Overview

PURA syndrome is a highly uncommon genetic disorder that affects the nervous system. It is characterised by moderate to severe developmental delays, learning disabilities, seizures and seizure-like movements, hypotonia (muscle weakness), challenges in regulating body temperature, abnormal vision, breathing problems, and other health issues.  

PURA syndrome was first described in 2014.¹ It occurs when one of the two copies of the PURA gene, located on chromosome 5, contains a de novo (new) pathogenic mutation (leading to an increased risk for a specific disease or condition)., This is known as a heterozygous (having two different copies of the gene in question) pathogenic mutation.¹ It can also be caused by a loss of a whole gene copy or a small insertion or deletion within the gene.²  

What does the PURA gene do?

The human PURA gene is located on the long arm of chromosome 5. Being both a DNA- and RNA-binding protein, PURA is involved in transcription (in which the cell copies the DNA into its RNA form) and localisation of RNA in the cytoplasm (liquid component inside the cell).

Research shows that PURA-knockout mice, (mice lacking the PURA gene) die shortly after birth, and the absence of this gene impacts both brain function and blood cell production. ³

The loss of a small portion of genetic material within the human PURA gene (microdeletion) has been linked to various neurological disorders. While specific traits can differ among affected individuals, common features of PURA microdeletion include: delays in neurodevelopment, learning disabilities, low muscle tone (hypotonia), early feeding challenges, speech impairments, walking difficulties, and seizure-like movements. ²

 In addition to PURA syndrome, the Pura protein has been implicated in various other brain diseases such as Fragile X Syndrome and a familial form of Amyotrophic Lateral Sclerosis/ Frontotemporal Dementia. In these diseases, a specific sequence known as the nucleic acid G-rich Pura binding element is repeated multiple times, constituting a distinctive shared feature.¹,^4,5

How common is PURA syndrome?

To date, according to the PURA Syndrome Foundation, there are over 500 individuals with PURA Syndrome worldwide. However, because modern genomic tests are becoming more affordable, it is likely that hundreds more people are expected to be diagnosed with PURA syndrome in the coming years.

What is the life expectancy for someone with PURA syndrome?

Unlike some of the more well-known degenerative disorders of the brain and nervous system, PURA syndrome is not classed with these conditions but is categorised as a neurodevelopmental disorder. Survival into adulthood is likely unless illness or other complications cause an earlier death. As more people are diagnosed, more information about the natural course and progression of the disease will emerge. This information is compiled specifically from the Global Patient Registry

Symptoms⁶

Newborns with PURA syndrome

• Often experience trouble with breathing or feeding: they may need respiratory support in the form of a breathing tube and ventilator. These problems usually do not last after age one 
• May have longer-lasting (chronic) feeding or swallowing difficulties (dysphagia) that are still noticeable beyond the age of one

Older children with PURA syndrome often

• Have difficulties walking properly and have poor motor skills
• Are unable to speak but can usually understand spoken words
• If speaking is possible then they typically only use two or three-word phrases to communicate.
• Epilepsy (seizures) or movements resembling seizures are a common symptom.
  • Usually:
    • Uncontrolled muscle twitching is the first sign and begins between the ages of one and four
    • Seizure control may be difficult to achieve even with treatment. 
    • Lennox-Gastaut syndrome (a severe form of epilepsy) may eventually be diagnosed

Other common symptoms may include

• Problems of the skeleton including bone and joint problems: this may include dislocated hips (hip dysplasia) and a curved spine (scoliosis)
• Challenges with breathing: including temporary pauses in breathing during sleep (sleep apnoea) or the inability to breathe deeply enough and at a normal rate (hypoventilation)
• Inability to regulate and maintain a normal body temperature - usually running a low temperature (hypothermia)
• Abnormally increased sleepiness (hypersomnia)
• Eye problems including the inability to look in the same direction simultaneously (crossed eyes  or strabismus)
• Slowed movement of food and stool through the gastrointestinal tract (constipation)
• Loss of coordination while walking (gait disorder)
• Floppy muscles and unable to provide good support while sitting or standing (hypotonia)

 Difficulty with visual clarity and acuity

•  Hiccups which happen more than would be expected for a normal child 

Infrequent symptoms include

•  Changes in the structure or function of the heart
• Changes in hormone levels from the expected values: including deficiencies in vitamins (such as vitamin D) or an earlier-than-expected onset of puberty
• Deformities in the kidneys and genitals including kidney stones, urine backing up from the bladder to the kidneys, swollen kidneys because of the urine back-up (hydronephrosis), undescended testicles, or a prolapsed uterus²

Diagnosis

How is PURA syndrome diagnosed?

PURA syndrome diagnosis involves Whole Genome Sequencing (WGS) using a blood or saliva sample collected from the affected child. In some instances, parents may also be tested.

Management and treatment

Is there a cure for PURA syndrome?

There is no cure for PURA syndrome, however, early intervention is important as it can help reduce the risk of some complications, such as scoliosis. Management and treatment strategies should be discussed between the family and the healthcare team. Children are able to enjoy a more normal quality of life when the right treatments and supportive care are given.

After being diagnosed, it's recommended for children to receive regular care from a team of specialists. This team, consisting of healthcare professionals from various specialities, collaborate to provide optimal treatment to children with PURA syndrome. The care team may include the following specialists:

• Paediatrician - to provide general care and care coordination
• Physiotherapist - to help the child learn how to move with any bone, joint, or muscle deformities
• Pulmonologist - to monitor breathing and make sure that breathing is effective, especially at night 
• Ophthalmologist - to ensure that eye health is maintained 
• Geneticist - to discuss the genetic implications of PURA syndrome on the child with the family and provide information regarding future pregnancy risk
• Neurologist - to monitor and treat neurological symptoms including seizures
• Occupational therapist - to teach parents and the child different techniques and tools they can use to make daily tasks easier to complete
• Orthopaedic surgeon - to provide care for any skeletal deformities
• Speech-language pathologist- to help with speech and language skills

How is PURA syndrome treated?

Treatment approaches may vary depending on the child's symptoms and severity. Newborns with PURA syndrome usually need treatment in the hospital including specialised monitoring, breathing support, and feeding care.

For older children, treatment may involve:

• Speech therapy to help them become more comfortable and clear with speaking and communication
• Physiotherapy to improve their ability to move and optimise their range of motion
• Surgery, if needed, to correct birth defects in the heart, bones or elsewhere

The child may also receive:

• Medications to help control any seizure symptoms
• Special tools to help aid in effective communication
• Specialised feeding devices to promote safe feeding and support to promote safe swallowing
• Targeted therapy to improve speech skills
• Therapy to help with movement and the ability to complete normal daily tasks

Assistive devices such as leg braces, walkers, or wheelchairs

Summary

PURA syndrome is an exceptionally rare genetic disorder that affects neurodevelopment, resulting in severe mental and physical disabilities and developmental delays. While recurrent seizures are common treatments can help in symptom management and improve quality of life. Treatment typically requires a team effort, including therapies such as speech and physical therapy, and may include surgeries to correct skeletal or other anatomical problems. While there is currently no cure, early intervention and comprehensive care can improve the quality of life for individuals with PURA syndrome.