FXR1-related congenital myopathy: expansion of the clinical and genetic spectrum

Abstract

Background: Biallelic pathogenic variants in FXR1 have recently been associated with two congenital myopathy phenotypes: a severe form associated with hypotonia, long bone fractures, respiratory insufficiency and infantile death, and a milder form characterised by proximal muscle weakness with survival into adulthood.

Objective: We report eight patients from four unrelated families with biallelic pathogenic variants in exon 15 of FXR1.

Methods: Whole exome sequencing was used to detect variants in FXR1.

Results: Common clinical features were noted for all patients, which included proximal myopathy, normal serum creatine kinase levels and diffuse muscle atrophy with relative preservation of the quadriceps femoris muscle on muscle imaging. Additionally, some patients with FXR1-related myopathy had respiratory involvement and required bilevel positive airway pressure support. Muscle biopsy showed multi-minicores and type I fibre predominance with internalised nuclei.

Conclusion: FXR1-related congenital myopathy is an emerging entity that is clinically recognisable. Phenotypic variability associated with variants in FXR1 can result from differences in variant location and type and is also observed between patients homozygous for the same variant, rendering specific genotype-phenotype correlations difficult. Our work broadens the phenotypic spectrum of FXR1-related congenital myopathy.

Keywords: Neuromuscular Diseases.

Figure 1

Pedigrees of all four families (A-D). Clinical photos of Patient AII:2: joint laxity (E) Patient BII:1: scoliosis (F) Patient CIII:1: hypotonia at 4 years (G) Patient CIII:3: axial hypotonia at 4 months (H). Muscle biopsy (right biceps) from BII:1 at 36 years NADH (I) and electron microscopy (J) reveal minicores and H&E stain shows prominent fatty replacement and internal nuclei (K). Muscle biopsy at 7 months from CIII:1 NADH (L) H&E (M) revealed cores and increased internal nuclei. Muscle biopsy (right triceps) from DII:4 at 11 years. Toluidine blue stained resin section shows multiple minicores giving a moth-eaten appearance to the fibres (N) NADH (O) and electron microscopy (P) reveals minicores that appear as focal disruptions in the myofibrillar striation pattern with absence of mitochondria.