Phenotypic Heterogeneity in ORAI-1-Associated Congenital Myopathy

Abstract

Introduction ORAI-1 is a plasma membrane calcium release-activated calcium channel that plays a crucial role in the excitation-contraction of skeletal muscles. Loss-of-function mutations of ORAI-1 cause severe combined immunodeficiency, nonprogressive muscle hypotonia, and anhidrotic ectodermal dysplasia. Autosomal dominant gain-of-function mutation causes Stormorken's syndrome, which includes tubular aggregate myopathy along with bleeding diathesis. Methods This is a description of a genetically confirmed case of ORAI-1-associated myopathy with clinical, histopathological, and imaging characteristics and a detailed literature review. Results We report an 18-year-old woman who presented with 2-and-a-half year history of slowly progressive proximal lower limb weakness and ophthalmoparesis. Her serum creatine kinase levels were normal. Magnetic resonance imaging of the muscle showed predominant fatty infiltration of the glutei and quadriceps femoris. Histopathological analysis of muscle biopsy was suggestive of congenital fiber-type disproportion (CFTD). Clinical exome sequencing showed novel homozygous nonsense pathogenic variant NC_000012.12 (NM_032790.3): c.205G > T (p.Glu69Ter) in ORAI-1 gene. Conclusion This report expands the phenotypic spectrum of ORAI-1-related myopathy to include congenital myopathy-CFTD with ophthalmoparesis, a novel manifestation.

Keywords: ORAI-1; congenital fiber-type disproportion; congenital myopathy; ophthalmoparesis.

Fig. 1

Muscle MRI of the patient: (A) and (B) show muscle MRI–T2 sequences that show fatty infiltration with atrophy of the glutei (blue arrow) and quadriceps (yellow arrow). MRI, magnetic resonance imaging.

Fig. 2

Histopathological images of muscle biopsy of the patient: (A) The hematoxylin and eosin–stained section shows an admixture of larger myofibers with several smaller fibers. (B), (C), and (D) reveal the more numerous hypotrophic, type 1 fibers that are dark on succinic dehydrogenase stain (B), light on ATPase 9.4 (C), and dark on ATPase ph4.6. Note somewhat fairly uniform size of the type 1 fibers. Ultrastructure of muscle biopsy: (E) Low power view of two adjoining myofibers separated by endomysial connective tissue. (F) A portion of a muscle fiber showing a subsarcolemmal myonucleus and focal disorganization of a myofilament (red star). No abnormal subsarcolemmal tubular aggregates or other deposits are seen. (G) Transverse and (H) longitudinal sections displaying disorganization of myofilamentous architecture with Z-band streaming and aggregation (red star). (Magnification included.)

Fig. 3

Electropherogram of patient and parents showing homozygous variant c.205G > T (p.Glu69Ter) in ORAI-1 gene.