Neuromuscular and Neuromuscular Junction Manifestations of the PURA-NDD: A Systematic Review of the Reported Symptoms and Potential Treatment Options

Abstract

PURA-related neurodevelopmental disorders (PURA-NDDs) are a rare genetic disease caused by pathogenic autosomal dominant variants in the PURA gene or a deletion encompassing the PURA gene. PURA-NDD is clinically characterized by neurodevelopmental delay, learning disability, neonatal hypotonia, feeding difficulties, abnormal movements, and epilepsy. It is generally considered to be central nervous system disorders, with generalized weakness, associated hypotonia, cognitive and development deficits in early development, and seizures in late stages. Although it is classified predominantly as a central nervous syndrome disorder, some phenotypic features, such as myopathic facies, respiratory insufficiency of muscle origin, and myopathic features on muscle biopsy and electrodiagnostic evaluation, point to a peripheral (neuromuscular) source of weakness. Patients with PURA-NDD have been increasingly identified in exome-sequenced cohorts of patients with neuromuscular- and congenital myasthenic syndrome-like phenotypes. Recently, fluctuating weakness noted in a PURA-NDD patient, accompanied by repetitive nerve stimulation abnormalities, suggested the disease to be a channelopathy and, more specifically, a neuromuscular junction disorder. Treatment with pyridostigmine or salbutamol led to clinical improvement of neuromuscular function in two reported cases. The goal of this systematic retrospective review is to highlight the motor symptoms of PURA-NDD, to further describe the neuromuscular phenotype, and to emphasize the role of potential treatment opportunities of the neuromuscular phenotype in the setting of the potential role of PURA protein in the neuromuscular junction and the muscles.

Heterozygous c.175C>T variant in PURA gene causes severe developmental delay

“…There is no effective FDA‐approved drug for PURA‐NDDs. However, pyridostigmine may be effective for the muscular/neuromuscular junction presentation observed in PURA‐NDDs because this drug inhibits the action of acetylcholinesterase and is generally used for symptomatic treatment in patients with myasthenia gravis 7,28 . Moreover, salbutamol, fluoxetine, and 4‐aminopyridine should also be considered as a treatment for specific symptoms associated with PURA‐NDDs 7 …”

“… 7 , 28 Moreover, salbutamol, fluoxetine, and 4‐aminopyridine should also be considered as a treatment for specific symptoms associated with PURA‐NDDs. 7 …”

“…[4][5][6] Consistently, PURA-related neurodevelopmental disorders (PURA-NDDs) have been defined, that is, neurodevelopmental disorders associated with variants and deletions encompassing PURA. 7 This classification also includes the PURA syndrome, which can be caused by pathogenic variants of PURA in addition to the 5q31.3 microdeletion syndrome. 8 Symptoms of PURA-NDDs include dysmorphic facial features, hypotonia, movement disorders, impaired intelligence, epilepsy, and brain abnormalities.…”

“… 4 , 5 , 6 Consistently, PURA ‐related neurodevelopmental disorders (PURA‐NDDs) have been defined, that is, neurodevelopmental disorders associated with variants and deletions encompassing PURA . 7 This classification also includes the PURA syndrome, which can be caused by pathogenic variants of PURA in addition to the 5q31.3 microdeletion syndrome. 8 …”

PURA and GLUT1: Sweet partners for brain health

“…Here, it binds to anomalous RNAs, serving a protective role against neurotoxicity. The advent of next-generation sequencing and high-throughput genetic technologies in clinical practice has led to increased identification of patients with PURA syndrome [26][27][28][29][30][31][32][33][34][35]. PURA syndrome, a rare genetic condition resulting from mutations in the PURA gene, manifests as a spectrum of clinical features, mainly neurological, including developmental delay, hypotonia, breathing difficulties, pituitary dysfunction, and seizures [26][27][28][29][30][31][32][33][34][35].…”