Homozygous/compound heterozygote RYR1 gene variants: Expanding the clinical spectrum

Abstract

The ryanodine receptor 1 (RYR1) is a calcium release channel essential for excitation-contraction coupling in the sarcoplasmic reticulum of skeletal muscles. Dominant variants in the RYR1 have been well associated with the known pharmacogenetic ryanodinopathy and malignant hyperthermia. With the era of next-generation gene sequencing and growing number of causative variants, the spectrum of ryanodinopathies has been evolving with dominant and recessive variants presenting with RYR1-related congenital myopathies such as central core disease, minicore myopathy with external ophthalmoplegia, core-rod myopathy, and congenital neuromuscular disease. Lately, the spectrum was broadened to include fetal manifestations, causing a rare recessive and lethal form of fetal akinesia deformation sequence syndrome (FADS)/arthrogryposis multiplex congenita (AMC) and lethal multiple pterygium syndrome. Here we broaden the spectrum of clinical manifestations associated with homozygous/compound heterozygous RYR1 gene variants to include a wide range of manifestations from FADS through neonatal hypotonia to a 35-year-old male with AMC and PhD degree. We report five unrelated families in which three presented with FADS. One of these families was consanguineous and had three affected fetuses with FADS, one patient with neonatal hypotonia who is alive, and one individual with AMC who is 35 years old with normal intellectual development and uses a wheelchair. Muscle biopsies on these cases demonstrated a variety of histopathological abnormalities, which did not assist with the diagnostic process. Neither the affected living individuals nor the parents who are obligate heterozygotes had history of malignant hyperthermia. K E Y W O R D S arthrogryposis multiplex congenita, fetal akinesia deformation sequence syndrome, lethal multiple pterygium syndrome, malignant hyperthermia, RYR1 Ebba Alkhunaizi and Shirley Shuster authors contributed equally.

Fetal arthrogryposis multiplex congenita/fetal akinesia deformation sequence (FADS)—Aetiology, diagnosis, and management

“…In a case series by Witters et al, up to 10% of cases with arthrogryposis were identified in the first trimester . All cases identified in the first trimester, as with many others reported in the literature, were initially identified due to increased nuchal translucency, cystic hygroma, or other major anomaly including abnormal limb positioning . A presentation at an earlier gestational age frequently correlates with severity …”

“…Contingent on local protocol or the presence of pregnancy complications, additional ultrasounds may be performed including a routine evaluation of fetal position, size, and fetal well‐being/biophysical profile in the third trimester. Ultrasound findings associated with AMC during each trimester of pregnancy are detailed in Table …”

“…Fetal movements are assessed subjectively at each ultrasound encounter, and atypical fetal movements can be detected as early as 12 weeks of gestation . Cases of AMC reported in the literature frequently note the finding of fetal hypomobility or complete akinesia in all three trimesters . Protocols surrounding assessment of fetal movement, however, are challenging to establish as movement patterns progress throughout gestation and are subjective.…”

“…Arthrogryposis is a feature of more than 400 distinct disorders, of which more than 50% have an underlying genetic diagnosis . The current genes reported to be associated with arthrogryposis are reviewed in Hall and Kiefer and Beecroft et al Ongoing studies using whole exome and genome sequencing will likely continue identifying genetic causes of AMC . To date, arthrogryposis has been associated with autosomal dominant, autosomal recessive (homozygous and compound heterozygous), and X‐linked modes of inheritance as well as mitochondrial, chromosome, and epigenetic abnormalities.…”

“…66 All cases identified in the first trimester, as with many others reported in the literature, were initially identified due to increased nuchal translucency, cystic hygroma, or other major anomaly including abnormal limb positioning. 2,14,36,[41][42][43][44][45][46][47][48][49]66,71,74 A presentation at an earlier gestational age frequently correlates with severity. 63 The majority of cases of arthrogryposis that are identified prena-…”