GGPS1‐associated muscular dystrophy with and without hearing loss

Abstract

Ultra-rare biallelic pathogenic variants in geranylgeranyl diphosphate synthase 1 (GGPS1) have recently been associated with muscular dystrophy/hearing loss/ ovarian insufficiency syndrome. Here, we describe 11 affected individuals from four unpublished families with ultra-rare missense variants in GGPS1 and provide follow-up details from a previously reported family. Our cohort replicated most of the previously described clinical features of GGPS1 deficiency; however, hearing loss was present in only 46% of the individuals. This report consolidates the disease-causing role of biallelic variants in GGPS1 and demonstrates that hearing loss and ovarian insufficiency might be a variable feature of the GGPS1-associated muscular dystrophy.

Biallelic variants inHMGCS1are a novel cause of rare rigid spine syndrome

“…68,69 Moreover, biallelic variants in GGPS1 have been associated with a muscular dystrophy (OMIM# 619518). 11,70 Of note, GGPS1 -related muscular dystrophy includes several overlapping phenotypes including scoliosis, joint contractures, hypotonia, elevated creatine kinase, as well as episodic worsening of muscle weakness and respiratory insufficiency during intercurrent disease. 11,70 Overall, the myopathic phenotypes implicated in the mevalonate pathway support HMGCS1 as an underlying genetic cause for our patients’ disorders.…”

“…11,70 Of note, GGPS1-related muscular dystrophy includes several overlapping phenotypes including scoliosis, joint contractures, hypotonia, elevated creatine kinase, as well as episodic worsening of muscle weakness and respiratory insufficiency during intercurrent disease. 11,70 Overall, the myopathic phenotypes implicated in the mevalonate pathway support HMGCS1 as an underlying genetic cause for our patients' disorders. 11 The mevalonate pathway branches into several critical other pathways including the cholesterol biosynthesis pathway, the isoprenoid pathway and the ubiquinone pathway, which are essential for regulating cell proliferation, maturation, and maintenance.…”

Expanding the phenotypic and genotypic spectrum of GGPS1 related congenital muscular dystrophy

“…CMD resulting from biallelic mutations in the GGPS1 is associated with extra‐muscular manifestations, mainly hearing loss and primary ovarian failure in affected females. Detailed phenotyping and genotyping of 26 individuals with GGPS1 mutations have been recently reported (Foley et al, 2020; Kaiyrzhanov et al, 2022). The onset of presentation and severity of symptoms were heterogeneous among affected patients, ranging from antenatal presentation with decreased fetal movements to slowly progressive muscle weakness.…”

“…Sensorineural hearing loss is considered a variable phenotype of GGPS1 and has been reported in 70% of affected patients. Interfamilial variability has been observed and a variant‐specific effect has been hypothesized (Kaiyrzhanov et al, 2022). The mechanism of ear involvement in GGPS1 defects is still being explored, but the expression of Ggps1 in the embryonic and postnatal mice cochlea has been studied (Foley et al, 2020; Kaiyrzhanov et al, 2022).…”

“…GGPS1 protein and the farnesyl pyrophosphate synthase (FPPS) (Roca‐Ayats et al, 2018) are involved in protein prenylation, serve as precursors for the squalene cholesterol pathway (Kainou et al, 1999; Kuzuguchi et al, 1999), and play essential roles in various important cellular functions such as osteoclast formation and function, cytoskeletal actin dynamics, and signal transduction (Foley et al, 2020; Roca‐Ayats et al, 2018; Vicent et al, 2000) and regulate negative feedback of the mevalonate pathway by stimulating ubiquitination and degradation of HMG‐reductase (Foley et al, 2020). GGPS1 is expressed in skeletal muscle, female reproductive organs at different developmental stages, and the inner ear of rodents (Kaiyrzhanov et al, 2022). Accordingly, GGPS1 mutations have been found to specifically affect muscle, inner ear, and ovary cell mechanisms.…”