PURA- Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum

Abstract

Background and objectives: Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.

Methods: Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.

Results: A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.

Discussion: The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Figure 1. The Faces of the PURA Syndrome

Faces of patients with pathogenic PURA variants. Recurrent similarities include a myopathic face, high anterior hairline, almond-shaped palpebral fissures, and full cheeks. A flat nasal bridge with a wide and triangular nasal tip, thickened nostrils, a well-defined philtrum, heavy eyebrows, and periorbital fullness was seen in a subset of individuals. PURA = purine-rich element-binding protein A.

Figure 2. EEG Changes in the PURA Syndrome

(A) The interictal EEG is characterized by slow background and multifocal spike/sharp and slow waves predominant either in the frontal regions (a, pt. #42) or in the posterior quadrants (b, pt. #30). The epileptiform activity is accentuated during sleep; this image (c, pt. #19) shows very frequent multifocal spike/polyspikes and waves and sharp and slow waves, independently in the right central, right parietal, and left central regions or diffuse. (B) The ictal EEG showed (a) cluster of epileptic spasms (each arrow corresponds to a spasm) (pt. #30), (b) a startle induced by acoustic stimulus (pt. #19), and (c) brief tonic seizures out of sleep with an EEG correlation consisting of diffuse rapid activity (3–6 seconds) followed by diffuse delta activity and trains of spike and slow waves in the posterior regions (pt. #30). PURA = purine-rich element-binding protein A.

Figure 3. The PURA Gene

The PURA gene with previously unpublished variants. Missense on top, protein-truncating variants below. With epilepsy in red, without epilepsy in blue, and recurrent variant in bold. PUR repeats indicated by yellow coloring: PUR-I position 42–106, PUR-II position 120–182, and PUR-III position 197–252. PURA = purine-rich element-binding protein A.