Markesbery and colleagues reported a late-onset distal myopathy in which weakness began in the distal leg muscles (tibialis anterior) and later spread to the hands; there was also cardiomyopathy and heart failure. A mutation in the ZASP gene has been found. Very similar distal myopathies have been described in Finnish patients by Udd and colleagues and caused by dominant mutations in the “titin” gene. A form beginning in childhood has been described and attributed to a mutation in the gene (MYHC7) that codes for myosin heavy chain 1 protein. The characteristic feature in all these cases is progressive bilateral foot-drop.
A type of distal dystrophy characterized by autosomal recessive pattern of inheritance is particularly prevalent in Japan (Miyoshi et al), but numerous cases exist in all parts of the world. The Miyoshi myopathy is the one we have encountered most often among the distal muscular dystrophies. Onset of the disease is in early adult life, with weakness and atrophy of the leg muscles most prominent in the peroneal or the gastrocnemius and soleus muscles. Over many years the weakness extends to the thighs, gluteal muscles, and arm muscles, including the proximal ones. Serum CK concentrations are greatly increased in the early stages of the disease. In this type of dystrophy the mutation lin DYSF leads to an absence of the muscle protein dysferlin, a membrane protein that does not interact with any of the dystrophin-binding elements. Whereas dystrophin and its binding partners are believed to confer tensile strength, dysferlin and its associated proteins (e.g., the annexins) function in calcium-mediated membrane repair (Lennon et al). As mentioned earlier, limb-girdle dystrophy 2B has been linked to the same chromosomal locus and it also lacks the dysferlin protein. It is also striking that different family members with the same dysferlin mutation can have disease onset in either a proximal (LGMD) or distal (Miyoshi) pattern, suggesting that additional factors modify the pattern of weakness produced by dysferlin deficiency. We have encountered a family in which 2 individuals with dysferlin mutations had proximal weakness at onset while another sibling with the same disease had anterior tibial weakness.
An apparently separate form of distal myopathy with autosomal dominant inheritance and onset before 2 years of age has been described. Whether these infantile-onset cases represent a true muscular dystrophy has not been established. Several even rarer distal myopathies with linkage to specific genetic sites are summarized in the review by Illa, but most are not well-enough characterized to require elaboration here. A discussion can be found in the text from our colleagues Amato and Russell.
Congenital Muscular Dystrophy (Fukuyama, Walker-Warburg, Merosin Deficient, Rigid Spine, and Other Types) (Table 45-4)