Expanding the neurodevelopmental phenotype of PURA syndrome

Abstract

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations.

Keywords: PURA; congenital apnea; deletion 5q31.3; epilepsy; intellectual disability.

Figure 1

Location of pathogenic sequence variations in domains of the PURA protein reported in this series.

Figure 2

Representative facial photographs of individuals with PURA syndrome. Facial photographs of subjects with PURA syndrome. (A) DB13-043; (B) DB15-021; (C) DB15-023; (D) DB15-027; (E) DB15-030; (F) DB15-033; (G) DB15-035; (H) DB15-037; (I) DB16-002; (J) DB16-009; (K) DB16-043. Facial images of subject DB16-016 across her lifespan at age 4 months (L), 4.5 years (M), 18 years (N), and 27 years (O) demonstrate early facial hypotonia in infancy that resolved with maturity. Other individuals (A,C,G) had similar hypotonic facies. Some had downslanting palpebral fissures (A,B) but overall there were no consistent dysmorphic facial features across this cohort of individuals with PURA syndrome.

Figure 3

Representative brain MRI findings in individuals with PURA syndrome. Subject DB13-043, a 5 year old girl with hypotonia and epilepsy, had thinning of the corpus callosum (A) and of the subcortical white matter with increased extra-axial fluid spaces (B). Subject DB15-027, a 4 year old boy with hypotonia and cortical visual impairment, had mildly increased extra-axial fluid in the posterior fossa (C) and thinning of the cerebral white matter (D). Subjects DB15-021 (E–G) and DB15-033 (H–J) had subarachnoid cysts (arrowhead). Subject DB16-002 had thickening of the corpus callosum and cerebellar tonsilar ectopia (asterix) develop over scans at ages 2 years (K), 6 years (L), and 9 years (M). Coronal T2 FLAIR image from subject DB16-016 at age 20 years showing mild dilation of the lateral ventricles and increased signal in the subcortical white matter (N). Gross brain specimen of subject DB16-016 confirming ventricular and white matter findings seen on neuroimaging (O).

Figure 4

Histologic examination of brain of subject DB16-016 revealed mild vacuolization and reactive gliosis within neuropil of the cerebral cortical (asterix; A). Subcortical deep white matter vessels were notably thickened and hyalinized, with prominent involvement of arterioles in the periventricular regions (B) and cerebellar hemispheres (C). The deep white matter vessels revealed variably high sclerotic indices (D to F), with occasional perivascular lymphocytes, hemosiderin-laden macrophages (E–F) and mild gliosis. Associated white matter rarefaction and perivascular space widening were present (G). The vascular and perivascular features were highlighted on luxol fast blue myelin stain (H).