LGMD1E is an autosomal dominant disorder characterized by adult onset of proximal muscle weakness, beginning in the hip girdle region and later progressing to the shoulder girdle region (Speer et al., 1999).
For a phenotypic description ... LGMD1E is an autosomal dominant disorder characterized by adult onset of proximal muscle weakness, beginning in the hip girdle region and later progressing to the shoulder girdle region (Speer et al., 1999). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMD1A (159000).
Schneiderman et al. (1969) reported a large 4-generation family with slowly progressive autosomal dominant limb-girdle muscular dystrophy. Symptom onset generally occurred during the third decade, with muscular weakness affecting both the upper and lower limbs, although most affected ... Schneiderman et al. (1969) reported a large 4-generation family with slowly progressive autosomal dominant limb-girdle muscular dystrophy. Symptom onset generally occurred during the third decade, with muscular weakness affecting both the upper and lower limbs, although most affected individuals recalled being slow and clumsy as children. Most retained ambulation, but 2 were bedridden in their seventies and eighties. None had facial involvement. Skeletal muscle biopsy showed dystrophic changes, including variation in fiber size, rounded fibers, vacuoles, and small basophilic fibers with vesicular nuclei. Electron microscopy showed focal degeneration and destruction of myofibrils, lamellar bodies, and dense granular lysosome-like structures. The Pelger-Huet anomaly (PHA; 169400) also segregated within this family, and linkage with muscular dystrophy was suggested. The recombination fraction was about 0.25, but the lod score was only 0.35. (The Pelger-Huet anomaly was later found to be caused by mutation in the lamin B receptor gene (LBR; 600024) on chromosome 1q42.) Using the diagnostic classification for LGMD outlined by Speer et al. (1992), Speer et al. (1995) described 2 families with autosomal dominant LGMD1. One of the families had previously been reported by Schneiderman et al. (1969) (family 1701). Individuals were considered affected when they had progressive proximal leg weakness with or without proximal arm weakness, absent ankle deep-tendon reflexes, and elevated creatine kinase values. The diagnostic evaluation of at least 1 affected member per family documented a myopathic process. Three of 15 members of family 1701 had moderately severe dysphagia. Clinically, they differed somewhat from other LGMD1 families linked to other chromosomes in their lack of other associated findings, i.e., dysarthria in LGMD1A, cardiac defects in LGMD1B (159001), and childhood onset in LGMD1C (607801). Linkage analysis excluded these families from the locus on chromosome 5q (LGMD1A). Sandell et al. (2010) reported a large 4-generation Finnish family with autosomal dominant LGMD. The age at onset ranged from 20 to 60 years, and all except 1 presented with difficulty climbing stairs; 1 patient presented with a slow running speed. All patients showed more severe involvement of the pelvic girdle than the shoulder girdle, resulting in a waddling gait, and 3 of 8 had no shoulder girdle signs at ages 69, 45, and 43 years. All were ambulatory except an 80-year-old patient. Some patients had mild calf hypertrophy. None had contractures, dysphagia, dysarthria, respiratory problems, or cardiac involvement. Most patients had increased serum creatine kinase and myopathic EMG. Muscle biopsies showed myopathic changes, such as fiber size variation, atrophic fibers, mild to moderate fibrosis, adipose tissue, rimmed vacuoles, and internal nuclei. Some biopsies showed cytoplasmic protein inclusions, and electron microscopy showed myofibrillar disintegration with filamentous inclusions and Z disc streaming. Hackman et al. (2011) reported 4 additional Finnish families with adult-onset slowly progressive autosomal dominant LGMD. The phenotype was homogeneous, with onset of muscle weakness in the pelvic girdle between the fourth and sixth decade, later involvement of the shoulder girdle, and marked walking difficulties by the eighth decade. Muscle biopsies showed myopathic and/or dystrophic features as well as myofibrillar disintegration and tubulofilamentous inclusions close to autophagic vacuoles. Some patients had mild calf hypertrophy, and none had cardiac or respiratory involvement. One patient had dysarthria and 2 had dysphagia. Harms et al. (2012) reported 2 unrelated families with LGMD1E. The first was a Caucasian family in which 5 individuals had onset of limb-girdle weakness beginning in the fourth decade. The disorder was manifest as difficulty in climbing stairs or getting up from the floor. In 2 patients, the quadriceps muscles were less affected than the hamstrings. None had cardiac, pulmonary, or bulbar involvement. The disorder was slowly progressive, but a wheelchair was required after about 20 years. Skeletal muscle biopsy from 3 patients showed a chronic myopathy with rimmed vacuoles, variation in fiber size, and internal nuclei. Immunostaining showed TDP43 (605078)- and DNAJB6-positive accumulations in multiple fibers; some inclusions were around and within the vacuoles. Serum creatine kinase was increased, and EMG showed clear myopathic changes. Three affected individuals from an African American family had a distal-predominant myopathy with onset between 18 and 35 years. Weakness began in the lower limbs, often manifest as tripping, but progressed to include the hands and proximal legs with loss of ambulation after about 20 to 40 years. There was no cardiac or pulmonary involvement.
In affected members of a Caucasian family with autosomal dominant limb-girdle muscular dystrophy, type 1E, Harms et al. (2012) identified a heterozygous mutation in the DNAJB6 gene (F93L; 611332.0001). The mutation was identified by whole-genome exome capture followed ... In affected members of a Caucasian family with autosomal dominant limb-girdle muscular dystrophy, type 1E, Harms et al. (2012) identified a heterozygous mutation in the DNAJB6 gene (F93L; 611332.0001). The mutation was identified by whole-genome exome capture followed by next-generation sequencing. Sequencing of the DNAJB6 gene in 13 additional probands with a similar disorder revealed a second mutation (P96R; 611332.0002) in affected members of an African American family with an autosomal dominant myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular cochaperones that protects client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. Sarparanta et al. (2012) identified 4 different heterozygous mutations in the DNAJB6 gene (611332.0001, 611332.0003-611332.0005) in affected members of 9 families with LGMD1E. Five of the families were of Finnish origin (Sandell et al., 2010 and Hackman et al., 2011) and carried the same mutation (611332.0003). Two additional families had previously been reported by Speer et al. (1995, 1999). Electron microscopy of patient muscle showed Z-disc myofibrillar disintegration and autophagic rimmed vacuoles. DNAJB6 was detected in protein accumulations together with its known ligands MLF1 (601402) and HSPA8 (600816). However, DNAJB6 appeared more in the periphery of the protein accumulations, in contrast to more pronounced colocalization seen in myotilinopathies. Three of the mutations resulted in a phe93-to-leu (F93L) substitution in a highly conserved residue. In vitro functional expression studies showed that the mutations increased the half-life of DNAJB6, extended this effect to the wildtype protein, and reduced the protective antiaggregation effect of DNAJB6. The mutations showed a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. The compromised antiaggregation function may lead to impaired protein quality control and accumulation of other proteins. DNAJB6 was found to interact with members of the chaperone-assisted selective autophagy (CASA) complex, including a myofibrillar myopathy (MFM6; 612954)-related protein BAG3 (603883). The findings indicated that LGMD1E is mediated by defective chaperone function, resulting in insufficient maintenance of sarcomeric structures or defective clearance of misfolded sarcomeric proteins.