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

Mroczek, Magdalena; Zafeiriou, Dimitrios; Gurgel-Gianetti, Juliana; Azevedo, Beatriz Vilela Morais; Roos, Andreas; Bartels, Enrika; Kohlschmidt, Nicolai; Phadke, Rahul; Feng, Lucy; Duff, Jennifer; Töpf, Ana; Straub, Volker

doi:10.1055/s-0040-1715625

Cited by 7 publications

(10 citation statements)

References 8 publications

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“…Indeed, two recent case studies support a muscular contribution to the symptoms. Whereas the first study reported a PURA-syndrome patient with electrical myotonia with hypotonia as clinical symptom (Trau and Pizoli, 2020), the second study provides direct evidence for myopathic changes, including fiber size variability and fast fiber atrophy as main features (Mroczek et al, 2020).…”

Section: The Neurodevelopmental Disorder Pura Syndromementioning

confidence: 99%

The Molecular Function of PURA and Its Implications in Neurological Diseases

et al. 2021

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In recent years, genome-wide analyses of patients have resulted in the identification of a number of neurodevelopmental disorders. Several of them are caused by mutations in genes that encode for RNA-binding proteins. One of these genes is PURA, for which in 2014 mutations have been shown to cause the neurodevelopmental disorder PURA syndrome. Besides intellectual disability (ID), patients develop a variety of symptoms, including hypotonia, metabolic abnormalities as well as epileptic seizures. This review aims to provide a comprehensive assessment of research of the last 30 years on PURA and its recently discovered involvement in neuropathological abnormalities. Being a DNA- and RNA-binding protein, PURA has been implicated in transcriptional control as well as in cytoplasmic RNA localization. Molecular interactions are described and rated according to their validation state as physiological targets. This information will be put into perspective with available structural and biophysical insights on PURA’s molecular functions. Two different knock-out mouse models have been reported with partially contradicting observations. They are compared and put into context with cell biological observations and patient-derived information. In addition to PURA syndrome, the PURA protein has been found in pathological, RNA-containing foci of patients with the RNA-repeat expansion diseases such as fragile X-associated tremor ataxia syndrome (FXTAS) and amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD) spectrum disorder. We discuss the potential role of PURA in these neurodegenerative disorders and existing evidence that PURA might act as a neuroprotective factor. In summary, this review aims at informing researchers as well as clinicians on our current knowledge of PURA’s molecular and cellular functions as well as its implications in very different neuronal disorders.

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Section: The Neurodevelopmental Disorder Pura Syndromementioning

confidence: 99%

The Molecular Function of PURA and Its Implications in Neurological Diseases

et al. 2021

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“…We included altogether 193 PURA-related neurodevelopmental disorder (PURA-NDD) patients; among them, 10 with 5q31.3 microdeletion syndrome and 183 with point variants in PURA locus only from 27 studies [6][7][8][9][34][35][36][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57]. The biggest study contained 67 participants, and there were 17 single case reports included.…”

Section: Resultsmentioning

confidence: 99%

“…These children were tested at the first instance for SMA in the neonatal period but resulted negative. There were no elicitable DTRs, and respiratory insufficiency requiring artificial ventilation at birth or shortly after birth has been reported [51]. In the case of one patient ([39], p. 25; [38], p. 2-the same patient described twice), the weakness was reported as proximally pronounced instead of usually described generalized weakness.…”

Section: Motor and Neuromuscular Symptoms In Pura Syndromementioning

confidence: 99%

“…However, the neuromuscular and synaptic weakness have been more appreciated recently (Figure 2). Especially, in a few cases, the weakness has been described as very severe (paralytic) (e.g., [51], p. 2, [34]). These children were tested at the first instance for SMA in the neonatal period but resulted negative.…”

Section: Motor and Neuromuscular Symptoms In Pura Syndromementioning

confidence: 99%

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

Mroczek

Iyadurai

2023

IJMS

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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.

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“…In fact, a muscle component to the symptoms is supported by two recent case studies. In contrast to the first study, which described a patient with PURA syndrome who had electrical myotonia with hypotonia as a clinical manifestation (Trau & Pizoli, 2020), the second study offers a concrete proof of myopathic alterations, with the major characteristics of variable fiber size and rapid fiber atrophy (Mroczek et al, 2021). The electroneuromyogram (ENMG) in our patient showed the presence of a myogenic pattern at the detection with normal PNS exploration, which translates into a primary affection of the muscle fibers, characterized clinically by the association of a loss of strength, with a feeling of weakness, a modification of muscle volume, and abnormal contraction or relaxation.…”

Section: Discussionmentioning

confidence: 98%

A new case with the recurrent PURA p.(Phe233del) pathogenic variant: Expansion of the phenotype and review of the literature

Ben Issa,

Ben Ayed,

Jallouli

et al. 2023

Intl J of Devlp Neuroscience

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In the process of neuronal development, the protein Purα (encoded by the PURA gene) is essential for neuronal proliferation, dendritic maturation, and the transportation of mRNA to translation sites. Mutations in the PURA gene may alter normal brain development and impair neuronal function, contributing to developmental delays and seizures. Recently, PURA syndrome is described as developmental encephalopathy with or without epilepsy, neonatal hypotonia, feeding difficulties, global developmental delay, and severe intellectual disability. In our study, we aimed to perform a genetic analysis by whole exome sequencing (WES) in a Tunisian patient presented with developmental and epileptic encephalopathy to provide a molecular explanation for the developed phenotype. We collected, also, clinical data of all PURA p.(Phe233del) patients reported yet and compared the clinical features with those of our patient. Results revealed the presence of the known PURA c.697_699del, p.(Phe233del) variant. Our studied case shares some clinical features including hypotonia, feeding difficulties, severe developmental delay, epilepsy, and language delay (nonverbal) but presents a radiological finding undescribed before. Our finding defines and expands the phenotypic and genotypic spectrum of the PURA syndrome supporting the absence of reliable genotype–phenotype correlations and the existence of a highly variable, wide‐ranging clinical spectrum.

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

Cited by 7 publications

References 8 publications

The Molecular Function of PURA and Its Implications in Neurological Diseases

The Molecular Function of PURA and Its Implications in Neurological Diseases

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

A new case with the recurrent PURA p.(Phe233del) pathogenic variant: Expansion of the phenotype and review of the literature

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