Dystrophia myotonica

57 Dystrophia myotonica



Instruction


Look at this patient’s face.


Examine this patient’s cranial nerves.



Salient features



History




• Onset usually in the third and fourth decade. However, if the mother is the carrier then the disease may manifest in infancy and undergo rapid deterioration at the usual age of onset


• Onset dominated by weakness or myotonia or both


• Difficulty in releasing grip


• Leg weakness (difficulty in kicking a ball)


• ‘Pseudo-drop attacks’ (caused by weakness of quadriceps muscle)


• Ask the patient if they have dysphagia (oesophageal involvement)


• Impotence (caused by gonadal atrophy)


• Recurrent respiratory infections (caused by weakness of muscles of bronchioles)


• Excessive urge to sleep (daytime somnolence is common).



Examination




• While shaking hands with the patient, note the myotonia


• Frontal baldness (the patient may be wearing a wig and it is important to mention if this is so)


• Ptosis (bilateral or unilateral) with a smooth forehead


• Cataracts (posterior capsular cataracts) or evidence of surgery for cataracts


• Difficulty in opening the eyes after firm closure


• Expressionless face (‘hatchet face’; Fig. 57.1) with wasting of temporalis, masseters and sternomastoids and ‘swan neck’ caused by thinning of the neck.


image

Fig. 57.1 Muscle wasting in myotonic dystrophy gives the characteristic drawn appearance of ‘hatchet facies.’


(With permission from Yanoff, Duker 2008.)


Proceed as follows:



• Test:


• Sternomastoids

• Distal muscles of the upper limbs, wasting, percussion myotonia over thenar muscles and weakness

• Deep tendon jerks (depressed).

• Tell the examiner that you would like to do the following:


• Check the urine for sugar (diabetes mellitus)

• Test higher intellectual function (low IQ)

• Examine for gynaecomastia and testicular atrophy.

Remember: Respiratory failure is the commonest cause of death.



Diagnosis


This patient has frontal balding, myotonia, cataracts and wasting of the sternomastoids (lesion) caused by dystrophia myotonica (aetiology). He has dysphagia and severe muscular weakness (functional status).



Advanced-level questions




What is the inheritance of this condition?


Autosomal dominant inheritance. Myotonic dystrophy type 1 (the more common and typically the more severe of the two major types) is caused by an expanded cytosine–thymine–guanine (CTG) repeat on chromosome 19q13.3 in the 3′-untranslated region of DMPK, a gene for a dystrophia myotonica protein kinase (a serine–threonine protein kinase). The condition usually presents in the third and fourth decades. The disease tends to be worse in successive generations (known as anticipation). As a result, the grandparent may merely have cataracts while the grandchild develops a severe progressive form of the disease. Positional cloning has helped to identify the gene for myotonic dystrophy and localized a dynamic mutation with an increase in the number of trinucleotide repeats. The repeat size typically increases from generation to generation, providing a molecular basis for the clinical phenomenon of anticipation.


The less common form of the disease, myotonic dystrophy 2, is caused by an expanded CCTG repeat (with expansions ranging from 80 to 11 000 repeats) in the first intron of ZNF9, the gene for zinc finger protein 9.


Transcribed RNA repeats fold into a hairpin, and the RNA is retained in the nucleus, where it alters the ratio of CUG RNA-binding proteins, such as CUG-binding protein 1 (CUG-BP1) and muscleblind-like 1 (MBNL1). Splicing misregulation in myotonic dystrophy results from altered functions of these two RNA-binding proteins, which were identified because they bind CUG repeats in RNA. CUG-BP1 and MBNL1 are direct and antagonistic regulators of alternative splicing events that are normally regulated during development and misregulated in myotonic dystrophy. Increased activity of CUG-BP1 and decreased activity of MBNL1 induce ‘embryonic pattern’ splicing (i.e. isoforms typically expressed in the developing embryo and fetus predominate). The fact that MBNL1 colocalizes with nuclear RNA foci in the cells of patients with myotonic dystrophy suggests that MBNL1 is sequestered by mutant RNAs. Increasing the expression of MBNL1 in a mouse model of myotonic dystrophy restores the adult splicing pattern of the muscle-specific chloride channel (ClC-1) protein and reverses the myotonia associated with ClC-1 misregulated splicing (Proc Natl Acad Sci USA 2006;103:11748–53). These data support for a primary role of MBNL1 depletion in the pathogenesis of the disease.

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Dec 4, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Dystrophia myotonica

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