Pura Syndrome: Symptoms, Types, Causes and Treatment

Pura syndrome is a rare genetic neurodevelopmental disorder that has only recently begun to be understood. Characterized by a complex array of symptoms affecting the brain, muscles, and other body systems, it often presents significant challenges for affected individuals and their families. In this article, we’ll explore the key features of Pura syndrome, the different types known so far, what causes the disorder, and the evolving strategies for its treatment and management.

Symptoms of Pura Syndrome

Understanding the symptoms of Pura syndrome is crucial for early diagnosis and effective management. The disorder presents a broad spectrum of clinical signs, often beginning in the neonatal period and evolving over time. While every individual is unique, several hallmark symptoms appear frequently and can guide clinicians and families in recognizing the condition.

Symptom	Frequency/Severity	Notable Features	Source(s)
Hypotonia	Neonatal onset, severe	Floppy infant, poor muscle tone	1 2 3 4 5 6 8 9 10 11
Developmental Delay	Moderate to severe	Affects motor and cognitive domains, often severe	1 2 3 4 6 8 10 11
Feeding Difficulties	Common, early onset	May require tube feeding or interventions	1 2 3 4 5 6 8 10 11
Epilepsy	~50-60%	Myoclonic, generalized, or focal seizures; often drug-resistant	1 2 3 4 7 8 10 11
Hypersomnolence	~66%	Excessive sleepiness in infancy	1 4 6 10 11
Apnea/Respiratory Issues	~57%	Central or obstructive apnea, recurrent respiratory distress	1 2 4 6 7 11
Dysmorphic Features	Subtle, variable	Facial dysmorphism, soft/loose skin	1 4 6 10
Ophthalmological Issues	~51%	Nystagmus, poor visual fixation or tracking	1 2 6 11
Muscular Weakness	Variable, sometimes prominent	Myopathic facies, ataxia, elevated CK	5 12 13
Gastrointestinal Disorders	~69%	Motility problems, reflux, constipation	1 2 4 11
Endocrine/Metabolic Issues	~42%	Hypothermia, pituitary dysfunction	1 4 8 11
Skeletal Abnormalities	~39%	Hip dysplasia, scoliosis, joint laxity	2 4 5 6 11

Table 1: Key Symptoms of Pura Syndrome

Core Neurological and Developmental Features

Pura syndrome’s most consistent and striking features are neurological. Nearly all affected infants display severe hypotonia—meaning a marked reduction in muscle tone—often described as “floppiness” at birth. This symptom is usually apparent in the first days of life and can persist throughout childhood and beyond 1 2 3 4 5 6 8 9 10 11. Global developmental delay, encompassing both motor and intellectual domains, is another hallmark. Most children experience moderate to severe delays, with many unable to walk independently or develop functional speech 1 2 3 4 6 8 10 11.

Feeding, Respiratory, and Sleep Challenges

Feeding difficulties are a major concern and frequently require interventions such as feeding tubes 1 2 3 4 5 6 8 10 11. Apneas—episodes when breathing stops—can be central or obstructive and often lead to hospitalizations, especially in infancy 1 2 4 6 7 11. Hypersomnolence, or excessive sleepiness, is notably common in infants, sometimes complicating feeding and developmental therapy 1 4 6 10 11.

Epilepsy and Movement Disorders

Seizures are reported in about half of cases, ranging from myoclonic and generalized tonic-clonic seizures to epileptic spasms and Lennox-Gastaut syndrome. Unfortunately, epilepsy in Pura syndrome is frequently drug-resistant, meaning that only about a third of affected children achieve seizure freedom 2 3 4 7 10 11. Some individuals also display abnormal, non-epileptic movements, including dystonia and dyskinesia 4 7 11.

Other Systemic Features

• Ophthalmological Issues: Poor visual tracking, nystagmus, and other vision problems are common 1 2 6 11.
• Muscular Weakness: Some children present with significant muscle weakness, myopathic facial features, and ataxia, occasionally with elevated creatine kinase (CK) levels 5 12 13.
• Gastrointestinal and Endocrine Problems: Motility issues, reflux, constipation, and hypothermia are frequently reported. Some cases suggest possible pituitary or other hormonal dysfunction 1 2 4 8 11.
• Skeletal and Dysmorphic Features: Hip dysplasia, scoliosis, joint laxity, and subtle facial dysmorphism (e.g., long philtrum, tented upper lip) can be seen. Occasionally, soft or loose skin is observed 1 4 5 6 10 11.

Variability and Evolution

Not every individual with Pura syndrome will have all symptoms, and the severity can vary widely even within families. Some symptoms (e.g., apnea) may improve over time, while others (e.g., developmental delay) are persistent and profound 2 3 4 10. The phenotype can also evolve, with new symptoms appearing as children grow.

Types of Pura Syndrome

Pura syndrome is not a single entity but comprises a spectrum of related neurodevelopmental disorders. These are primarily defined by the underlying genetic change affecting the PURA gene, as well as the clinical presentation. Understanding the types helps guide diagnosis, management, and genetic counseling.

Type	Genetic Cause	Clinical Overlap	Source(s)
PURA Syndrome	Pathogenic sequence variant in PURA	Core features: hypotonia, DD/ID, seizures	1 4 6 8 10 11
5q31.3 Deletion Syndrome	Microdeletion including PURA (and sometimes adjacent genes)	Largely overlapping; may have additional features	6 9 10 11
PURA-NDD (umbrella term)	Either of above	Encompasses both, highlights spectrum	6 10 11

Table 2: Types of Pura Syndrome and Related Disorders

PURA Syndrome (Monogenic Form)

The classic form of Pura syndrome results from a heterozygous pathogenic sequence variant (mutation) in the PURA gene. Over 90% of individuals with Pura-related disorders fall into this category. The clinical spectrum is broad but shares core features: neonatal hypotonia, developmental delay, feeding difficulties, and epilepsy 1 4 6 8 10 11.

5q31.3 Deletion Syndrome

A smaller subset of patients (~10%) have a deletion on chromosome 5q31.3 that includes all or part of the PURA gene, sometimes with neighboring genes. The clinical presentation is largely similar to classic PURA syndrome, but may include additional features if more genes are lost 6 9 10 11. Subtle differences, such as higher rates of abnormal brain MRI or more distinctive facial features, have been reported, but overall the syndromes are clinically indistinguishable in most cases 6 10.

PURA-Related Neurodevelopmental Disorders (PURA-NDDs)

This term is increasingly used to encompass both classic PURA syndrome and 5q31.3 deletion syndrome, reflecting their shared features and overlapping management needs 6 10 11.

Phenotypic Variants

Within these types, variations exist in severity and specific symptoms. Rare presentations can include features resembling congenital myasthenic syndromes (affecting the neuromuscular junction) or early-onset bradykinetic-rigid syndromes 7 12 13.

Causes of Pura Syndrome

Pura syndrome is a genetic disorder, and recent advances in genomic technology have illuminated its causes. Understanding the underlying mechanisms is key for diagnosis, counseling, and future therapies.

Cause	Mechanism	Inheritance Pattern	Source(s)
PURA Mutation	De novo heterozygous variant in PURA gene	Autosomal dominant, primarily de novo	1 3 4 8 10 11
5q31.3 Deletion	Chromosomal microdeletion including PURA	Autosomal dominant, de novo	6 9 10 11
Parental Mosaicism	Rare, possible	Slightly increased recurrence risk	11

Table 3: Genetic Causes of Pura Syndrome

The PURA Gene and Pur-α Protein

PURA encodes Pur-α, a highly conserved protein essential for normal postnatal brain development and neuronal function. It is involved in DNA and RNA binding, gene regulation, and possibly in synaptic development and maintenance 1 3 8. Loss of functional Pur-α disrupts brain development, leading to the clinical features of Pura syndrome.

Genetic Mutations

• De Novo Variants: Most affected children have a new (de novo) mutation in the PURA gene not inherited from either parent 1 3 4 8 10 11.
• Sequence Variants: These can include missense, nonsense, frameshift, and in-frame deletions or duplications. Over 90 different pathogenic variants have been reported without clear genotype-phenotype correlations; that is, the type or location of the mutation does not reliably predict severity or symptoms 1 2 3 4 10 11.
• 5q31.3 Microdeletions: Some children have a chromosomal deletion that includes the PURA gene. When this deletion is small and only includes PURA (and possibly IGIP), the clinical presentation closely matches classic PURA syndrome 6 9 10 11.

Inheritance and Recurrence Risk

Pura syndrome is inherited in an autosomal dominant manner, but almost all cases arise de novo. The risk of recurrence in future pregnancies is low, but not zero, due to the possibility of parental germline mosaicism (when a parent carries the mutation in some of their reproductive cells) 11.

Related Genetic Findings

No clear correlation has been found between the type of PURA mutation and the severity or specific symptoms, though some early reports suggested certain domains might result in more severe phenotypes 1 2 3 4 8 10 11.

Treatment of Pura Syndrome

Currently, there is no cure for Pura syndrome, but advances in research and clinical experience have led to a more targeted, multidisciplinary approach to management. Early recognition and intervention can substantially improve quality of life and developmental outcomes.

Treatment Approach	Focus/Modality	Evidence/Notes	Source(s)
Multidisciplinary Care	Developmental, neurologic, medical	Standard of care; ongoing support	1 2 3 4 6 11
Physical/Occupational Therapy	Motor and functional skills	Essential for maximizing potential	1 2 3 4 6 11
Speech/Feeding Therapy	Swallowing, communication	Often required long term	1 2 3 4 6 11
Epilepsy Management	Antiepileptic drugs (AEDs)	Drug-resistant epilepsy common	3 7 11
Respiratory Support	Monitor/apnea management	May require interventions in infancy	1 2 4 6 11
Nutritional Support	Tube feeding, diet	For those with severe feeding difficulties	1 2 4 5 6 11
Vision Care	Ophthalmology	For nystagmus, impaired tracking	1 2 6 11
Musculoskeletal Interventions	Orthopedics, physiotherapy	For joint/skeletal abnormalities	2 4 5 6 11
Medication (Pyridostigmine/Salbutamol)	Experimental, for neuromuscular symptoms	Some case reports of benefit	12 13
Surveillance	Ongoing monitoring	For development, seizures, feeding	4 6 11

Table 4: Treatment Strategies in Pura Syndrome

Multidisciplinary and Supportive Care

The primary treatment approach is comprehensive, coordinated care tailored to each individual’s needs. This usually includes:

• Physical and Occupational Therapy: To address hypotonia, motor delay, and improve daily functioning 1 2 3 4 6 11.
• Speech and Feeding Therapy: Many children require specialized help for feeding and communication challenges, sometimes including assistive technology 1 2 3 4 6 11.
• Educational and Behavioral Interventions: Early intervention programs and special education services are crucial for maximizing cognitive and social development 1 2 3 4 6 11.

Neurological and Medical Management

• Epilepsy: Seizure management is a major challenge. Many children require multiple antiepileptic drugs, and about a third achieve full seizure control. Lennox-Gastaut syndrome is a common epilepsy type 3 7 11.
• Respiratory Issues: Apnea and respiratory distress may necessitate close monitoring, oxygen supplementation, or mechanical support, especially in infancy 1 2 4 6 11.
• Nutritional Support: Severe feeding difficulties may require gastrostomy tube placement or specialized feeding regimens 1 2 4 5 6 11.
• Skeletal and Musculoskeletal Issues: Management may involve orthopedics for hip dysplasia, scoliosis, or joint instability, with regular physiotherapy 2 4 5 6 11.

Vision and Other Systemic Care

• Ophthalmology: For children with nystagmus or tracking issues, regular vision assessments and, if appropriate, interventions are recommended 1 2 6 11.
• Endocrine and Metabolic Monitoring: Some children benefit from evaluation for hypothermia, pituitary dysfunction, and other metabolic issues 1 4 8 11.

Emerging and Experimental Therapies

Recent reports have described the use of medications such as pyridostigmine (an acetylcholinesterase inhibitor) or salbutamol (a beta-agonist) in children with neuromuscular junction involvement, with observed improvements in muscle tone and reduction in apnea episodes 12 13. While promising, these are considered experimental and require further study.

Long-Term Surveillance

Routine monitoring for developmental progress, seizure activity, feeding/growth, orthopedic complications, and vision is vital to adjust care as the child grows 4 6 11.

Genetic Counseling

Families benefit from genetic counseling to understand recurrence risk and discuss reproductive options. Most cases are de novo, but rare parental mosaicism can increase risk for future pregnancies slightly 11.

Conclusion

Pura syndrome is a rare, complex neurodevelopmental disorder with a wide spectrum of symptoms and significant care needs. Although research is ongoing, clear patterns have emerged regarding its presentation, genetic origins, and optimal management strategies.

Key Takeaways:

• Symptoms: Core features include neonatal hypotonia, severe global developmental delay, feeding difficulties, epilepsy, and a range of systemic issues.
• Types: The disorder includes both classic PURA syndrome (from single-gene mutations) and 5q31.3 deletion syndrome (involving chromosomal microdeletions), together referred to as PURA-related neurodevelopmental disorders.
• Causes: Most cases are caused by de novo mutations in the PURA gene or chromosomal deletions that include PURA; inheritance is autosomal dominant but almost always sporadic.
• Treatment: There is no cure, but multidisciplinary care, early intervention, and targeted therapies for seizures, feeding, and neuromuscular issues can significantly improve outcomes. Experimental treatments are being explored for selected symptoms.
• Outlook: Ongoing surveillance and supportive care remain essential, and as research progresses, new therapies and improved diagnostic pathways are likely to emerge.

Pura syndrome exemplifies the importance of genetic diagnosis and comprehensive, patient-centered care for rare neurodevelopmental disorders. Early recognition, family support, and ongoing research are key to helping affected children reach their fullest potential.