Under this name, Ricker and colleagues (1994) described a myopathy characterized by autosomal dominant inheritance (unlike the limb-girdle dystrophies, the numeral 2 denotes the second type of DM, not recessive inheritance), proximal muscle weakness, myotonia, and cataracts. Seventeen families containing 50 affected members were studied by these authors. Onset was between 20 and 40 years of age, with intermittent myotonic symptoms of the hands and proximal leg muscles, followed by a mild, slowly progressive weakness of the proximal limb muscles without significant atrophy. In contrast to DM1, cataracts developed in one-half of their patients and cardiac arrhythmias in only two. Onset in infancy, ptosis, weakness of facial, jaw, and distal limb muscles, and mental abnormalities were notably absent, further distinguishing PROMM from the conventional (DM1) form of myotonic dystrophy.
Histologically, there are many fibers with multiple (5 to 10 or more) internalized nuclei, without ringbinden or subsarcolemmal masses. In addition, there are atrophic fibers with nuclear clumps. Analysis of leukocyte and muscle DNA discloses no expansion of the CTG component of the myotonic dystrophy gene. Rather, the gene defect for this disease has been mapped to the CNBP gene on chromosome 3q where there is an expansion of a CCTG repeats. Like the expanded CTG repeat in myotonic dystrophy, the CCTG expansion in PROMM is associated with intranuclear accumulation of the expanded RNA transcript, and like the CTG repeats of myotonic dystrophy, the CCTG segments do not code for a protein.
Distal Muscular Dystrophies (Welander, Miyoshi, and Other Types) (See Table 45-3)
Included in this group are several slowly progressive distal myopathies with onset principally in adult life. Weakness and wasting of the muscles of the hands, forearms, and lower legs, especially the extensors, are the main clinical features. Although such cases had been reported by Gowers and others, their differentiation from myotonic dystrophy and peroneal muscular atrophy was unclear until relatively recently. Several types of distal dystrophies are inherited as autosomal dominant traits.
A different dominantly inherited distal dystrophy was described by Welander in a study of 249 patients from 72 Swedish pedigrees (not to be confused with the
Kugelberg-Welander juvenile spinal muscular atrophy affecting proximal muscles; see Chap. 38). Weakness developed first in the small hand muscles and then spread to the distal leg muscles, causing a steppage gait. Fasciculations, cramps, pain, sensory disturbances, and myotonia were notably absent. Some patients have a low-grade sensory neuropathy, suggesting that pathology in this disorder may not be exclusively in muscle. Cataracts appeared after the age of 70 years in 3 patients and can be discounted as having special significance. No endocrine disorders were detected. Dystrophic changes were demonstrated in 3 autopsies and 22 biopsy specimens. Some muscle biopsy material has shown rimmed vacuoles and inclusions that are similar to inclusion body myopathy. Progression of the disease was very slow; after 10 years or so, some wasting of proximal muscles was seen in a few of the patients. Welander dystrophy has been linked to mutations in T1A1 on chromosome 2p13, near the locus for the below described Miyoshi myopathy.