Introduction

Definition of pura syndrome

Pura syndrome is a rare genetic disorder that affects neurodevelopment.¹ It can cause mild to moderate developmental delay, including physical and learning disabilities.² Pura syndrome is caused by a genetic mutation within the PURA gene which codes for the Pur-Alpha protein that is crucial for DNA replication.³ When this gene is mutated, neurodevelopmental disorder arises, which often leads to movement difficulties, breathing difficulties, seizures, and intellectual disability impairment.² 

Rarity and prevalence

Pura syndrome was first described in 2014 and is named after the PURA gene where the mutation occurs.² Pura syndrome is a disease affecting the nervous system that is present at birth.² It is a rare condition that has affected more than 500 individuals around the world including both adults and children.⁴ However, due to the improvement in genetic testing and them becoming cheaper and more accessible, there is an expected increase in patients with Pura syndrome in the coming years.⁴ 

Genetic basis

Overview of genetic mutations

In humans, there are four nucleotide bases that make up the building blocks of DNA. they are: 

1. Adenine (A)
2. Cytosine (C)
3. Guanine (G)
4. Thymine (T)

These 4 bases are paired up (A and T, C and G), together to form a DNA sequence that codes for the cells to produce proteins which are essential for cell function and survival.⁵ DNA is an essential molecule produced in living cells as it contains instructions for the cell to survive. A complete, undamaged DNA sequence is crucial for normal development and for an individual to survive without medical complications.⁵ Within each cell are two copies of genes, each inherited from one parent. 

Genetic mutations are changes in the DNA sequences, which leads to changes in the nucleic acids.⁶  Mutations can occur from:

• Errors during DNA replication (when the cell is dividing)
• Mutagen exposure (chemicals, UV radiation, smoking)
• Viral infection

Mutations lead to changes in the human genome sequence, where even a single nucleotide change can cause a genetic disorder an individual will have to live with.⁷ There are also different types of mutations:

1. Insertion or deletion: where a nucleotide is added or removed to the DNA sequences, causing a frameshift.⁵ To make proteins, three nucleotide bases are “read", and this is called a codon. When a nucleotide is added or removed, the reading is shifted, leading to an incomplete form of protein or a completely new protein being formed.⁸
2. Substitution: where one nucleotide is changed for another nucleotide; for example, a Thymine nucleotide is replaced with a Guanine base.⁸ This can change the DNA sequence, leading to a changed or incomplete formation of a protein product.⁸
3. Silent mutation or neutral mutation: where there is a change in the DNA sequence, but there is no observational difference to the function of the cell. 

Mutations can occur in every cell. Mutations occurring in body cells (somatic) like muscle cells, skin cells and nerve cells will only affect an individual. However, mutations occurring in the germ-line cells, like the sperm and egg, will be inherited by their offspring.⁶ 

Pura gene mutation

Pura syndrome is caused by a mutation occurring at the PURA gene (purine-rich element binding protein A)⁸. PURA encodes for pur-alpha protein^3, which has several functions:¹¹

• Involved in controlling DNA replication,
• Regulate DNA replication,
• Binding site for DNA 

 PURA is expressed in every human tissue including the heart, brain and muscles⁴. Therefore it is a crucial protein, and any mutation in this gene can have devastating effects on the individual.

There is a deletion mutation occurring at chromosome 5, band q31 (at position 5q131.2q31.3).¹⁰ The deletion can be a single nucleotide or a large portion of the gene being changed.⁴ Pura syndrome is caused by a gene variant in the PURA gene - this means that the DNA sequence differs due to deletional and insertional mutation.³ The severity of the disorder depends on the genetic variant of the PURA gene.³ 

Inheritance patterns

In most cases of Pura syndrome, the genetic mutation occurs randomly during fertilisation and is not inherited by any of the parents.⁴ In some rare cases, Pura syndrome can be inherited by a parent who carries the mutation in an autosomal dominant inheritance pattern.¹² This means that an individual will suffer from Pura syndrome if they inherit one copy of the mutated gene from their parents.¹³ 

Clinical features and symptoms

Symptoms of Pura syndrome can affect individuals differently depending on the mutation and severity of their syndrome. Symptoms change depending on the age of the patient.

Neurodevelopmental abnormalities

Neurodevelopmental delays are clinical features found in reported Pura syndrome.¹⁰ They include:

1. Physical features
2. Cognitive abilities, including motor skills and speech impairments
3. Neurological abnormalities
4. Behavioral symptoms

Physical features

Common physical features a Pura syndrome patient may suffer from include:⁴

• Low muscle tone (Hypotonia)
• Flexible joints, especially around the hands
• Sensitive skin
• Feeding difficulties - where patients may struggle with feeding and swallowing food and drink^{4, 2} 
• Some patients, especially new-borns may struggle to breathe and will require breathing tubes until the age of 1.^4,2
• Puberty can also be affected: it can be either delayed or come early⁴

Cognitive abilities

All patients diagnosed with PURA syndrome have a moderate to severe learning disability and developmental delay.⁴ Patients with PURA syndrome can have the following symptoms:

• Some patients have language delay where the age of the first word is delayed abnormally¹⁰ 
• In many cases, speech is absent, and patients are nonverbal, but children can understand the language and respond without speaking⁴
• Motor delay is observed, where the age of sitting unsupported and age of first steps are delayed abnormally¹⁰ 
• Mobility is also limited, where patients cannot walk properly and have poor muscle skills

Neurological abnormalities

• Younger patients may struggle with staying awake and being aware and alert during the day (Hypersomnia)¹²
• Epilepsy is a common feature, where half of the affected population has reported cases of epilepsy¹²

Behavioural symptoms

• Sensory processing challenge: some patients are sensitive to certain noises like loud noises, children crying)⁴
• Irregular hand movements like hand-flapping, hand-biting and hand-sucking⁴
• Anxiety⁴
• In rare cases, some patients may be aggressive and can self-harm⁴

Other symptoms include²

• Involuntary muscle twitching that is difficult to control
• Bone and joint issues
• Hypothermia - difficulty in regulating body temperature
• Frequent hiccups
• Can be constipated
• Heart defects
• Vitamin D deficiency
• A gait disorder where the individual may be walking unsteadily

Diagnosis

Diagnosing Pura syndrome is difficult due to symptoms being similar to other medical conditions. To diagnose Pura syndrome, a doctor will need to conduct genetic testing and clinical evaluations.²

Genetic testings

Whole genome sequencing is carried out on a patient’s  DNA sample.¹⁴ The DNA is sequenced and data analysis can be done. The advantage of whole genome sequencing is that it can detect changes in the DNA sequence, even by a single nucleotide deletion or insertion, with high accuracy. This means that using DNA sequencing, a doctor can detect where the mutation is, leading to a diagnosis.¹⁴

Clinical evaluation

Depending on the symptoms, a doctor may conduct a clinical evaluation to confirm the diagnosis from the genetic testing and to rule out other conditions.² These can include:

• Blood tests,
• Breathing tests,
• Eye examination,
• MRI testing,
• Ultrasound testing.

Differential diagnosis

Pura syndrome shares similar symptoms and clinical features as other medical conditions, making diagnosing difficult. The differential diagnoses are:^4,10

• Congenital Central Hypoventilation syndrome
• Spinal muscular atrophy
• Angelman syndrome
• Rett syndrome
• Prader-willi syndrome

Treatment and management

There is no cure for Pura syndrome but there are treatments available to treat the symptoms of Pura syndrome.³ Early treatments and managing the symptoms can allow Pura syndrome patients to partake in many activities and live life without any major medical complications like scoliosis.² Each patient will have different treatment depending on their symptoms and how severe their disorder is.² Treatment will require a large multidisciplinary medical team consisting of a neurologist, geneticist, ophthalmologist (eye doctor), paediatrician, respiratory doctor and an orthopaedic surgeon.⁴

Treating symptoms

Epilepsy or seizures is a symptom that half of Pura syndrome patients suffer from, but managing epilepsy is difficult.⁴ Some patients respond well to anti-epileptic medicine, but more often, there are patients who are resistant to these drugs and can continue to have seizures.⁴ Newborn patients who have breathing and eating difficulties are monitored in the hospitals using medical supports such as breathing and feeding tubes.²

Therapies for developmental and behavioural aspects²

Due to developmental delay, treatments also include therapies to help support development:

• Speech therapist to improve communication of patients
• Physical therapy to improve fine motor skills and mobility
• Surgery is also used to correct physical abnormalities, like fixing heart defects or correcting facial features²

Research and potential future treatments

There has been exciting research recently aiming for a future where patients with Pura Syndrome can live a healthy life.¹⁵ There are three therapies that have the potential to treat and improve the lives of Pura syndrome patients:¹⁵

1. Antisense oligonucleotides (ASO)

ASO are small nucleic acid bases that can target specific genetic sequences, and this therapy works by increasing the expression of the specific ASO, which increases the gene expression of the healthy gene. This will lead to healthy expression of the PURA gene, which will make pur-alpha protein, which is essential for DNA replication.¹⁵ 

2. Drug repurposing

Drug repurposing is investigating whether there are available FDA-approved drugs that can be repurposed to treat Pura syndrome or to reduce the severity of the symptom. Screening currently available drugs can allow for further investigation in clinical trials.15

3. Gene replacement

Gene replacement is a therapy where a healthy copy of the PURA gene is delivered to target tissues using a vector.¹⁵ Delivering the healthy PURA gene will allow for the tissue to express the pur-alpha protein, leading to healthy cell function.

Prognosis

Pura syndrome is a lifelong neurological disorder where there is no cure. Current treatments available focus on improving the symptoms.² Patients will suffer from moderate to severe learning disabilities and developmental delays. Pura syndrome cannot be prevented as it is caused by a genetic mutation during fetal development and is a lifelong disorder. However, early intervention and effective treatment can improve the patient's quality of life.

Coping and support

There are over 500 diagnosed cases of Pura syndrome around the world, and cases increasing as the years go on.⁴ Pura syndrome is a very rare genetic disorder that affects the nervous system which causes both learning and developmental delays, but there is support available:

1. Pura syndrome foundation,
2. Pura Family support,

Both of these foundations support parents with children diagnosed with Pura syndrome and for newly diagnosed individuals too. Healthcare professionals are excellent support sources, and discussing effective treatments with them can alleviate symptoms patients may suffer from and can improve the quality of life the patients will have.⁴

Conclusion

Pura syndrome is a rare lifelong genetic disorder that affects the nervous system that individuals are born with. It can cause mild to moderate developmental delay, including both physical and learning disabilities.² Pura syndrome is caused by a genetic mutation at the PURA gene, which codes for the Pur-Alpha protein that is crucial for DNA replication.³ Patients can suffer from a range of symptoms, but the main symptoms are developmental delays, learning disabilities and seizures. There is no treatment available that can cure Pura syndrome, and current treatments aim to reduce the symptoms and provide therapies to improve developmental delays. There is exciting new research on the horizon that can potentially treat Pura syndrome and allow individuals who are diagnosed with Pura syndrome to live a healthy life.