Proximal Myotonic Myopathy and the Type 2 Myotonic Dystrophy Mutation: Implications for Our Understanding of Myotonic Dystrophy

INTRODUCTION

Proximal myotonic myopathy (PROMM) received brief mention in the eighth edition of MMBID (page 5530) and in other reviews of myotonic dystrophy (Harper,⁸) as a recently recognized (1994) progressive myotonic disorder resembling myotonic dystrophy but with distinct clinical features. An extensive and unusual family reported with myotonic dystrophy but showing no chromosome 19 expansion (Ranum et al,¹⁹) was also noted, and the possible relationship to PROMM was raised.

The past 2 years have seen remarkable developments in this area that have not only clarified the relationships of PROMM and classic myotonic dystrophy, but have also made a major contribution to our understanding of the pathogenesis of this group of disorders, with novel and potentially wide biological and medical implications.

PROMM AND TYPE 2 MYOTONIC DYSTROPHY: CLINICAL ASPECTS

The original recognition of PROMM as a clinical entity came from two different but overlapping approaches. Careful clinical and electrophysiologic studies by Ricker and colleagues (Ricker et al,²²; Ricker et al,²¹; Ricker et al,²⁰) showed that there was a progressive myotonic disorder, recognizably distinct from myotonic dystrophy, dominantly inherited but not showing the chromosome 19 CTG expansion. Table 1 shows the principal clinical similarities and differences as documented in these and other reports and in the two European PROMM consortium workshops (Moxley et al,¹⁷; Moxley et al,¹⁶).

Parallel with these studies was the recognition that a small proportion (∼1%) of patients diagnosed with myotonic dystrophy and included in molecular studies of the gene failed to show the expected CTG expansion (Harley et al,⁷; Meola, Sansone,¹⁵; Thornton et al,²⁷). Reassessment clinically showed that a number of these were atypical, with features resembling PROMM, suggesting that the two conditions might be the same (Abbruzzese et al,¹; Gomez et al,⁶; Meola, Sansone,¹⁵).

This has now been confirmed conclusively. The first step was the recognition of a large Minnesota kindred diagnosed as having myotonic dystrophy but lacking the CTG expansion; this was sufficiently extensive to allow mapping to chromosome ...