Case reportClinical and muscle MRI features in a family with tubular aggregate myopathy and novel STIM1 mutation
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.
Section snippets
Patients and methods
We performed clinical (N = 6), electromyographic (N = 2), muscle biopsy (N = 2) and whole-body muscle MRI (N = 3) examinations in the patients in routine workup for diagnostic purposes at the Departments of Neurology, Pathology and Radiology at the University Hospitals Leuven (Belgium). Patients underwent spirometry (N = 3), transthoracal echocardiography (N = 6) and 24-hours-electrocardiography (24h-ECG) (N = 6) (Table 1). We sampled blood to measure creatine kinase (CK) levels, thrombocyte
Clinical features
In this Belgian pedigree, we identified eight patients affected by muscle disease (Fig. 1), of which DNA samples were available in six of them. In the affected patients II-2 and II-3, the mutation was not tested, since these patients had died prior to the study (not included in Table 1). In four family members (I-1, I-2, IV-2, V-3) the clinical status was unclear: three of them had died prior to the study and one individual (V-3) did not consent to participate in the study (Fig. 1). The
Discussion
We reported the clinical, histopathological and muscle MRI characteristics in a large Belgian family with a novel heterozygous missense mutation c.325C > T (p.H109Y) in the EF-hand domain of STIM1. 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
Declarations of Competing Interest
Dietmar R. Thal, MD, PhD: Speaker honorary from Novartis Pharma AG (Switzerland) and Biogen (USA), travel reimbursement from GE-Healthcare (UK) and UCB (Belgium) and collaborated with Novartis Pharma AG (Switzerland), Probiodrug (Germany), GE-Healthcare (UK), and Janssen Pharmaceutical Companies (Belgium).
Kristl G. Claeys, MD, PhD: Advisory board honoraria and research grant from Alnylam, Biogen, CSL Behring, Sanofi-Genzyme; travel reimbursement from Sanofi-Genzyme. KGC holds the Emil von
Acknowledgments
We are grateful to the patients for their participation in this study. We want to thank the personnel of the Departments of Pathology, Radiology and Human Genetics for their technical support. Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN Euro-NMD) and of the European Reference Network for Rare Neurological Diseases (ERN-RND).
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