Expanding the neurodevelopmental phenotype ofPURAsyndrome

Abstract

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals. Congenital apnea was present in 56% during infancy, but all cases in this cohort resolved during the first year of life. Feeding difficulties were frequently reported, with gastrostomy tube placement required in 28%. Epilepsy was present in 50% of the subjects, including infantile spasms and Lennox-Gastaut syndrome. Skeletal complications were found in 39%. Disorders of gastrointestinal motility and nystagmus were also recurrent features. Autism was diagnosed in one individual, potentially expanding the neurodevelopmental phenotype associated with this syndrome. However, we did not find 56 |

Expansion of PURA-Related Phenotypes and Discovery of a Novel PURA Variant: A Case Report

“…At age 20, he is one of the oldest PURA-syndrome patients described, adding important natural history about puberty, growth and development for other similarly affected patients. Short stature has been described previously in PURA syndrome cohorts, 1,6 but to the best of our knowledge has not been as severe as observed in this patient. Delayed puberty was also previously reported in 2 individuals, 6 and is therefore rare in the context of PURA syndrome.…”

“…His phenotypic presentation is similar to previously described patients including neonatal hypotonia, severely delayed psychomotor development, absent speech, early-onset feeding difficulties, seizures, and kyphoscoliosis. 1 – 7 Additional features included short stature, delayed bone age, and delayed puberty which has required testosterone treatment. At age 20, he is one of the oldest PURA-syndrome patients described, adding important natural history about puberty, growth and development for other similarly affected patients.…”

“…Truncating variants downstream of this position have been identified in many individuals with clinical features of PURA-syndrome. 1 , 5 , 7 This variant was reported as pathogenic based on the presence of other truncating pathogenic variants in the literature, the gene’s intolerance to loss of function, the highly specific phenotypic features observed in the proband matching PURA-syndrome, and the absence of other pathogenic or likely pathogenic variants in genes related to the phenotype. Additional in vitro functional studies were not performed.…”

“…PURA-syndrome has been described in 73 individuals to date, with either loss-of-function or missense de novo variation in PURA. 1 – 7 Interestingly, these patients have significant phenotypic overlap with the 5q31.3 microdeletion syndrome, the region within which PURA resides, suggesting that the loss of PURA in the microdeletion syndrome may be the cause of the overlapping phenotypes. 5 , 8 …”

Three Individuals with PURA Syndrome in a Cohort of Patients with Neuromuscular Disease

“…PURA syndrome manifests in a broad phenotypic range with neurodevelopmental delay, dysmorphic features, epilepsy, ataxia, neonatal hypotonia, and feeding difficulties among the most common symptoms. 4 The patients reported here display some of the aforementioned features, yet others, such as epilepsy, were absent. Although cognitive developmental delay and abnormalities in brain MRI are pointing toward central origin of hypotonia, other features described here, such as diminished reflexes, elevated CK levels, and a myopathic electromyogram (EMG) are suggestive of a neuromuscular contribution to the symptoms.…”