PURA. This is the Epilepsiome page for PURA. Heterozygous pathogenic variants in this gene are associated with a complex neurodevelopmental disorder. Since the discovery of PURA as a disease gene in 2014 and our initial blog post, many more individuals have been diagnosed with this condition. With this increase in diagnoses comes an increase in our understanding of the associated genotypic and phenotypic spectrum.
Here are the most recent blogs that mention PURA
In a nutshell. PURA codes for Purine-rich single-stranded DNA binding protein alpha, also known as Pur-alpha. Pur-alpha is a ubiquitously expressed protein that binds to specific sequences of RNA and single stranded DNA known to be essential for postnatal brain development. The associated clinical phenotype is a neonatal-onset neurodevelopmental syndrome with distinct features. Below, we will summarize the current understanding of the associated phenotypes, highlighting the lessons learned from larger patient cohorts.
Summary In brief, heterozygous pathogenic variants in the PURA gene were first described in four individuals with overlapping features such as neonatal respiratory difficulties, hypotonia, developmental delay, and intellectual disability. Only one of these first reported individuals had a history of definite seizures, specifically epileptic spasms. Since then, many more individuals have been reported in the medical literature and diagnosed in clinical practice. So, what have we learned with this increased volume?
The neonatal course The initial presenting feature in many individuals is neonatal hypotonia, which may be profound, so much so that this could be mistaken for other neuromuscular conditions such as spinal muscular atrophy. This can also often go along with feeding difficulties, respiratory distress, hypersomnolence, and difficulty regulating body temperature. While hypotonia persists in many individuals beyond the neonatal period and into adulthood, typically other features that are a hallmark of this condition in the neonatal period resolve over time.
Epilepsy Our recent publication analyzed a cohort of 142 patients with heterozygous pathogenic variants in the PURA gene with an eye towards epilepsy presentations. Roughly 60% of individuals have epilepsy, and the only somewhat unifying feature was drug resistance in 2/3 of cases. There is a wide range of ages of onset ranging from neonatal to adulthood, with median onset at 3 years. The most common seizure types were myoclonic, generalized tonic-clonic, and focal. Although familiar epilepsy syndromes such as ESES and Lennox-Gastaut Syndrome were observed, there was not a pattern or association with particular variants. Notably, hypsarrhythmia and burst suppression were rarely observed.
Neurodevelopment All individuals with heterozygous pathogenic variants in PURA have delayed development, with many individuals not using words to communicate and not independently ambulating. Individuals typically have moderate-severe intellectual disability.
Movement disorders Dystonia, dyskinesia, hand stereotypies, ataxia, and chorea-like movements. Nonepileptic paroxysmal episodes of twitching/staring and pathologic startles are also seen. There is no particular association with movement disorders being present in individuals with or without epilepsy, and movement disorders are present in approximately one quarter of individuals overall.
Multi-systemic features Although this is an epilepsy genetics blog first and foremost, it is important to mention the non-neurological features for two reasons – 1) recognition of these features in addition to the neurological symptoms may lead to improved diagnostic recognition of PURA and 2) these features are important to living with PURA and overall medical management. Such symptoms include constipation and other GI concerns, scoliosis, hip dysplasia, delayed puberty, dysphagia, small stature, and cardiac and large vessel abnormalities.
Treatment Although there is no specific gene therapy for PURA-related conditions at this time, there was a recent case report of an individual with the recurrent p.Phe233del variant with profound hypotonia and severe apneic episodes responding well to treatment with pyridostigmine, an acetylcholinesterase inhibitor. Further study is needed to replicate this effect, but this study may represent a promising use of a previously established drug to treat a genetic neurodevelopmental condition.
Genotype vs. phenotype The PURA protein has three essential repeat motifs (PUR I, PUR II, and PUR III). Most reported missense variants to date occur within the three repeat motifs with some exceptions, while truncating variants are reported throughout the gene. There are no known genotype-phenotype associations, although there is emerging evidence that genetic variants within the PUR III repeat cause a more severe phenotype.
Recurrent variants There are several recurrent variants in this gene, although as described above these do not seem to have a distinct phenotype compared to other pathogenic variants in this gene. Recurrent variants includep.Lys97Glu, p.Arg199Pro, p.Phe233del, p.Arg245Pro, and p.Phe271del.
5q31.3 deletions Non-recurrent deletions in this region that include the partial or full PURA gene have been reported in individuals with similar features to individuals with point mutations in this gene. For this reason, PURA is thought to be the main driver of the associated condition. Some individuals with larger deletions have a more severe phenotype, which is thought to be explained by the contribution of additional genes.
Segregation All reported cases have either occurred de novo or were inherited from an unaffected parent with a low level of mosaicism.
Genetic mechanism The presumed genetic mechanism of disease is haploinsufficiency as truncating variants and partial/whole gene deletions have been reported in many individuals with this condition. This gene is also depleted for putative loss-of-function variation in the general population (pLI=0.94). However, the PURA protein forms homodimers, which allows for the possibility of a dominant negative mechanism if a genetic variant produces a mutant protein that could still dimerize.
An emerging process. The PURA protein is ubiquitously expressed and yet leads to a primary neurodevelopmental syndrome, the mechanism of which remains unclear. Homozygous PURA knockout mice are typical at birth but after several weeks show tremor, spontaneous seizures, and abnormal gait, and ultimately early lethality. This suggests that the role of PURA in neurodevelopment as postnatal. However, heterozygous PURA knockout mice do not have an associated phenotype, although there were reduced numbers of neurons and dendrites upon neuropathological study and overall higher prevalence of spontaneous early death. There is more limited pathophysiological study in humans, but neuropathologic studies of one individual show chronic inflammatory changes around the arterioles within the deep white matter. Taking all of this together, we know that the PURA protein is essential for postnatal brain development and there is a similar phenotype in the homozygous mouse model – but the connecting link between what is known about the protein and the phenotype in humans has not yet been elucidated.
The PURA Syndrome Foundation is a non-profit organization for both families and researchers. They are currently working with the University of Southampton to curate a global patient registry and conduct a natural history study.
Resources & References
Hunt D, Leventer RJ, Simons C, et al. Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability. J Med Genet. 2014;51(12):806-813. doi:10.1136/jmedgenet-2014-102798
Johannesen KM, Gardella E, Gjerulfsen CE, et al. PURA-Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum. Neurol Genet. 2021 Nov 15;7(6):e613. doi: 10.1212/NXG.0000000000000613. PMID: 34790866; PMCID: PMC8592566.
Lee BH, Reijnders MRF, Abubakare O, Tuttle E, et al. Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A. 2018 Jan;176(1):56-67. doi: 10.1002/ajmg.a.38521. Epub 2017 Nov 17. PMID: 29150892; PMCID: PMC5821266.
Molitor L, Bacher S, Burczyk S, Niessing D. The Molecular Function of PURA and Its Implications in Neurological Diseases. Front Genet. 2021 Mar 11;12:638217. doi: 10.3389/fgene.2021.638217. PMID: 33777106; PMCID: PMC7990775.
Reijnders MRF, Janowski R, Alvi M, et al. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature. J Med Genet. 2018;55(2):104-113. doi:10.1136/jmedgenet-2017-104946
Reijnders MRF, Leventer RJ, Lee BH, et al. PURA-Related Neurodevelopmental Disorders. 2017 Apr 27. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK426063/
Wyrebek R, DiBartolomeo M, Brooks S, Geller T, Crenshaw M, Iyadurai S. Hypotonic infant with PURA syndrome-related channelopathy successfully treated with pyridostigmine. Neuromuscul Disord. 2022 Feb;32(2):166-169. doi: 10.1016/j.nmd.2022.01.005. Epub 2022 Jan 16. Erratum in: Neuromuscul Disord. 2022 Aug;32(8):e1. PMID: 35094889.