Difficulty in swallowing and change in voice are associated with slowly progressive ptosis. Swallowing becomes so difficult that food intake is limited, resulting in cachexia, which can be ameliorated by cutting the cricopharyngeus muscles, or, if that fails, by a gastrostomy or nasogastric tube. Later in the disease, in some families the external ocular muscles and shoulder and pelvic muscles become weakened and atrophic to a varying extent. In the few autopsied cases, a loss of fibers of modest proportions was widespread in these and many other muscles. Rimmed vacuoles in the sarcoplasm and, by electron microscopy, intranuclear tubular filaments are characteristic but not specific histologic findings (these features are seen in other myopathies, particularly in inclusion body myositis). The brainstem nuclei and cranial nerves are normal. As in the other mild and restricted muscular dystrophies, the serum CK and aldolase levels are normal and the EMG is altered only in the affected muscles.
The gene product of the mutatued gene, PABN1, is a protein that binds to RNA (poly-A binding protein). The defect is an expansion of a string of alanines. Normally, there are 6 repeats; in dominantly inherited oculopharyngeal dystrophy, there are 8 to 13 repeats; in the recessively inherited form there are 7 repeats on each allele. Thus this represents one of the most subtle nucleotide expansion diseases yet discovered.
There are 2 types of myotonic dystrophies (DM1 and DM2/PROMM). Type 1 (DM1) is the most common adult muscular dystrophy. It was described in 1909 by Steinert, who considered it to be a variant of congenital myotonia (Thomsen disease; see Chap. 46) and in the same year by Batten and Gibb, who recognized it as a unique clinical entity.
DM1 is distinguished by an autosomal dominant pattern of inheritance with a high level of penetrance, special topography of the muscle atrophy, associated obvious myotonia, and occurrence of dystrophic changes in nonmuscular tissues (lens of eye, testicle and other endocrine glands, skin, esophagus, heart, and, in some cases, the cerebrum). Certain muscles, the levator palpebrae, facial, masseter, sternocleidomastoid, and forearm, hand, and pretibial muscles, are consistently involved in the dystrophic process. It is possible that Gowers’ famous case of an 18-year-old youth with weakened and wasted anterior tibial and forearm muscles and sternocleidomastoids, in conjunction with paresis of the orbicularis and frontalis muscles, was an example of this disease.
Despite some clinical variability of myotonic dystrophy, the defective gene in the first type has been the same in every population that has been studied. At this locus on chromosome 19q there is a specific molecular defect, an unstable trinucleotide sequence (CTG) in the DMPK gene that is longer in affected individuals than it is in healthy siblings or unaffected subjects. Whereas healthy individuals will have 5 to 30 CTG repeats, patients with myotonic dystrophy have 50 to 2,000. Longer sequences are associated with more severe disease, and they increase in size through successive generations lead to earlier occurrence (genetic anticipation), particularly in DM1. The CTG repeats reside within the myotonin protein kinase gene. It is of considerable interest that these CTG repeating segments do not code for a protein (i.e., they are intronic), quite unlike conditions such as Huntington disease in which the triplet expansion codes for amino acid sequences within a protein.
The milder type 2 myotonic dystrophy (DM2) is caused by an expanded triplet repeat in the CNBP gene on chromosome 3, as discussed further on under “Proximal