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.

What are the other features of this condition?

• Cardiomyopathy and cardiac conduction defects (Fig. 57.2). A severe abnormality on the ECG and a diagnosis of an atrial tachyarrhythmia predict sudden death (N Engl J Med 2008;358:2688–97). An implantable cardioverter defibrillator should be considered in all patients

• Respiratory infection (low serum immunoglobulin G levels)

• Somnolence

• External ophthalmoplegia (occasionally).