Introduction to PURA syndrome

PURA syndrome is a rare genetic disorder that causes moderate-to-severe neurodevelopmental delay. The following clinical features may be suggestive of the condition:

• Low muscle tone (hypotonia)
• Excessive daytime sleepiness (hypersomnia)
• Dystonia and dyskinesia
• Feeding difficulties (i.e., gastroesophageal reflux disease)
• Excessive hiccups
• Seizures
• Abnormal vision

Other findings include congenital heart defects, skeletal abnormalities and endocrine disorders.¹

Genetic basis

Genes are the basic units of inheritance because they carry the information that determines the physical and biological traits passed on from your parents, for example, your eye and hair colour.

Normally, we have two copies of the PURA gene, but in PURA syndrome one of these two copies does not function normally. This fault arises upon a genetic mutation to the PURA gene during foetal development, for instance, a deletion within the gene that affects its overall functioning.

The PURA gene encodes for a protein termed ‘pur-alpha’ which plays a role in normal postnatal brain development. Therefore, if the gene is faulty, we see a neurodevelopmental delay and an onset of the clinical features described above.

Understanding seizures

According to the Epilepsy Foundation, seizures are ‘sudden, temporary, bursts of electrical activity in the brain’. These episodes may cause changes in body movement, sensation, behaviour, and awareness. 

Seizure types

Generalised seizures affect both sides of the brain and can be subtyped into 4 categories:

• Tonic-clonic – involves a loss of consciousness and stiffening and jerking of the limbs
• Absence – involves staring with unresponsiveness to external verbal stimuli, and may be accompanied by eye blinking or head nodding
• Myoclonic – involves involuntary muscle contractions with no disturbance of consciousness
• Atonic – involves loss of body tone, often causing the person to fall

The clinical manifestations of focal seizures depend on the area of the brain affected. For instance, if the seizure originates in the occipital lobe, the patient may experience visual phenomena since the occipital lobe is responsible for visual processing.² 

Finally, epileptic spasms are short episodes in which the individual extends or flexes the extremities.³ 

Causes and triggers

The following list is not exhaustive but includes some of the reasons which are known to cause seizures:

• Fever
• Meningitis
• Head injury
• Drug overdose
• Poisoning
• Brain tumour
• Stroke
• Hypoglycaemia
• Low sodium levels in the blood (hyponatremia) 
• Side effects of certain medications (i.e., antidepressants)

Diagnosis and evaluation

Discussion of seizure history usually provides the clinician with sufficient certainty about the seizure type. For example, if the person lost consciousness, this would be highly indicative of a tonic-clonic seizure.

However, if the history is unclear or episodes are unwitnessed, an electroencephalogram (EEG) reading may be used. This procedure records abnormal electrical activity through the placement of electrodes on the head.

Lastly, neuroimaging techniques, such as CT and magnetic resonance imaging (MRI) scans can be used to identify structural abnormalities in the brain that may indicate the cause of the seizures.⁶ 

Relationship between PURA syndrome and seizures

Prevalence

PURA syndrome is a rare disorder; statistics published in 2017 stated that only 71 individuals were known to have PURA syndrome.¹ However, advancements in diagnostic technology mean we can expect many more cases in the future.

Impact on quality of life

PURA syndrome is a lifelong condition with no cure. Many of those affected survive into adulthood provided there are no complications in early life.

Speech is absent in most individuals and many experience seizures and delayed motor development, making it difficult for those with PURA syndrome to live independently. They may be unable to work and will require constant care.

Aside from neurodevelopmental delay, PURA syndrome impacts the body in other ways too. For instance, individuals are at higher risk of skeletal abnormalities, including scoliosis, which may hinder their ability to walk, and congenital heart defects may cause cardiovascular problems.² 

Characteristics of seizures in PURA syndrome

Common seizure types observed in PURA syndrome include tonic-clonic, myoclonic, and epileptic spasms. Some also suffer from a specific type of epilepsy called Lennox-Gastaut syndrome.¹ This is known as an ‘epileptic encephalopathy’ because it is thought that the seizures themselves contribute to cognitive impairment.³ Seizures tend to begin in the first five years of life although onset may be as late as 16 years of age. They are often refractory to drug treatment too.

Diagnosis of PURA syndrome

PURA syndrome is diagnosed using molecular genetic testing approaches, including gene-targeted and genomic testing.

Gene-targeted testing uses a multigene panel to include PURA and other genes of interest. Clinicians need to decide which multigene panel is most likely to identify the genetic cause of the condition while avoiding identifying genes which are irrelevant to the suspected condition.

Genomic testing, such as chromosomal microarray analysis, can help detect PURA syndrome when gene-targeted testing is unable to do so.²

Differential diagnosis

Disorders with similar characteristics include:

• Central hypoventilation syndrome
• Prader-Willi syndrome
• Angelman syndrome
• Rett syndrome
• Pitt-Hopkins syndrome
• Myotonic dystrophy

Treatment approaches

Treatment of PURA syndrome is tailored to the specific symptoms that each individual is presenting with. A multidisciplinary approach is needed and healthcare professionals such as neurologists, geneticists, and paediatricians could all be involved.

Antiepileptic drugs (AEDs)

AEDs treat seizures by decreasing the electrical activity of the brain. Many antiseizure medications have become licensed for use over the years.⁴

First-generation drugs include phenytoin and phenobarbital, which have been in use for over 100 years. Drugs such as carbamazepine, valproate, and clonazepam are classed as second-generation AEDs and were introduced for epilepsy treatment in the 1960s.

Finally, the most recent class of AEDs, otherwise known as third-generation drugs, have been in use since the 1990s. Examples of these drugs include:⁴

• Lamotrigine
• Gabapentin
• Levetiracetam
• Pregabalin
• Topiramate
• Lacosamide
• Perampanel
• Brivaracetam

The benefits of the newer, third-generation AEDs, are that they tend to cause fewer adverse effects and patients find they can better tolerate these drugs, compared to previous-generation drugs.

Certain AEDs are effective for specific seizure types. Clinicians initially prescribe the first-line AED that has proven to be most effective for treating that particular seizure type. If this fails to control the seizures, an alternative drug may be offered or multiple AEDs may be prescribed as add-on therapy.⁴

Non-pharmacological interventions

For patients who fail to respond to AEDs, a ketogenic diet may be recommended. Experiments have shown that the diet generates a hormone called leptin which prevents seizures.

Breathing and meditation techniques, such as yoga, may also be effective for seizure treatment since they aim to restore balance to the nervous system to control seizure frequency.

Some find alternative therapies, including acupuncture, aromatherapy, and stress-reduction techniques, are effective in controlling their seizures too.⁵

Surgical options

For seizures that do not respond to other treatment methods, neurosurgery may be required. Although a risky procedure, it reduces the chance of permanent neurologic deficit caused by seizures and avoids the need for patients to trial various medications repeatedly. Uncontrolled seizures are also associated with an increased long-term mortality rate, such as sudden unexpected death in epilepsy (SUDEP), so surgery may provide an effective solution to minimise this risk.⁶

Challenges and future directions

Research efforts

The PURA Syndrome Foundation states the importance of the ‘PURA Biobank’. This involves collecting bio-samples from patients with PURA syndrome so that research can be undertaken to improve our understanding of the condition’s cellular mechanisms, thereby enabling the development of effective treatment strategies.

The Global Patient Registry is a project that involves collating clinical data from those with PURA syndrome throughout their lifetime. This will allow researchers to consider the entire spectrum of the condition and analyse its natural history too.

Genetic counselling and family support

Genetic counselling includes educating families on the nature, mode of inheritance, and implications of genetic disorders to help them make informed decisions about their health. Genetic counselling is often most appropriate before pregnancy, to inform the parents about the potential risks for their offspring.¹

The PURA Syndrome Global Research Network is formed of medical and non-medical researchers who help educate families and institutions about PURA syndrome.

Emerging therapies and potential breakthroughs

There are three potential therapeutic strategies for PURA syndrome in the future. These are:

Drug repurposing

As the name suggests, this involves screening existing small molecules and drugs for their potential use to treat PURA syndrome. The screening tests whether these drugs improve symptoms in vivo in experimental animal models, and then further trials are carried out to ensure these drug candidates are safe for human use.

Gene replacement

This involves replacing the faulty PURA gene to cure the condition.

Antisense oligonucleotides

Antisense oligonucleotides are used to decrease the expression of the faulty PURA gene and/or increase that of the healthy PURA gene.

These emerging therapies help to drive treatment of PURA syndrome, improve the lives of those with the condition, and ultimately establish a cure.

Summary

• PURA syndrome is a lifelong genetic disorder which can cause seizures, including tonic-clonic, myoclonic, epileptic spasms, and Lennox-Gastaut syndrome.
• Due to the nature of the condition, PURA syndrome is diagnosed using molecular genetic testing.
• The use of antiepileptic drugs (AEDs) is a key part of PURA syndrome treatment. Examples of drugs include valproate, lamotrigine, and levetiracetam.
• The PURA Syndrome Foundation supports ongoing research into the condition. For example, the PURA Biobank and Global Patient Registry.
• Genetic counselling helps to support families who are at risk of the condition.