as being as sever as for HD.

Most centres would follow a truncated PST protocol with 2 appointments prior to testing.