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 Here, we describe 11 affected individuals from four unpublished families with ultra-rare missense variants in GGPS1 and provide follow-up details from a previously reported family.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.

Figure 1

Genetic summary, muscle MRI, and muscle histopathology of the affected individuals with biallelic GGPS1 variants. (A) Pedigrees of the five families described in the present report. Square = male; circle = female; black filled symbol = affected individual; white symbols = unaffected individuals; diagonal line = deceased individual. Double lines indicate consanguinity. The allele with the variant is indicated by the + sign. Wild type allele is indicated by the—sign. Inheritance of the compound heterozygous variant in Family 3 is indicated by the underlined + sign. (B) Schematic representation of the GGPS1 gene showing the position of the variants. (C) Schematic diagram indicating the predicted domains and active sites of the GGPS1 protein containing 300 amino acid residues. The blue box represents the polyprenyl synthetase domain. The green circle indicates a magnesium D metal ion binding. Black boxes II, III, and V represent conserved regions that are believed to be involved in ligating the magnesium and the pyrophosphate on the allylic substrate. Box I contains two basic residues involved in IPP pyrophosphate binding. Box IV is the KT sequence containing Thr‐152 proposed to be involved in catalysis by stabilizing a carbocation intermediate. Boxes A, B, C are regions thought to be responsible for the hexameric organization of protein. The two yellow boxes are proposed active sites. (D) Muscle biopsies from affected individuals showed myopathic to dystrophic changes. Family 3 (P10): Quadriceps biopsy performed at 8 months of age (I‐IV). Hematoxylin & eosin‐stained section shows well‐populated fascicles with mild variation in fiber size (I). Staining with NADH‐TR shows normal internal architecture and predominance of type I fibers (II). Myosin heavy chain immunohistochemistry shows corresponding predominance of fibers expressing slow myosin heavy chain (III). Aberrant foetal myosin heavy chain expression of varying intensities can be seen in several scattered mature fibers, as well as a population of very small fibers (IV, circles), dispersed across the fascicles. Family 4 (P11): Biceps brachii biopsy performed at 4 years of age (V–VII). Hematoxylin and eosin‐stained section shows moderate variation in fiber size (V). There are several scattered (arrow) and clustered (circle) basophilic regenerating fibers (V). Few fibers contain internal nuclei. NADH‐TR shows preserved fiber typing, and there are several dark‐staining fibers (VI) The cytochrome oxidase stain (COX) also highlights the population of dark staining fibers, but there are no COX‐negative fibers (VII). Scale bar: A–D = 50 μm. (E) Muscle MRI of the lower limbs from Family 3 (P10) aged 8 months: Showing generalized atrophy in the absence of muscle fat infiltration. [Colour figure can be viewed at wileyonlinelibrary.com]