Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders

Abstract

PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype associated with decreased PRS-1 function in two affected male siblings. Using whole exome and Sanger sequencing techniques, we identified a novel missense mutation in PRPS1. The clinical phenotype in our patients is characterized by high prenatal maternal α-fetoprotein, intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis. Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus. Exome sequencing of the two affected male siblings identified a shared putative pathogenic mutation c.586C>T p.(Arg196Trp) in the PRPS1 gene that was maternally inherited. Follow-up testing showed normal levels of hypoxanthine in urine samples and uric acid levels in blood serum. The PRS activity was significantly reduced in erythrocytes of the two patients. Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate. This presentation is the most severe form of PRPS1-deficiency syndrome described to date and expands the spectrum of PRPS1-related disorders.

Figure 1

Clinical findings. Patients 1 (a and c) and 2 (b and d) presented with strikingly similar dysmorphic features and neurological phenotype. Characteristic facial features included dolichocephalic skull, hypertelorism, deep-set eyes, hypoplastic nares and low-set ears. Additionally, the patients developed truncal hypotonia and axial hypertonia.

Figure 2

Neuroimaging results in patient 1. (a–d) MRI age 18 months: T1W sagittal image (a) shows a thin corpus callosum with the lack of isthmus and a tapered splenium (arrow). The optic chiasm is atrophied or hypoplastic. T1W axial image (b) demonstrates age-appropriate gyral development and mild delay in juxtacortical myelin maturation. T2W axial (c) and coronal (d) reveals prominence of the lateral ventricles, particularly anteriorly. There is flattening of the lateral walls of the frontal horns (arrow). Anterior pericerebral space is increased. (e–h) MRI age 6 years 10 months: T1W sagittal image (e) shows that corpus callosum remains thin, with a tapered splenium and with a lack of isthmus. The chiasm remains significantly small (arrow). MRS TE 144 (f) performed in the basal ganglia shows age-appropriate spectra. T2W axial images (g and h) reveal that myelin maturation is now age appropriate, although the white matter is thinned. The ventricles, in particular the anterior horns, remain prominent with flattening of the lateral walls (arrow).

Figure 3

Neuroimaging results in patient 2. (a–d) MRI age 8 months: T1W sagittal image (a) shows a thin corpus callosum with the lack of isthmus and a tapered splenium. The optic chiasm is atrophied or hypoplastic. T1W axial image (b) demonstrates age-appropriate gyral development. There is delay in myelin maturation, appropriate for 4–5 months of age. T2W axial (c) and coronal (d) reveals prominent lateral ventricles, particularly the frontal horns. The anterior pericerebral space is increased. (e–g) MRI at 5 years 2 months: T1W sagittal image (e) shows that corpus callosum remains thin, with a tapered splenium and with a lack of isthmus. The chiasm remains significantly small. The pituitary gland is small. Three-dimensional MRI surface reconstruction (f) reveals open mouth and mildly rotated pinna. T2W axial image (g) reveals age-appropriate myelin maturation. The white matter is thinned to a lesser degree than Child 1. The ventricles, particularly the frontal horns, remain prominent. T2W axial (h) view of the orbits demonstrates hypertelorism.

Figure 4

Family pedigree and Sanger sequencing confirmation of the mutation and conservation of mutated residue across species.