Clinical and muscle MRI features in a family with tubular aggregate myopathy and novel STIM1 mutation

Highlights

• We report on six affected family members with TAM and a novel mutation in STIM1.

• Our results support a continuous spectrum between TAM and Stormorken syndrome.

• Whole-body muscle MRI reveals an apparent pattern of muscle involvement.

Abstract

Heterozygous mutations in the stromal interaction molecule-1-gene (STIM1) cause a clinical phenotype varying from tubular aggregate myopathy with single or multiple signs of Stormorken syndrome to the full Stormorken phenotype. We identified a novel heterozygous mutation c.325C > T (p.H109Y) in the EF-hand domain of STIM1 in six patients of a large Belgian family, and performed a detailed clinical (N = 6), histopathological (N = 2) and whole-body muscle MRI (N = 3) study. The clinical phenotype was characterized by a slowly progressive, predominant proximal muscle weakness in all patients (100%), and additional exercise-induced myalgia in three (60%). Patients experienced symptom onset between 10 and 20 years, remained ambulatory into late adulthood, showed elevated serum creatine kinase levels and tubular aggregates in type 1 and type 2 fibers on muscle biopsy. Interestingly, jaw contractures and hyperlaxity, as well as non-muscular multisystemic features such as menorrhagia, easy bruising and ichthyosis occurred in one patient, and miosis in another. Whole-body muscle MRI revealed predominant involvement of superficial neck extensors, subscapularis, obliquus abdominis externus, lumbar extensors, rectus femoris, biceps femoris longus, medial head of gastrocnemius and flexor hallucis longus. Our findings in patients with myopathy with tubular aggregates and a STIM1 mutation further support the concept of a continuous spectrum with Stormorken syndrome.

Introduction

Tubular aggregate myopathy (TAM) is a rare, hereditary, progressive muscle disorder involving weakness, myalgia and cramps, and showing tubular aggregates as the main histopathological hallmark on muscle biopsy [1], [2], [3], [4], [5], [6], [7]. Clinically, tubular aggregate myopathy overlaps with Stormorken syndrome, which is a rare multisystemic disorder associating TAM with bleeding diathesis, hyposplenia/asplenia, mild anemia, ichthyosis, short stature, low body weight, hypocalcemia, dyslexia and miosis, the latter being a consistent feature of Stormorken syndrome [7], [8], [9], [10], [11], [12], [13], [14]. TAM patients often present with single or multiple signs of Stormorken syndrome with variable degree, whereas Stormorken syndrome refers to the full penetrance of the phenotype. Thus, both disorders are considered to be part of a continuous clinical spectrum.

Both TAM and Stormorken syndrome are characterized by the presence of tubular aggregates, consisting of regular arrays of densely packed membrane tubules in skeletal muscle that originate from the sarcoplasmic reticulum (SR) [1,4,6,7,12]. However, tubular aggregates can also be found in a number of different muscle and neuromuscular junction disorders caused by several different genes and presenting with distinct clinical features [15,16]. Furthermore, tubular aggregates can appear as secondary features in for example ethyltoxic and inflammatory myopathies, in diabetes and other endocrine disorders, and even in normal aging [1,5].

TAM and Stormorken syndrome are caused by heterozygous mutations in the stromal interaction molecule 1 (STIM1) gene [4] or ORAI calcium release-activated calcium modulator 1 (ORAI1) gene [9]. In skeletal muscle, intracellular Ca²⁺ is stored in the SR and is released in the cytoplasm upon stimulation, where it triggers muscle contraction. STIM1 is the main luminal Ca²⁺ concentration sensor on the endoplasmic/sarcoplasmic reticulum. STIM1 is composed of a luminal N-terminal part comprising Ca²⁺sensing EF-hand domains, a single transmembrane domain, and a cytosolic C-terminus with coiled-coil domains encompassing the STIM1-ORAI1 activating domain, and is able to activate the plasma membrane Ca²⁺ channel ORAI1 to refill the Ca²⁺ stores [17], [18], [19], [20]. To date, only 15 different heterozygous mutations in STIM1 have been reported in TAM/Stormorken syndrome, including 12 mutations in the luminal EF-hands [4,6,[11], [12], [13],21,22].

Here, we report a large Belgian family with TAM caused by a novel heterozygous c.325C > T (p.H109Y) missense mutation in the STIM1-gene and studied the clinical (N = 6), histopathological (N = 2) and whole-body muscle magnetic resonance imaging (MRI) (N = 3) features in greater detail.