Written by members of the PURA Syndrome Global Research Network.
*For more information and how you can help, visit http://www.purasyndrome.org*
What is PURA syndrome?
PURA syndrome is a rare genetic disorder. The PURA gene is located on the long arm of chromosome 5 (at position 5q31.2). PURA syndrome occurs when one of a person’s two copies of the PURA gene does not function normally. This can be caused by a spelling mistake in the gene or by loss of one copy of the gene (a whole gene deletion). Genes are instructions, which have important roles in our growth and development. They are made of DNA and are incorporated along with many other genes into organised structures called chromosomes.
The PURA gene has a number of different roles. It encodes for a protein, pur-alpha, that is expressed in all tissues, including the brain, muscle, heart, and blood. The protein has a number of different roles in the human cell, including regulatory functions in DNA replication, transcription and translation of mRNA, and is known to be particularly important in brain development. This is why problems with the PURA gene are primarily associated with a neurodevelopmental disorder.
Most common features
All children with PURA syndrome who have been identified to date have at least a moderate to severe degree of learning disability and developmental delay. Other typical features include:
Seizures and seizure-like abnormal movements
Hypotonia (Low muscle tone)
Respiratory problems (including obstructive and central apneas)
Hypersomnolence (excessive sleepiness)
Orthopedic issues including hip dysplasia and scoliosis
Endocrine disorders such as Vitamin D deficiency
How many people have this condition?
PURA syndrome is a rare condition, first described in the medical literature in 2014. To date, just over 250 individuals have been reported with this condition, both adults and children. However, with the increasing use of the latest ‘gene sequencing’ technology, it is expected that many more people will be diagnosed with this condition over the next few years.
Why did this happen?
When children are conceived their parents’ genetic material is copied in the egg and sperm that makes a new child. The biological copying method is not perfect and occasionally random, rare changes occur for the first time. Such changes, therefore, cannot be found in a child’s parents. In almost all of the families that we know about so far, the DNA change in PURA occurred ‘out of the blue’ in this way (this is what you may hear a geneticist referring to as a de novo change).
Can it happen again?
Provided that neither parent is found to carry the same PURA change as their child, the chance of having another child with the same genetic change would be considered extremely low. Empirically, this risk would be considered less than 1%.
The reason why there is some residual risk of recurrence is due to a rare phenomenon called ‘gonadal mosaicism’. This is when a parent carries a genetic change, but it is limited to a small cluster of egg or sperm cells. The genetic change would not, therefore, be detected on this parent’s blood test. For specific advice about the chance of this happening again, it would be sensible to speak to a clinical geneticist or genetic counsellor.
Development and Learning
Babies with PURA syndrome are usually born at a normal weight and grow appropriately.
Sitting, moving, walking
All children have delayed motor development and most do not achieve independent walking. Those who do manage to walk independently tend to have an unsteady, wide-based gait.
Almost all patients with PURA syndrome do not develop meaningful speech. Those who do develop speech may achieve single words, short phrases or rarely basic sentences.
Parents have reported good receptive language skills (understanding of spoken language) in non-verbal children with PURA syndrome. Devices to enable and encourage expressive communication, such as symbol-based touch screen communication devices and eye gaze devices, may be of benefit to some children.
All individuals that we know of have moderate to profound learning disability and require specialist support with learning.
Individuals with PURA syndrome typically have behaviour in keeping with their overall degree of developmental delay.
Low muscle tone
Low muscle tone (hypotonia) is most obvious in the newborn period and may persist throughout childhood and adulthood. This is likely to contribute to feeding difficulties, breathing problems and delay in reaching motor milestones.
Feeding difficulties are typical in newborn babies. Many babies with PURA syndrome ultimately require temporary feeding by nasogastric tube. A minority require gastrostomy feeding because of swallowing problems. In many children, feeding difficulties may persist.
Respiratory difficulties are common to most children, and usually become apparent in the newborn period. These may include central apnoea (in which the brain does not control breathing properly) and obstructive sleep apnoea (in which the upper airway becomes blocked due to low muscle tone during sleep). Tracheostomies (an opening in the neck to put in a tube to help breathing) have been required by some children.
Almost all children with PURA syndrome have seizures or seizure-like episodes warranting further investigation at some point in early childhood. Different patterns of seizures have been reported, but myoclonic jerks and generalised tonic- clonic seizures are most common. In some cases, seizures have proved extremely difficult to manage with standard anti-epileptic drugs.
Eyes and eyesight
A wide range of eye and eyesight problems have been reported. These include – but are not limited to – short-sightedness, squint, and abnormal eye movements. Most children are affected in some way.
There is some evidence that endocrine dysfunction (especially of the anterior pituitary gland) may represent a less common part of PURA syndrome. More research is needed to also investigate hormonal issues related to puberty.
Reduced bone density
Reduced bone density (known as osteoporosis) has been identified in a small number of patients. Problems in maintaining vitamin D levels, which has an important role in regulating bone density, are not uncommon.
Some children have abnormal findings on their brain imaging. This can include ‘delayed myelination’, which refers to a delay in the normal formation of the white matter in the brain and spinal cord.