Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

Abstract

ObjectiveThe aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies.Patients and methodsClinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy.ResultsGenetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness.ConclusionThe findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.

The unfolding spectrum of inherited distal myopathies

“…The coexistence of a TIA1 variant (p.Asn357Ser) and a pathogenic sequestosome‐1 (SQSTM1) variant has been recently recognized as a cause of distal myopathy. Patients with the combined TIA1‐SQSTM1 variants manifest in the 5th decade of life or later with weakness of the finger extensors, often preceding that of the ankle dorsiflexor muscles . Hypercapnic respiratory insufficiency, secondary to respiratory muscle weakness, preceded the onset of the distal weakness in one patient .…”

“…Patients with the combined TIA1‐SQSTM1 variants manifest in the 5th decade of life or later with weakness of the finger extensors, often preceding that of the ankle dorsiflexor muscles . Hypercapnic respiratory insufficiency, secondary to respiratory muscle weakness, preceded the onset of the distal weakness in one patient . The weakness can extend to the proximal muscles, clinically or subclinically, and the involvement can be detected by MRI studies.…”

“…There is also mounting evidence that genes causative of motor neuron disease, hereditary neuropathy or multisystem proteinopathies can result in distal myopathies . In addition, recent studies have demonstrated the digenic nature of certain distal myopathies in which the phenotype results from co‐existing defects in independent genes or from the interplay between different genes and proteins . All this adds complexity to the diagnostic process, the understanding of the pathomechanisms leading to muscle weakness, and the provision of genetic counseling to patients.…”

High diagnostic yield and novel variants in very late-onset spasticity

“…The very poor genotype-phenotype correlation may be due to the interaction of additional genetic factors that may explain the observation of patients with HSP7 phenotypes associated with single heterozygous mutations S anchez-Ferrero et al, 2013). There is precedent for the interaction of different Mendelian disease genes causing unique phenotypes (Balci et al, 2017;Posey et al, 2017), and detailed study of such situations can produce novel mechanistic insights (Lee et al, 2018;Niu et al, 2018). Given the extensive unexplained heterogeneity in HSP, particularly in SPG7-and SPAST-related disease, these conditions would appear to be the best candidates for study, to identify novel modifier mechanisms.…”

TFG: At the crossroads of motor neuron disease and myopathy

“…Multisystem proteinopathy was also subsequently described in association with mutations in SQSTM1 , an adaptor protein involved in recruitment of ubiquitinated protein aggregates to autophagosomes. SQSTM1 mutations have been found to cause ALS, FTD, and PDB as well as a digenically inherited myopathy in combination with a variant in TIA1 …”