Severe congenital RYR1-associated myopathy: the expanding clinicopathologic and genetic spectrum

Abstract

Objective: To report a series of 11 patients on the severe end of the spectrum of ryanodine receptor 1 (RYR1) gene-related myopathy, in order to expand the clinical, histologic, and genetic heterogeneity associated with this group of patients.

Methods: Eleven patients evaluated in the neonatal period with severe neonatal-onset RYR1-associated myopathy confirmed by genetic testing were ascertained. Clinical features, molecular testing results, muscle imaging, and muscle histology are reviewed.

Results: Clinical features associated with the severe neonatal presentation of RYR1-associated myopathy included decreased fetal movement, hypotonia, poor feeding, respiratory involvement, arthrogryposis, and ophthalmoplegia in 3 patients, and femur fractures or hip dislocation at birth. Four patients had dominant RYR1 mutations, and 7 had recessive RYR1 mutations. One patient had a cleft palate, and another a congenital rigid spine phenotype-findings not previously described in the literature in patients with early-onset RYR1 mutations. Six patients who underwent muscle ultrasound showed relative sparing of the rectus femoris muscle. Histologically, all patients with dominant mutations had classic central cores on muscle biopsy. Patients with recessive mutations showed great histologic heterogeneity, including fibrosis, variation in fiber size, skewed fiber typing, very small fibers, and nuclear internalization with or without ill-defined cores.

Conclusions: This series confirms and expands the clinical and histologic variability associated with severe congenital RYR1-associated myopathy. Both dominant and recessive mutations of the RYR1 gene can result in a severe neonatal-onset phenotype, but more clinical and histologic heterogeneity has been seen in those with recessive RYR1 gene mutations. Central cores are not obligatory histologic features in recessive RYR1 mutations. Sparing of the rectus femoris muscle on imaging should prompt evaluation for RYR1-associated myopathy in the appropriate clinical context.

Figure 1. Clinical features

(A and B) Myopathic facies, ophthalmoplegia, and severe respiratory involvement in patient 5. (C) Mild myopathic facies and feeding difficulties requiring nasogastric tube in patient 3. (D) Cleft palate in patient 1. Arthrogryposis is seen with characteristic extended fingers and adducted thumb in patient 3 (E), patient 1 (F), and patient 6 (J). Early-onset scoliosis is seen in patient 1 (G) and in patient 2 (H and I). (K) Muscle ultrasound in patient 4 showing involvement of the vastus lateralis (VL), intermedius (VI), and medialis (VM) with a dense, mostly granular pattern, with relative sparing of the rectus femoris (RF).

Figure 2. Histologic features

(A) Skeletal muscle of patient 6 demonstrates a large majority of rounded fibers with severe variation in size and occasional fibers with internally placed nuclei. (C) Patient 1 demonstrates mild increase in connective tissue and significant variation in fiber size, but no internally placed nuclei. (E) Patient 5, similarly to patient 1, demonstrates variation in fiber size and shape, but not significant fibrosis; in addition, scattered fibers have internally placed nuclei. Whereas oxidative enzyme stain (NADH-TR) reveals no cores in patients 1 (D) and 5 (F), there are numerous, well-defined cores centrally and peripherally located present in patient 6 (B). A, C, E: hematoxylin & eosin; B, D, F: NADH-TR; A–F calibration bar 50 µm. NADH-TR = nicotinamide adenine dinucleotide dehydrogenase–tetrazolium reductase.

Figure 3. Histologic features

(A) Mild fibrosis and adipose tissue infiltration with moderate variation in size and shape but scattered fibers with internally placed nuclei are seen in patient 4. (C) Patient 2 demonstrates rounded fibers, most of which are surrounded by excess connective tissue, occasional dark, hypercontracted-appearing fibers, and severe variation in size with clusters of small fibers. (E) In patient 3, there is pronounced increase in adipose and connective tissue with numerous minute fibers and rounded hypertrophic fibers. Oxidative enzyme stain (NADH-TR) reveals scattered fibers with ill-defined cores in patients 2 (D) and 3 (F) and unevenness of stain with ill-defined cores in patient 4 (B). A, C, E: hematoxylin & eosin; B, D, F: NADH-TR; C, D, F calibration bar 100 μm; E, A, B calibration bar 200 μm. NADH-TR = nicotinamide adenine dinucleotide dehydrogenase–tetrazolium reductase.