Distal Myopathies

Abstract

Over a century ago, Gowers described two young patients in whom distal muscles weakness involved the hand, foot, sternocleidomastoid, and facial muscles in the other case the shoulder and distal leg musculature. Soon after, , similar distal myopathy cases were reported whereby the absence of sensory symptoms and of pathologic changes in the peripheral nerves and spinal cord at postmortem examination allowed differentiation from Charcot-Marie-Tooth disease. In 1951, Welander described autosomal dominant (AD) distal arm myopathy in a large Scandanavian cohort. Since then the number of well-characterized distal myopathies has continued to grow such that the distal myopathies have formed a clinically and genetically heterogeneous group of disorders. Affected kindred commonly manifest weakness that is limited to foot and toe muscles even in advanced stages of the disease, with variable mild proximal leg, distal arm, neck and laryngeal muscle involvement in selected individuals. An interesting consequence of the molecular characterization of the distal myopathies has been the recognition that mutation in a single gene can lead to more than one clinical disorder. For example, Myoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) type 2B are allelic disorders due to defects in the gene that encodes dysferlin. The six well described distal myopathy syndromes are shown in Table 1. Table 2 lists advances in our understanding of the myofibrillar myopathy group and Table 3 includes more recently delineated and less common distal myopathies. In the same manner, the first section of this review pertains to the more traditional six distal myopathies followed by discussion of the myofibrillar myopathies. In the third section, we review other clinically and genetically distinctive distal myopathy syndromes usually based upon single or smaller family cohorts. The fourth section considers other neuromuscular disorders that are important to recognize as they display prominent distal limb weakness.

Clinical Reasoning: A 40-year-old woman presenting with distal leg weakness

“…Rimmed vacuoles can be seen in sIBM, but are nonspecific with a broad differential diagnosis including hIBM, myofibrillar myopathies, Udd myopathy, Welander myopathy, oculopharyngeal muscular dystrophy, and some limb-girdle muscular dystrophies. 4 Cytoplasmic protein aggregates typical of myofibrillar myopathies were not observed. The combination of rimmed vacuoles, p62/TDP-43 immunopositive inclusions, and the intramyonuclear inclusions seen on electron microscopy are all consistent with sIBM, but the minimal inflammation and lack of major histocompatibility complex upregulation in this case were less than expected for sIBM.…”

“…Distal myopathies are mainly inherited myopathies causing weakness and atrophy of the distal arms and legs. 4,5 Family history may be absent in cases with de novo sporadic mutations. 5 Some genes are co-allelic with those causing limbgirdle muscular dystrophies.…”

“…MRI can be useful in narrowing down the differential diagnosis based on muscles affected. 4,6 If a specific genetic cause is suspected, gene testing should be done before muscle biopsy. When choosing genes to test, careful consideration should be given to family history, ethnicity, age at onset, and clinical site of onset.…”

“…hIBM can be differentiated from sIBM as the latter (1) typically presents at an older age, (2) more commonly has dysphagia, (3) often involves the quadriceps, (4) is more frequently asymmetric, (5) is more likely to have increased CK, (6) and has more inflammatory/immune-related changes on biopsy. 4,5,7 There are several types of hIBM. 8 Nonaka myopathy (GNE mutation) often presents at a young age involving the distal anterior leg compartment.…”

“…The combination of distal arm weakness with proximal leg weakness raises the question of sporadic inclusion body myopathy (sIBM), but this is very uncommon in patients under age 50 and finger flexors are usually weak. 4 Unenhanced MRI of the cervical, thoracic, and lumbosacral spine were normal. Routine chemistry including creatine kinase (CK) was normal.…”