Atypical presentation of Arts syndrome due to a novel hemizygous loss-of-function variant in the PRPS1 gene

Abstract

The PRPS1 gene, located on Xq22.3, encodes phosphoribosyl-pyrophosphate synthetase (PRPS), a key enzyme in de novo purine synthesis. Three clinical phenotypes are associated with loss-of-function PRPS1 variants and decreased PRPS activity: Arts syndrome (OMIM: 301835), Charcot-Marie-Tooth disease type 5 (CMTX5, OMIM: 311070), and nonsyndromic X-linked deafness (DFN2, OMIM: 304500). Hearing loss is present in all cases. CMTX5 patients also show peripheral neuropathy and optic atrophy. Arts syndrome includes developmental delay, intellectual disability, ataxia, and susceptibility to infections, in addition to the above three features. Gain-of-function PRPS1 variants result in PRPS superactivity (OMIM: 300661) with hyperuricemia and gout. We report a 6-year-old boy who presented with marked generalized muscular hypotonia, global developmental delay, lack of speech, trunk instability, exercise intolerance, hypomimic face with open mouth, oropharyngeal dysphagia, dysarthria, and frequent upper respiratory tract infections. However, his nerve conduction velocity, audiologic, and funduscopic investigations were normal. A novel hemizygous variant, c.130A > G p.(Ile44Val), was found in the PRPS1 gene by panel sequencing. PRPS activity in erythrocytes was markedly reduced, confirming the pathogenicity of the variant. Serum uric acid and urinary purine and pyrimidine metabolite levels were normal. In conclusion, we present a novel PRPS1 loss-of-function variant in a patient with some clinical features of Arts syndrome, but lacking a major attribute, hearing loss, which is congenital/early-onset in all other reported Arts syndrome patients. In addition, it is important to acknowledge that normal levels of serum and urinary purine and pyrimidine metabolites do not exclude PRPS1-related disorders.

Keywords: Arts syndrome; Autophagy; PRPS1; Purines.

Fig. 1

(A) The phenotype of our patient at the age of 4 years; (B) family pedigree; (C) and multialignment of the PRPS1 residues across species, showing strict conservation of Ile-44.

Fig. 2

PRPS-1 structure and Ile44Val substitution site. (A) The crystal structure of PRPS-1 (PDB entry 2HCR), with each subunit colored differently. AMP (stick model colored by atom) and a Cd²⁺ ion (grey sphere) indicate the location of the ATP-Mg²⁺ binding site in the interface between the N- and C-terminal domain; the binding site for the second substrate R5P is occupied by a sulfate ion shown as a space-fill model colored as the corresponding subunit. In the crystal structure, allosteric sites I and II are also occupied by sulfate ions, shown as space-fill models in brown and cyan, respectively. The mutation site is indicated by a space-fill model of the Ile-44 side chain in red. The respective binding sites are labeled only for the green subunit. (B) Close-up view of the Ile44Val substitution site. For the valine (shown as sticks with carbon atoms in magenta), the same side chain conformer as adopted by Ile-44 (sticks with carbon atoms in green) in the crystal structure is chosen. Subunits and ligands are depicted as in (A). Residues interacting with Ile-44 or involved in ligand binding that are mentioned in the text are shown as sticks with carbon atoms in the same color as the subunit to which they belong. Hydrogen bonds are indicated as black dotted lines.

Fig. 3

(A) ATPase at pH 10.2 and (B) ATPase at pH 4.3, showing slightly larger type 1 fibers compared to type 2 fibers; (C and D) anti- SQSTM1/p62 antibody expression in muscle fibers in transverse section (C) and in longitudinal section (D) in the patient, showing many diffuse punctae; (E and F) and anti- SQSTM1/p62 antibody expression in muscle fibers in transverse section (E) and in longitudinal section (F) in a control muscle biopsy, showing single dots.