Myopathy, Tubular Aggregate, 1

A number sign (#) is used with this entry because autosomal dominant tubular aggregate myopathy-1 (TAM1) is caused by heterozygous mutation in the STIM1 gene (605921) on chromosome 11p15.

Heterozygous mutation in the STIM1 gene can also cause Stormorken syndrome (STRMK; 185070), a similar disorder with additional features.

Description

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).

Genetic Heterogeneity of Tubular Aggregate Myopathy

See also TAM2 (615883), caused by mutation in the ORAI1 gene (610277) on chromosome 12q24.

Clinical Features

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.

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.

Hedberg et al. (2014) reported 3 unrelated Caucasian females with TAM1. All had normal early motor development, but showed difficulties walking, running, and climbing stairs due to proximal muscle weakness between 3 and 4 years of age. All had a positive Gowers sign; upper limb girdle muscles were also weakened. Two patients had no dysarthria or ophthalmoplegia at ages 7 and 15 years, but 1 developed mild manifestations of these symptoms at age 31 years. Muscle biopsies showed type 1 fiber predominance, hypotrophic fibers, and an increased number of centralized nuclei. The biopsies showed tubular aggregates with uneven staining for myophosphorylase (PYGM; 608455) in 2 patients.

Bohm et al. (2014) reported 7 patients from 6 families with TAM1 confirmed by genetic analysis. All patients were adults at the time of the report except 1, who was 13 years old. Five patients had onset of symptoms in childhood, whereas 2 had onset as adults. The phenotype was somewhat variable: some patients presented with myalgia or postexercise fatigability and increased serum creatine kinase and later developed muscle weakness mostly affecting the proximal lower limbs, whereas others presented with limb-girdle muscle weakness and later developed myalgia. Three patients had walking difficulties associated with heel contractures. Two patients had only myalgia or postexercise fatigability without muscle weakness or walking difficulties. One patient had eye movement deficits. Muscle biopsy of all patients showed tubular aggregates consisting of single- or double-walled membranes and originating from the endoplasmic reticulum. The aggregates were observed in both fiber types and were often accompanied by internal nuclei and fiber size variability. There was no correlation between tubular aggregate types and mutation, age of onset, or disease severity.

Inheritance

The transmission pattern of tubular aggregate myopathy in the families reported by Bohm et al. (2013) was consistent with autosomal dominant inheritance.

Molecular Genetics

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.

In 3 unrelated Caucasian females with TAM1, Hedberg et al. (2014) identified a de novo heterozygous mutation in the STIM1 gene. Two patients had the same mutation (H109R; 605921.0006) previously identified by Bohm et al. (2013), whereas the third had a novel mutation (I115F; 605921.0009).

In 7 patients from 6 families with TAM1, Bohm et al. (2014) identified 5 different heterozygous missense mutations in the STIM1 gene (see, e.g., 605921.0005 and 605921.0010). In vitro functional expression studies in myoblasts showed that the mutations resulted in constitutive clustering of STIM1 independent of intraluminal calcium levels. The 6 families were ascertained from a larger cohort of 38 unrelated families with features suggestive of tubular aggregate myopathy who underwent direct sequencing of the STIM1 gene.