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Expanding the neurodevelopmental phenotype of PURA syndrome.

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 additional PURA sequence variations in a cohort of 120 subjects with autism. We also present the first neuropathologic studies of PURA syndrome, and describe chronic inflammatory changes around the arterioles within the deep white matter. We did not find significant correlations between mutational class and severity, nor between location of the sequence variation in PUR repeat domains. Further studies are required in larger cohorts of subjects with PURA syndrome to clarify these genotype-phenotype associations.

SUBMITTER: Lee BH

PROVIDER: S-EPMC5821266 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Expanding the neurodevelopmental phenotype of PURA syndrome.

Lee Bo Hoon BH Reijnders Margot R F MRF Abubakare Oluwatobi O Tuttle Emily E Lape Brynn B Minks Kelly Q KQ Stodgell Christopher C Bennetto Loisa L Kwon Jennifer J Fong Chin-To CT Gripp Karen W KW Marsh Eric D ED Smith Wendy E WE Huq Ahm M AM Coury Stephanie A SA Tan Wen-Hann WH Solis Orestes O Mehta Rupal I RI Leventer Richard J RJ Baralle Diana D Hunt David D Paciorkowski Alex R AR

American journal of medical genetics. Part A 20171117 1

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, bu ...[more]

PMID: 29150892

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Project description:BackgroundPURA syndrome is rare autosomal dominant condition characterized by moderate to severe neurodevelopmental delay with absence of speech in nearly all patients and lack of independent ambulation in many. Early-onset problems include excessive hiccups, hypotonia, hypersomnolence, hypothermia, feeding difficulties, recurrent apneas, epileptic seizures, and abnormal nonepileptic movements. Other less common manifestations comprise congenital heart defects, urogenital malformations, and various skeletal, ophthalmological, gastrointestinal, and endocrine anomalies. Up to now, 78 individuals with PURA syndrome and 64 different pathogenic variants have been reported, but no clear-cut genotype-phenotype correlations have emerged so far. Herein, we report the clinical and molecular characterization of a 3-year-old girl with severe hypotonia, global developmental delay, and soft, loose skin, who came to our attention with a suspicion of cutis laxa (CL), which denotes another condition with variable neurodevelopmental problems.MethodsAmplicon-based whole exome sequencing was performed, and an in-house pipeline was used to conduct filtering and prioritization of variants. New prediction algorithms for indels were used to validate the pathogenicity of the PURA variant, and results were confirmed with the Sanger method. Finally, we collected clinical and mutational data of all PURA syndrome patients reported yet and compared the clinical features with those of our patient.ResultsClinical evaluation and biochemical investigations excluded CL and prompted to perform whole exome sequencing, which confirmed the absence of pathogenic variants in all CL-related genes and revealed the known PURA c.697_699del, p.(Phe233del) variant, identified hitherto in seven additional children with PURA syndrome.ConclusionsOur data expand the phenotypic spectrum of PURA syndrome by showing that it can be regarded as a differential diagnosis for cutis laxa in early infancy. Our patient and literature review emphasize that a wide clinical variability exists not only between individuals with different PURA variants, but also among patients with the same causal mutation.

Project description:BackgroundDe novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.ObjectivesTo delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.MethodsDiagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.ResultsWe report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.ConclusionWe delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

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Expanding the neurodevelopmental phenotype of PURA syndrome.

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Expanding the neurodevelopmental phenotype of PURA syndrome.

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