At a molecular level, FSHD1 has been found to have a consistent association with deletions of variable size on DUX4, located at the tip of chromosome 4q. This disorder is a consequence of alterations of a noncoding portion of DNA. Deletions in a repeated segment interfere with the structure of chromatin and allow the expression of normally inactive genes such as DUX4. Only patients with an allele that contains a repeat segment FSHD2 (called D4Z4 repeats) are susceptible to the disease. An entirely different mutation in a gene that maintains the structural integrity of chromatin accounts for the less common FSHD2; this change results in hypomethylation of the D4Z4 segments (an epigenetic mechanism) and is therefore also dependent on the permissive repeat allele.
A variant in which only the shoulder and arm muscles are affected, sparing the face, and a form with bilateral foot-drop are known (Krasnianski et al). In some cases, usually with severe deletions at the FSH locus on chromosome 4, there is an early-onset, relatively rapid progression and an association with facial diplegia, sensorineural deafness, and, sometimes, exudative retinal detachment (Coats disease). Using fluorescein angiography, Fitzsimmons and others have found a variety of other retinal abnormalities: telangiectasia, occlusion, leakage, and microaneurysms; in the majority of cases, suggesting that these retinal abnormalities are an integral part of the disease. Less common manifestations of FSHD include isolated scapular winging or other focal weakness such as foot drop, sparing of facial muscles, a variant with limb-girdle weakness, and rare instances of progressive external ophthalmoplegia (PEO).
This is a hetergenous group of myopathies that share the denominative topographic distribution of weakness and atropy, usually beginning in childgood but with wide variability. Beginning with Brossard in 1886, there were numerous reports of a distinctive pattern of progressive muscular weakness and wasting that involved the muscles of the neck, shoulders, and upper arms, and of the anterior tibial and peroneal groups, causing severe foot-drop. The nature of this disorder has been a matter of controversy, some writers claiming it to be a progressive muscular dystrophy and others, a muscular atrophy of spinal or neuropathic type. Probably both are correct in that either process can produce more or less the same pattern of weakness. Davidenkow, who wrote extensively on this subject, described a form of familial scapuloperoneal weakness and atrophy associated with areflexia and distal sensory loss (a spinal-neuronopathic form) that was later found to have a mutation in the desmin gene, and others have confirmed these findings (see discussions of Munsat and Serratrice). Nevertheless, the existence of a purely myopathic form has been established. The mutation in the most common form of the disease has been found in TRPV4 but others have been connected to FHL-1 on the X-chromosome (see Table 45-1). A mutation in TRIM32 has also causes this phenotype. The onset of symptoms in their 6 patients was in early or middle adult life, with difficulty in walking because of bilateral foot-drop; symptoms referable to scapulohumeral involvement came later. Progression was slow, and none of the patients became severely incapacitated.
Limb-Girdle Muscular Dystrophies (LGMD, Scapulohumeral and Pelvifemoral Muscular Dystrophies, Erb Dystrophy) (See Table 45-1)