Introduction

PURA syndrome is a rare genetic disorder that affects the nervous system.  Statistics published in 2017 indicate that only around 71 individuals had been diagnosed worldwide at that time.¹ More recent studies suggest that approximately 62 people are currently identified globally, though the actual number is likely higher due to underdiagnosis.²

Background on PURA syndrome 

PURA syndrome is caused by a heterozygous pathogenic variant in the PURA gene. It causes a spectrum of features, including developmental delay, abnormal breathing patterns, seizures, profound hypotonia, and feeding difficulties.³ Although the recurrence risk for parents with one affected child is low, genetic counselling and prenatal or preimplantation genetic testing are recommended, as the risk remains slightly higher than in the general population.⁴

Genetic background

The PURA gene encodes the purine-rich element binding protein A (Pur-alpha). Pur-alpha is a 322-amino acid protein with repeated nucleic acid-binding domains conserved across species.⁵ Pur-alpha plays an essential role in neuronal development, DNA replication, transcription, RNA transport, and translation. It is particularly important in neuronal proliferation, migration, synapse formation, and plasticity.^6,7

This condition is typically not inherited; most cases arise de novo due to a spontaneous mutation in either the egg or sperm.⁸ In these cases, the affected child is usually the first in the family with the condition. However, in rare instances, the condition can be inherited when one parent carries germline mosaicism—meaning the mutation is present in some cells, often limited to reproductive tissue.⁶ When inherited, the disorder follows an autosomal dominant pattern, where a single mutated allele is sufficient to cause disease.

At the molecular level, Pur-alpha binds to purine-rich DNA and RNA sequences, regulating transcription, replication, and translation.⁵

Pathophysiology 

Pur-alpha mutations can contribute to a variety of neurodevelopmental and neurodegenerative disorders, such as Fragile X-associated tremor/ataxia syndrome (FXTAS).⁷ These mutations disrupt gene expression during critical stages of neural maturation, leading to global developmental delay and intellectual disability.

Clinical presentation

PURA syndrome presents a broad spectrum of neurological and physical symptoms that often overlap with other neurodevelopmental conditions such as cerebral palsy, mitochondrial disorders, Rett syndrome, Prader-Willi syndrome, and autism spectrum disorder (ASD).²

Common symptoms may include:⁹

• Hypotonia
• Developmental delay
• Intellectual disabilities
• Seizures
• Feeding difficulties
• Movement disorders

Physical features that may be noticed include hypotonia (low muscle tone), sensitive skin, almond eye openings, and an early onset or delayed puberty.¹⁰

Behavioural characteristics are variable and can include an affectionate and highly social personality, repetitive behaviours such as hand-flapping, hand-biting or sucking, as well as anxiety and episodes of aggression or self-injury.¹¹

Cognitive impairment primarily affects speech and language. Many individuals are non-verbal or use only single words or short phrases. Repetitive language skills tend to be better preserved. Learning difficulties are common, including challenges with handwriting, slow processing speed, and attention deficits.⁶

PURA syndrome: age of onset

During the neonatal period (birth 4 weeks), affected individuals present with hypotonia and feeding difficulties, which can lead to poor weight gain.^1;12 However, during infancy, affected individuals may present global developmental delay and may struggle with motor skills such as rolling over, sitting and crawling.¹³ In the toddler and early childhood stages (1–5 years), delays in language and cognitive development become more apparent, often leading to misdiagnosis with other conditions due to overlapping features.⁶

Early diagnosis and recognition of early features such as hypotonia and developmental delay are crucial. Although PURA syndrome is lifelong and currently incurable, early diagnosis enables supportive management through physical, speech, occupational, and behavioural therapies that improve quality of life.

Challenges in clinical diagnosis

Diagnosing PURA syndrome based on clinical features alone can be problematic because:¹⁴

• Symptoms overlap with other neurodevelopmental conditions
• Not all individuals present all clinical features for accurate diagnosis
• Distinctive facial or structural features are often absent
• Access to advanced genetic testing may be limited, delaying recognition

Roles of healthcare professionals

• Paediatricians: Identify early signs such as hypotonia, delayed milestones, or feeding issues
• Neurologists: Assess seizure activity and tone abnormalities; conduct EEG and neuroimaging
• Geneticists and counsellors: Confirm the diagnosis, explain inheritance patterns, and guide families in management and reproductive decision-making^15,16

Genetic testing

Types of tests used

1. Whole-Exome Sequencing (WES) – The gold standard for diagnosing PURA syndrome. This technique sequences all protein-coding regions in the genome, identifying mutations that may disrupt gene function. In PURA syndrome, WES detects pathogenic deletions or sequence variants in the PURA gene¹⁷
2. Targeted Gene Panels – Pre-designed or custom panels that analyse specific genes associated with neurodevelopmental disorders, including PURA¹⁸
3. Chromosomal Microarray (CMA) – Detects large chromosomal deletions or duplications. Although valuable for identifying structural variants, CMA has limited sensitivity for single-gene mutations like PURA¹⁹

Challenges and limitations

The cost of genetic testing—particularly WES and targeted panels—can be substantial, especially where insurance coverage is limited.²⁰,²¹ In addition, access to these diagnostic tools may be restricted in rural or low-resource settings, resulting in diagnostic delays. The shortage of paediatric neurologists, counsellors, and geneticists further compounds the problem.²² Patients may need to travel long distances to specialised centres, adding emotional and financial strain.

Moreover, due to the rarity of the disorder, awareness remains low among healthcare providers and families, often leading to delayed or missed diagnoses.

Future directions

Although PURA syndrome is rare, research continues to advance understanding and improve outcomes. Genotype–phenotype correlation studies are shedding light on how specific PURA mutations influence clinical severity and symptom variability.

The expansion of newborn genomic screening programmes provides opportunities for earlier detection. As sequencing technologies become more affordable, early diagnosis may help track symptom progression and optimise developmental support.⁶

Conclusions

PURA syndrome is a rare neurodevelopmental disorder caused by mutations in the PURA gene, usually arising de novo. It manifests with developmental delay, seizures, hypotonia, and intellectual disability.²³

Accurate genetic testing is essential for diagnosis, guiding management, and offering families appropriate counselling. However, high costs, limited access, and variability in interpretation remain significant challenges.¹,²³ Despite these barriers, early and precise diagnosis is fundamental for initiating supportive interventions that can improve long-term outcomes.²⁴

FAQs

What is PURA syndrome?

PURA syndrome is a rare genetic neurodevelopmental disorder caused by mutations in the PURA gene. It causes symptoms such as developmental delay, seizures, hypotonia and intellectual disability.²³ 

How common is PURA syndrome?

It is a rare condition. The true prevalence is likely higher due to misdiagnosis and under-recognition.

Is PURA syndrome inherited?

In most cases, it is not inherited but results from a spontaneous mutation. Rarely, it can be inherited if a parent carries the mutation in some of their reproductive cells (mosaicism).

What are the early signs of PURA syndrome?

Key early signs include poor muscle tone (hypotonia), feeding difficulties, delayed motor milestones, and developmental delay.