Expanding the clinical phenotype and genetic spectrum of PURA-related neurodevelopmental disorders

Abstract

Background: PURA-related neurodevelopmental disorders (PURA-NDDs) include 5q31.3 deletion syndrome and PURA syndrome. PURA-NDDs are characterized by neonatal hypotonia, moderate to severe global developmental delay/intellectual disability (GDD/ID), facial dysmorphism, epileptic seizures, nonepileptic movement disorders, and ophthalmological problems. PURA-NDDs have recently been identi ed and underestimated in neurodevelopmental cohorts, but their diagnosis is still challenging. We retrospectively reviewed the clinical characteristics, genetic spectrum, and diagnostic journey of patients with PURA-NDDs.Results: We report 2 patients with 5q31.3 microdeletion and 5 with PURA pathogenic variants. They demonstrated hypotonia (7/7, 100%), feeding di culties (4/5, 80%), and respiratory problems (4/7, 57%) in the neonatal period. All of them had severe GDD/ID and could not achieve independent waking and verbal responses. Distinctive facial features of open-tented upper vermilion, long philtrum, and anteverted nares and poor visual xation and tracking with or without nystagmus were most commonly found (5/7, 71.4%). There were no signi cant differences in clinical phenotypes between 5q31.3 microdeletion syndrome and PURA syndrome. PURA-NDDs need to be considered as a differential diagnosis in individuals who show severe hypotonia, including feeding di culties since birth and severe developmental retardation with distinctive facial and ophthalmological features.Conclusions: Our data expands the phenotypic and genetic spectrum of PURA-NDD. Next-generation sequencing methods based on the detailed phenotypic evaluation would shorten the diagnostic delay and would help this rare disorder become a recognizable cause of neurodevelopmental delay.

Research Article Characterization of a complex chromosomal rearrangement in a girl with PURA syndrome

“…(2021) considered that PURA-disorder might add to the growing list of developmental and epileptic encephalopathy. Patients with microdeletions 5q31.3 or pathogenic variants in PURA have also demonstrated developmental brain changes on MRI, including delayed myelination, white matter abnormalities, widening of the lateral ventricles and the underdeveloped rostrum of the corpus collosum (Lee et al, 2018;Choi et al, 2021).…”

Movement Disorders in PURA Syndrome: A Video Case Series

“…1,2 PS has recently been identified 3 and still may be underestimated. [4][5][6] Since the initial description, 97 different pathogenic variants have been reported, but no clear genotype-phenotype correlations have emerged so far. 1,[3][4][5][6] PS is a heterogeneous condition, characterized by neonatal hypotonia, epileptic seizures, complex nonepileptic movement disorders, neurodevelopmental delay with the absence of speech and lack of independent ambulation in most patients.…”

“…[4][5][6] Since the initial description, 97 different pathogenic variants have been reported, but no clear genotype-phenotype correlations have emerged so far. 1,[3][4][5][6] PS is a heterogeneous condition, characterized by neonatal hypotonia, epileptic seizures, complex nonepileptic movement disorders, neurodevelopmental delay with the absence of speech and lack of independent ambulation in most patients. Patients may also present in variable frequency: feeding difficulties, ophthalmological disorders, hypersomnolence, hypothermia, central apnea, urogenital malformations, skeletal abnormalities, and craniofacial dysmorphisms.…”

“…Patients may also present in variable frequency: feeding difficulties, ophthalmological disorders, hypersomnolence, hypothermia, central apnea, urogenital malformations, skeletal abnormalities, and craniofacial dysmorphisms. 1,[3][4][5][6] Movement disorders in PS are very rich phenomenologically. The patient may present complex hyperkinetic movements, in which chorea-like dyskinesia may be the core movement, but often, associated with dystonic movements, myoclonus, hand stereotypies, and ataxia.…”

“…The patient may present complex hyperkinetic movements, in which chorea-like dyskinesia may be the core movement, but often, associated with dystonic movements, myoclonus, hand stereotypies, and ataxia. 1,4,5,7,8 The presence of those movements is variable, but when present, can be very useful to the diagnosis. 7,8 In this study, we aimed to describe and discuss the complex phenomenology of the movements exhibited by four patients diagnosed with PS.…”