Tubular aggregates in muscle, first described by Engel (1964), are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. They are a nonspecific pathologic finding that may occur ... Tubular aggregates in muscle, first described by Engel (1964), are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. They are a nonspecific pathologic finding that may occur in a variety of circumstances, including alcohol- and drug-induced myopathies, exercise-induced cramps or muscle weakness, and inherited myopathies. Tubular aggregates are derived from the sarcoplasmic reticulum (Salviati et al., 1985) and are believed to represent an adaptive mechanism aimed at regulating an increased intracellular level of calcium in order to prevent the muscle fibers from hypercontraction and necrosis (Martin et al., 1997; Muller et al., 2001).
Rohkamm et al. (1983) described a family in which 7 persons in 3 generations had slowly progressive weakness without atrophy, myalgia, cramps, or episodic weakness. Creatine kinase was normal, and EMG showed only slight myopathic changes. Neuromuscular transmission ... Rohkamm et al. (1983) described a family in which 7 persons in 3 generations had slowly progressive weakness without atrophy, myalgia, cramps, or episodic weakness. Creatine kinase was normal, and EMG showed only slight myopathic changes. Neuromuscular transmission was undisturbed. Muscle biopsy showed that 60 to 90% of all fibers contained tubular aggregates. There was marked variation in fiber size and marked atrophy of type II fibers. Male-to-male transmission was observed, and the authors postulated autosomal dominant inheritance. Pierobon-Bormioli et al. (1985) reported a family in which 5 persons in 3 generations showed tubular aggregates on muscle biopsy associated with mild weakness and muscle aching. Type 1 fiber predominance and type 2 hypotrophy were noted. Electron-microscopic studies confirmed that tubular aggregates originated from the sarcoplasmic reticulum of muscle. Cameron et al. (1992) observed tubular aggregate myopathy in a father and daughter who presented with slowly progressive proximal weakness, limitation of eye movement, Achilles tendon contractures, and increased serum creatine kinase. Martin et al. (1997) reported a 19-year-old man with exercise-induced myalgia, easy fatigability, and increased serum creatine kinase. Muscle biopsy showed very large amounts of subsarcolemmal and intermyofibrillar tubular aggregates. The aggregates consisted of closely packed vesicles and tubules filled with electron-dense material or with smaller tubules. Although neither his father nor paternal grandfather had clinical symptoms, both showed increased serum creatine kinase and similar muscle biopsy findings, consistent with autosomal dominant inheritance. Muller et al. (2001) reported a father and 2 sons with myopathy with tubular aggregates. All had onset in middle age of slowly progressive muscle weakness associated with fatigue, muscle cramps, and myalgia. Muscle biopsy of the 2 sons showed type 2 fiber atrophy and tubular aggregates. Shahrizaila et al. (2004) reported a family in which a mother and her 3 children had myopathy with tubular aggregates associated with pupillary abnormalities. Inheritance was autosomal dominant. The mother and 2 sons had late adult-onset mild proximal muscle weakness with increased serum creatine kinase and areflexia of the lower limbs; the daughter denied muscle weakness but was found to have increased serum creatine kinase and areflexia of the lower limbs. Quadriceps muscle biopsies of the 2 affected sons showed endomysial fibrosis, fatty infiltration, abnormal fiber size variation with atrophic muscle fibers, and tubular aggregates mainly in type 1 fibers. Electron microscopy of 1 son showed that the aggregates contained granular electron-dense material consistent with dilated elements of the sarcoplasmic reticulum. Pupillary abnormalities included decreased night vision and pupillary miosis. Bohm et al. (2013) reported 4 unrelated families with autosomal dominant tubular aggregate myopathy associated with heterozygous mutations in the STIM1 gene (605921.0004-605921.0007). In 3 families, the onset of disease was variable, occurring during childhood, adolescence, or even early adulthood in 1 patient. All presented with mild and slowly progressive lower limb muscle weakness causing frequent falls and difficulty running. More variable features included ophthalmoparesis without ptosis and contractures of the elbows, wrist and fingers, heel cords, and neck. Four patients had mild respiratory insufficiency, but none had cardiac involvement. Three affected individuals from 1 family were asymptomatic, but had a slight myopathic pattern on EMG and increased serum creatine kinase. Muscle biopsies from all patients showed type II fiber atrophy and tubular aggregates of a reticular origin. Ultrastructural analysis showed massive tubular aggregation with single- or double-walled membranes of different diameters. The aggregates appeared to originate from the sarcoplasmic reticulum.
In affected members from 4 unrelated families with autosomal dominant tubular aggregate myopathy, Bohm et al. (2013) identified 4 different heterozygous mutations in the intraluminal EF hand domains of the STIM1 gene (605921.0004-605921.0007). The initial mutations were identified ... In affected members from 4 unrelated families with autosomal dominant tubular aggregate myopathy, Bohm et al. (2013) identified 4 different heterozygous mutations in the intraluminal EF hand domains of the STIM1 gene (605921.0004-605921.0007). The initial mutations were identified by whole-exome sequencing. In vitro studies showed that the mutations induced STIM1 clustering, indicating that calcium sensing was impaired and resulting in a gain-of-function effect. TAM myoblasts showed a higher level of basal calcium and dysregulation of intracellular calcium homeostasis compared to controls. Because recessive STIM1 loss-of-function mutations are associated with immunodeficiency (612783), Bohm et al. (2013) concluded that the tissue-specific impact of STIM1 loss or constitutive activation is different, and that a tight regulation of STIM1-dependent calcium entry is fundamental for normal skeletal muscle structure and function. None of the patients with TAM had evidence of immune dysfunction.