Overview   

PURA syndrome is a very rare genetic condition, affecting about 650 people around the world. PURA syndrome affects the growth of the brain which causes severe developmental delays, intellectual and learning disabilities, epilepsy, and other health complications. Developmental delays occur when children reach developmental milestones like sitting, walking, and speaking  later than other children of the same age. 

Signs and symptoms can be seen early in patients, sometimes from birth, so a prompt diagnosis improves health outcomes and quality of life for the patients. With a clear diagnosis, parents, caregivers, and the team of health professionals involved can closely monitor the child's development, intervene, and provide the appropriate support to ensure the best possible outcomes.^1,2 

Understanding PURA syndrome  

Genetic basis and inheritance pattern

PURA syndrome is caused by the absence of one copy of the PURA gene pair, which is found on chromosome 5 inside the person’s DNA. The missing genetic information (known as a deletion) affects the function of Pur-α (purine-rich element binding protein A), a protein found in the body that is important for normal brain development. This is why PURA syndrome affects the development of the child and causes various delays in skill acquisition.^3,4 

PURA syndrome occurs “de novo” in a child, meaning that the DNA mutation occurs randomly and the child did not inherit the disorder from their parents. However, parents may have some genetic errors, but these are limited to the reproductive cells. This is called “gonadal mosaicism”, and this means that if they already have a child with PURA syndrome, there is around a 1% risk that their next child would also have the condition. 

Are PURA syndrome and 5q31.3 deletion syndrome the same thing? 

The missing information from chromosome 5 can be limited to the PURA gene; in this case, the patient has PURA syndrome. However, when the deletion includes the PURA gene and other genes nearby, the patient has 5q31.3 deletion syndrome. 

These two conditions share overlapping clinical symptoms, but 5q31.3 deletion syndrome is more severe. Studies show that PURA deletion contributes somewhat to the cause of 5q31.3 deletion syndrome, which is responsible for developmental delay, seizures, and hypotonia.^2,3,4   

Clinical signs and symptoms 

Neurological manifestations and developmental delays

PURA syndrome is a neurodevelopmental disorder that primarily affects brain development, function, and structure, often showing abnormalities on MRI scans.¹ The patients have moderate to severe intellectual disability, global developmental delays, and epilepsy. Developmental delays, particularly in motor skills (e.g., sitting, crawling, or walking), are severe and can be detected early in children. 

Patients often have significant learning and language disabilities, with some of them being unable to speak. Around 60% of patients suffer from epilepsy with focal or generalised seizures that do not respond to medication. Developing Lennox-Gastaut or West syndrome is also possible. Sometimes doctors call it developmental and epileptic encephalopathy (DEEs). 

Affected children’s already achieved skills may regress, caused by the onset of seizures. Patients may exhibit an exaggerated response to sounds, which is called an “acoustic startle response”. Hypotonia (low muscle tone) is very common and present from birth, negatively impacting the child’s development.^1,3,5  

Growth, physical, and other characteristics

PURA syndrome affects many systems in the body beginning from the newborn period. Newborns often have feeding and breathing difficulties with possible complications that may require gastrointestinal tube feeding, mechanical ventilation, or oxygen administration. In addition to hypotonia, affected newborns struggle to maintain their body temperature (hypothermia), and are very sleepy (hypersomnolence). 

Patients may experience gastrointestinal problems such as difficulty swallowing, drooling, and constipation. The eyes, bones, urinary system, and even the heart can also be affected. Moreso, abnormal movements and movement disorders have been reported. Doctors may also identify particular facial characteristics when diagnosing PURA syndrome, known as “facial dysmorphism”.^1,3 

Developmental delays in PURA syndrome 

Developmental milestones 

Developmental delays are severe, and common in all patients with PURA syndrome. A study on DEEs associated with PURA syndrome presented the average age of their patients’ when they reached developmental milestones. Patients achieved head control at around 16 months, sitting at around 17 months, and independent walking at about 5 years. 

Other studies reported patients reaching their first steps between 2 and 7 years while others reported some individuals never achieved independent walking. Some patients also lost their ability to walk, after initially achieving it.^1,2,6

Movement problems and delays

Besides epilepsy, some patients also have abnormal non-epileptic movements, which affect their motor skills, coordination, and balance. The problems associated with movement negatively impact the child’s development, and are known as ataxia, hand stereotypies, dyskinesia, and “chorea-like” movements. The patient’s eyes can also be affected by abnormal movements known as “disconjugated eye movements”.^1,5,6

Cognitive delays and intellectual disability

PURA syndrome affects the brain’s development and structure, causing significant cognitive delays (delays involving memory, attention, learning, and problem-solving) that lead to moderate to severe intellectual disability. MRI scans may reveal structural changes in the brain that possibly contribute to mental disability.^1,2,8,9 

Language delays

PURA syndrome majorly impacts speech development, and some patients are not able to speak. In some cases, they can have a limited vocabulary, gaining the ability to use some words, and even form short sentences. Communication is very difficult, but they can have a good understanding of what they are being told and can follow instructions.^1,2,6 

Diagnosis

Clinical evaluation and assessment of developmental delays

PURA syndrome is difficult to diagnose. A child born post-term, presenting with hypotonia, feeding and respiratory difficulties, difficulty regulating body temperature, and excessive sleepiness should be suspected of having PURA syndrome. However, these symptoms are not specific to PURA syndrome and genetic testing is necessary as many other conditions need to be taken into consideration when dealing with a newborn with these symptoms.² 

Besides paediatric clinical examination, the patient may need to have: 

• Genetic consultations 
• Feeding and respiratory evaluations 
• EEG test
• MRI scan
• Eye tests 
• Kidney tests
• Heart tests
• Bone tests 

The doctor will conduct a developmental assessment, to see if the baby reached the normal developmental milestones expected by a certain age, and note if they have a delay regarding motor, sensory, thinking, language, and social skills.^1,4 

Genetic testing 

A diagnosis of PURA syndrome cannot be confirmed without a genetic test. The technology is called next generation sequencing (NGS) which is used for whole exome (WES) and whole genome sequencing (WGS), or chromosomal microarray technologies (arrayCGH). 

When making a differential diagnosis between more genetic syndromes with similar characteristics related to neurodevelopmental disorders or epilepsy, specific “gene panels” are chosen.^3,6,8

Management and treatment of developmental delays 

Multidisciplinary approach

Patients suffering from PURA syndrome require complex and prompt care. A team of healthcare professionals must work together to ensure they attend to the patient’s needs and health complications, providing the support needed.^1,2,5 

 These healthcare professionals can include:

• Paediatrician 
• Geneticist 
• Child neurologist 
• Ophthalmologist 
• Pulmonologist 
• Gastroenterologist 
• Surgeon 
• Physiotherapist
• Speech and language therapist

Therapeutic interventions   

Epilepsy treatment 

Seizures are a significant neurological problem in patients that can worsen developmental delay by causing the loss of already achieved skills. Epilepsy requires medication - though the best drug options for PURA syndrome are yet unknown, and seizures can be unresponsive to treatment. In some cases, epilepsy medication works, reducing or even stopping the seizures.^1,2,6

Feeding and respiratory difficulties

Newborns affected by PURA syndrome may require feeding and breathing support. A gastroenterologist should be consulted for feeding difficulties and other gastrointestinal problems, such as gastroesophageal reflux disease (GORD), dysphagia, drooling, and constipation. The pulmonologist should be consulted for breathing problems, such as hypoventilation, apnoea, or aspiration pneumonia.^4,6

Physical and occupational therapy

Physical therapy improves mobility for PURA patients. Even if they do not achieve independent walking, they can use strollers, wheelchairs, or walkers as needed. Physical therapy can also prevent further complications such as scoliosis or hip problems. 

Occupational therapy helps patients improve their motor skills, which are useful in everyday life and self-care.⁶

Speech and language therapy

A speech and language therapist can help patients improve their communication skills, according to their level of speech development. 

Although they struggle to express themselves, they have a good understanding of what they are being told, so augmentative and alternative communication therapy can improve their communication skills.^1,2,6

Prognosis and outlook 

PURA syndrome is a lifelong disorder and currently has no cure. Even though affected patients have moderate to severe developmental delays, there are options to treat complications and ways to intervene. The prognosis depends on the severity of the delays and complications, but developmental progress can be achieved with the appropriate help. 

PURA syndrome has recently been discovered and requires further research on its characteristics, treatment options, prognosis, and life expectancy. As more people are diagnosed, more information about the syndrome will become available. Studies need to further explore the role of the PURA gene beyond the brain cells, to unveil how the syndrome affects the whole body.⁸

Summary

PURA syndrome causes significant developmental delays. The problem with the PURA gene has an impact primarily on the brain, but also on other parts of the body. Thus, managing the condition requires a team of healthcare professionals to be involved in the treatment and care of the patient. If a case is detected early, correctly diagnosed, and prompt intervention is given, this will improve the prognosis, overall health outcomes, and quality of life for the patients and their families. Further research, therapies, treatment options, increased awareness, and more support from organisations are needed to ensure the best possible care for a patient with PURA syndrome.