PURA syndrome is caused by heterozygous de novo pathogenic variants in PURA. It is characterized by moderate to severe neurodevelopmental disability with a wide clinical spectrum and an evolving phenotype. We present two individuals with genetically confirmed PURA syndrome who had severe neonatal signs and symptoms and a novel phenotype suggestive of neuromuscular junction pathology. We demonstrate that PURA syndrome shares features consistent with a congenital myasthenic syndrome; we thus recommend electrodiagnostic study in neonates and infants with PURA syndrome, and consideration of salbutamol as a therapeutic option.

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 identified 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. We report 2 patients with 5q31.3 microdeletion and 5 with PURA pathogenic variants. They demonstrated hypotonia (7/7, 100%), feeding difficulties (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 walking and verbal responses. Distinctive facial features of open-tented upper vermilion, long philtrum, and anteverted nares and poor visual fixation and tracking with or without nystagmus were most commonly found (5/7, 71.4%). There were no significant 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 difficulties since birth and severe developmental retardation with distinctive facial and ophthalmological features. 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.

Purine-rich element binding protein A (PURA, MIM 600473), is considered the crucial phenocritical gene for an emerging 5q31.3 microdeletion syndrome. To date, at least seven affected individuals with overlapping 5q31.2q31.3 deletions, varying in size from 2.6 to 5 Mb, have been reported sharing neurologic features such as severe developmental delay, neonatal hypotonia, early feeding difficulties, respiratory distress and EEG abnormalities. The recent finding that de novo PURA point mutations are indeed sufficient to cause the severe neurological symptoms also observed in patients with 5q31.2q31.3 deletion further reinforces the gene's causative role in 5q31.3 microdeletion syndrome. The present patient, aged 26 years, is the oldest reported individual and carries the smallest de novo 5q31.2q31.3 microdeletion encompassing PURA (360 kb). Her clinical history summarizes the mainly neurodevelopmental phenotype described in children with 5q31.3 microdeletion syndrome. In addition, our patient exhibited a remarkable deterioration of clinical symptoms, starting at the beginning of adolescence, pubertal delay and primary amenorrhea. While epileptic seizures were successfully treated during her life, feeding problems showed a poor outcome, her respiratory problems increased and eventually became severe enough to cause her death. The clinical and molecular findings reported here provide further evidence that 5q31.3 microdeletion syndrome is a clinically discernible PURA-related disorder and describe the previously unreported natural evolution of the disease in a 26 years old patient.