Individual Treatment Trial of PIGV-Associated Mabry Syndrome with D-Mannose in a Young Child

We describe the first individual treatment trial with D-mannose in a young girl with PIGV-CDG. PIGV-CDG belongs to the GPI anchor deficiencies leading to intellectual disability, dysmorphic features, epilepsy, and, less frequently, organ malformations. A hallmark of the GPI anchor deficiencies is the elevated serum alkaline phosphatase (AP). Our patient carried the germline homozygous PIGV variant c.1022C>A, p. (Ala341Glu), the most commonly reported pathogenic variant leading to PIGV-CDG so far. We aimed to improve the impaired enzymatic function of PIGV through elevated substrate levels by giving D-mannose orally. We monitored the clinical status, developmental progress as well as serum AP levels. Our patient experienced no side effects. Standardized developmental testing showed better developmental progress during the 21-month treatment period with D-mannose than in the 12 months following the discontinuation of treatment. The D-Mannose treatment might have had a positive effect on the development of our patient with PIGV-CDG

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

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-alpha, 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spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature.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.ResultsA 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.DiscussionThe 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