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Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026.

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PURA-Related Neurodevelopmental Disorders

Synonym: PURA-Related Developmental and Epileptic Encephalopathy

, MD, PhD, , MBBS, BMedSci, PhD, FRACP, , MD, , MBBS, MD, FRCP, , MD, SBOT, FRACS, , MD, FACMG, , BSc, MAppLing, MspPath, PhD, , BSpPath (AudHons), PhD, , BEd
PGDip, , PhD, , MD, and , MBBS, PhD, MRCP.

Author Information and Affiliations

Initial Posting: ; Last Update: March 25, 2026.

Estimated reading time: 42 minutes

Summary

Clinical characteristics.

PURA-related neurodevelopmental disorders (PURA-NDDs) comprise PURA syndrome caused by a heterozygous PURA pathogenic variant and 5q31.3 deletion syndrome caused by a nonrecurrent 5q31.3 deletion encompassing all or part of PURA. PURA-NDDs are characterized by moderate-to-severe neurodevelopmental delay; most individuals are non-speaking and many lack independent ambulation. Early-onset issues can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements (dystonia, dyskinesia, and dysconjugate eye movements), and abnormal vision. Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur but are less common.

Diagnosis/testing.

The diagnosis of PURA syndrome is established in a proband with a heterozygous PURA pathogenic variant (~93% of individuals with a PURA-NDD); the diagnosis of 5q31.3 deletion syndrome is established in a proband with a nonrecurrent 5q31.3 deletion encompassing all or part of PURA (~7% of individuals with a PURA-NDD) identified by molecular genetic testing.

Management.

Treatment of manifestations: PURA-NDDs are incurable genetic disorders that are managed supportively and symptomatically. Ongoing routine care by a multidisciplinary team is recommended including treatment and/or therapy for developmental delays, neurologic findings (hypotonia, seizures, abnormal movements), speech and language disorders, feeding difficulties, apnea, visual impairment, and malformations of the heart, genitalia in males, kidneys and/or urinary tract, and skeleton (hip dysplasia and scoliosis).

Surveillance: Long-term follow up to assess neurologic findings (such as seizures or suspected seizures; new manifestations such as changes in tone and/or movement disorders); developmental progress and educational needs; speech and language progress and changes (including reassessment of alternative communication systems); vision; feeding issues including dysphagia; vitamin D deficiency and/or evidence of low bone density; and musculoskeletal complications (hip dysplasia and scoliosis).

Genetic counseling.

PURA-NDDs – including PURA syndrome and 5q31.3 deletion syndrome – are autosomal dominant disorders.

Almost all individuals diagnosed with PURA syndrome have the disorder as the result of a de novo constitutional PURA pathogenic variant. Rarely, individuals have the disorder as the result of a postzygotic somatic mosaic pathogenic variant or a pathogenic variant inherited from a heterozygous or mosaic parent. The risk to the sibs of the proband depends on the genetic status of the parents: if a parent of the proband is affected and/or is known to have the PURA pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the PURA pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental gonadal mosaicism (the recurrence risk for PURA syndrome due to parental gonadal mosaicism is expected to be higher than the standard parental gonadal mosaicism risk of <1% because loss-of-function variants in PURA have a selective advantage resulting in clonal expansion).

To date, all reported 5q31.3 deletions have been de novo. If neither parent has a detected 5q31.3 deletion or a predisposing chromosomal rearrangement, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the possibility of parental gonadal mosaicism.

Once an intragenic pathogenic variant in PURA or a 5q31.3 chromosomal deletion encompassing all or part of PURA has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

GeneReview Scope

PURA-Related Neurodevelopmental Disorders: Included Disorders

Diagnosis

No consensus clinical diagnostic criteria for PURA-related neurodevelopmental disorders (PURA-NDDs) have been published.

Suggestive Findings

PURA-NDDs should be considered in probands with the following clinical and brain MRI findings and family history.

Clinical findings

  • Neonates/infants
    • Hypotonia
    • Feeding difficulties, including gastroesophageal reflux disease
    • Neonatal hypoventilation
    • Hypersomnolence
    • Exaggerated startle response
    • Hypothermia
  • Older individuals
    • Hypotonia
    • Intellectual disability, usually in the moderate-to-profound range
    • Non-speaking
    • Seizures
    • Abnormal nonepileptic movements (e.g., dystonia, dyskinesia, and dysconjugate eye movements)

Imaging findings

  • Brain MRI. Although brain MRI abnormalities are present in most individuals, they are usually nonspecific and not diagnostic. The most common of these are:
    • Delayed myelination
    • Parenchymal atrophy and/or ventriculomegaly
    • Excessive extra-axial fluid spaces

Laboratory findings. The results of routinely performed laboratory profiles are generally normal; however, hypoglycorrhachia was noted in at least six individuals [Colombo et al 2024].

Family history. Because PURA-NDDs are typically caused by a de novo genetic alteration (either a pathogenic variant in PURA or a deletion of 5q31.3 that includes PURA), most probands represent a simplex case (i.e., a single occurrence in a family). Rarely, the family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations) [Hildebrand et al 2024].

Establishing the Diagnosis

The diagnosis of a PURA-NDD is established in a proband with suggestive findings and one of the following identified by molecular genetic testing [Johannesen et al 2021, Taniguchi et al 2025] (see Table 1):

Note: (1) Per American College of Medical Genetics and Genomics / Association for Molecular Pathology variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous PURA variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with exome sequencing / genome sequencing [Manickam et al 2021, van der Sanden et al 2023]. Other options include use of chromosomal microarray analysis (CMA) or a multigene panel. Note: Single-gene testing (sequence analysis of PURA, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

  • Comprehensive genomic testing. Exome sequencing is most commonly used; genome sequencing is also possible. Trio sequencing is recommended as almost all reported pathogenic variants arise de novo. To date, the majority of PURA pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing. However, as genome sequencing becomes increasingly used it is possible that deep intronic pathogenic variants that disrupt PURA splicing will be detected.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
  • A multigene panel analysis that includes PURA and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

PURA-Related Neurodevelopmental Disorders: Molecular Genetic Testing

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
PURA Sequence analysis 393% 4, 5
Gene-targeted deletion/duplication analysis 6Unknown 7
Chromosomal microarray deletion/duplication analysis 87% 5, 9
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.
6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

8.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 5q31.3 region.

9.

Clinical Characteristics

Clinical Description

PURA-related neurodevelopmental disorders (PURA-NDDs) comprise PURA syndrome (caused by a heterozygous PURA pathogenic variant) and 5q31.3 deletion syndrome (caused by a nonrecurrent 5q31.3 deletion encompassing all or part of PURA).

PURA-NDDs are characterized by moderate-to-severe neurodevelopmental delay; most affected individuals are non-speaking and many do not achieve independent ambulation. Individuals with 5q31.3 deletion syndrome have a core PURA syndrome phenotype that can be more severe (presumably due to the involvement of neighboring genes). Features of 5q31.3 deletion syndrome that overlap with those of PURA syndrome include neonatal hypotonia, feeding difficulties, hypersomnolence, and respiratory difficulties as well as severe intellectual disability and epilepsy [Shimojima et al 2011, Hosoki et al 2012, Brown et al 2013, Bonaglia et al 2015, Bonaglia et al 2015, Choi et al 2021, Dai et al 2023].

The data below for reported frequencies of clinical features in individuals with PURA syndrome are based on 223 individuals reported in the literature with a heterozygous PURA pathogenic variant. Frequencies of clinical features in individuals with 5q31.3 deletion syndrome have not been included, as these nonrecurrent chromosomal deletions are of varying sizes; thus, genetically, they represent a comparatively heterogeneous group.

PURA Syndrome

Early-onset manifestations are wide ranging and can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements, including an exaggerated startle, and vision problems.

Musculoskeletal manifestations, congenital heart defects, urogenital malformations, and endocrine disorders are less commonly described [Hunt et al 2014, Lalani et al 2014, Tanaka et al 2015, Johannesen et al 2021, Taniguchi et al 2025].

Development. All 223 individuals reported to date have had moderate-to-severe neurodevelopmental delay.

Motor development is almost always delayed, but with variable severity. Many individuals never achieve independent ambulation. However, 56% (67/120) achieved ambulation with or without support (minimum prevalence: 39% in those older than age 18 months). The age of ambulation achievement ranges from 16 months to 10 years. The gait of affected children is typically broad based but can be normal or near normal in some.

Speech, language, and communication. Both speech and language are typically impaired. Most individuals are non-speaking, meaning speech is significantly impacted or not used at all; only 6.5% (12/184) of all individuals older than age 12 months are reported to have developed speech. For those who are non-speaking, other means of communication should be supported early and throughout life. The use of augmentative and alternative communication (AAC) has proven beneficial in some children, especially when implemented early and consistently. This can include the use of unaided AAC (i.e., gesture and body movement) and/or aided AAC (i.e., picture-based communication systems or eye gaze tablet devices). Speech-language pathologist input should be in collaboration with physical or occupational therapists to optimize AAC selection and use [M St John & A Morgan, unpublished data].

Some non-speaking children have better receptive language skills compared to expressive language skills; however, both can be significantly impacted. Thus, individuals with PURA syndrome may be able to understand more than they can communicate (either with speech or AAC) [M St John & A Morgan, unpublished data].

A smaller proportion of individuals use speech to communicate. These individuals may have delayed communication milestones (i.e., first words after age 2 years). There is a wide range of ability within this speaking subgroup, ranging from mild-to-severe speech disorder (e.g., dysarthria and childhood apraxia of speech) [Kaspi et al 2023; Hildebrand et al 2024; M St John & A Morgan, unpublished data].

Intellectual disability is considered a universal feature; although almost all affected individuals are in the moderate-to-profound range of intellectual disability, very rarely the degree of intellectual disability may be milder [D Hunt, personal observation].

Neurologic. Hypotonia (98% [180/184]; minimum prevalence: 81%) and hypersomnolence (83% [71/86]; minimum prevalence: 32%) are common at birth.

Epilepsy has been reported in at least 50% of individuals (52% [98/187]; minimum prevalence: 44%). However, given that the median age of seizure onset is three years, this is likely to have been underestimated, as 30% of individuals in the published literature were younger than age three years at the time of the report. The age of seizure onset ranges from the neonatal period to 24 years.

The lifetime risk of developing epilepsy is very high: 87% (20/23) of individuals age 18 years or older were reported to have epilepsy.

Seizure types can be varied, including infantile spasms, focal, complex focal, tonic, generalized tonic-clonic, atonic, absence, and myoclonic. Myoclonic seizures are common. Nonepileptic myoclonus is also common and should be distinguished from true seizures (see Management). Reflex epilepsy has been reported. In some instances, the seizure disorder progresses to Lennox-Gastaut syndrome. The seizures are often resistant to anti-seizure medications.

Nonepileptic movements. Exaggerated startle response is very common, particularly in individuals specifically examined for this finding (74% [50/68]; minimum prevalence: 22%). Other nonepileptic movements that may be seen include subcortical myoclonus, dystonia, dyskinesia, and dysconjugate eye movements (50% [30/60]; minimum prevalence: 14%).

Nystagmus is present in 43% (35/82; minimum prevalence: 16%) of individuals specifically examined for this finding.

Abnormal MRI brain findings present in most individuals (64% [117/184]) are:

  • Delayed myelination (17% [32/184])
  • Parenchymal atrophy and/or ventriculomegaly (15% [27/184])
  • Excessive extra-axial fluid spaces (10% [18/184])
  • Focal white matter signal abnormalities (6% [11/184])
  • Abnormalities of white matter volume, excluding abnormalities of the corpus callosum (7% [12/184])
  • Volume loss of the corpus callosum (5% [10/184])

Less common MRI findings include arachnoid cysts, intraparenchymal cysts, periventricular leukomalacia (PVL), other types of white matter abnormalities (notwithstanding delayed myelination, hypomyelination, or PVL), and cerebellar vermis hypoplasia.

Single reports of MRI findings include bilateral polymicrogyria, basal ganglia calcifications, mesial temporal sclerosis, absent septum pellucidum, mild cerebellar tonsillar ectopia, persistent cavum septum pellucidum and cavum vergae, and cystic dilatation of the quadrigeminal cistern and mega cisterna magna.

MR spectroscopy, performed in some individuals, was reported as abnormal in at least one individual, who had lactate peaks in the lateral ventricles [Mroczek et al 2021].

Nerve conduction studies / electromyography. Electrodiagnostic studies were normal in about half of the individuals on whom they have been reported. When abnormal, findings were most often suggestive of myopathy or neuromuscular junction pathology.

Ophthalmologic. Strabismus (53% [50/94]; minimum prevalence: 22%) and refraction abnormalities (33% [18/54]; minimum prevalence: 8%) are the most frequently reported abnormalities in individuals specifically examined for these findings. Cerebral visual impairment is present in 18% of affected individuals (11/61; minimum prevalence: 5%).

Respiratory. Apnea and hypoventilation are present in more than three quarters of affected neonates (78% [117/150]; minimum prevalence: 53%), of whom 32% (38/117) required mechanical ventilation, usually as temporary non-invasive ventilation. In at least three instances, tracheostomy was required [Lalani et al 2014, Johannesen et al 2021].

In most affected individuals, the episodes of apnea and hypoventilation resolved after the first year of life; however, in a minority, apnea persisted or recurred during an acute respiratory illness (43% of individuals specifically examined for these findings; minimum prevalence: 10%).

Aspiration pneumonia due to hypotonia and dysphagia has been reported.

Gastrointestinal. A significant number of neonates have severe feeding difficulties (94% [165/176]; minimum prevalence: 74%) and/or gastroesophageal reflux disease (50% [17/34]; minimum prevalence: 8%). Dysphagia often persists throughout life. Drooling is common. Constipation has been reported in most individuals (69% [61/88]; minimum prevalence: 27%).

Genital. Genital abnormalities occur less frequently. The most frequently reported is cryptorchidism (29% [9/31]; minimum prevalence: 8%). Other rare abnormalities include hypoplastic external female genitalia.

Congenital anomalies of the kidneys or urinary tract. Hydronephrosis and urolithiasis occur rarely.

Skeletal. The skeletal phenotype is often overlooked in the published literature. Of those individuals in whom any reference is made to spinal issues, nearly half had scoliosis (47% [34/72]). However, it is likely that the true prevalence is lower, as pertinent negative findings may have been omitted in many reports. Nonetheless, the prevalence of scoliosis in the published medical literature is at least 15% (34/223). Scoliosis often develops in adolescence or early teenage years; in some individuals, progression can be rapid, especially during the pubertal growth spurt.

In individuals in whom any reference was made to hip issues, approximately one third had hip dysplasia (34% [19/56]). Although this may be an overestimate, the prevalence is at least 8% (19/223). Similarly, the prevalence of hip subluxations or dislocations (7/7) is at least 3% (7/223). Little has been published about the natural history of hip dysplasia in PURA syndrome; usually, it is not detected at birth but can develop later.

Bone density is infrequently assessed in individuals with PURA syndrome; however, in those in whom any reference is made to bone density, half had osteopenia or osteoporosis (50% [7/14]). The true prevalence of low bone density may be significantly lower, but it is at least 3% (7/223). Anecdotally, bone density can be very low, even in the absence of any pathologic fractures [D Hunt, personal observation].

Endocrine. Anterior pituitary dysregulation may be within the spectrum of PURA syndrome based on the following observations [Hunt et al 2014]:

  • Disturbed levels of gonadotropins (40% [4/10]; minimum prevalence: 2%) and medical treatment for precocious puberty (100% [3/3]; minimum prevalence: 1%). Delayed puberty has been reported in at least 10 individuals (minimum prevalence: 5%).
  • A blunted cortisol response (25% [2/8]; minimum prevalence: 1%)
  • Hypothyroidism (19% [8/43]; minimum prevalence: 4%)
  • Elevated prolactin levels in one reported individual

Although low serum vitamin D concentrations (41% [16/39]; minimum prevalence: 7%) have been reported, the true prevalence may be higher, as serum vitamin D concentrations are often not measured routinely and deficiency may not be obvious clinically.

Cardiovascular. Structural heart defects in 20% of individuals (13/66; minimum prevalence: 6%) include ventricular septal defect, persistent foramen ovale, persistent ductus arteriosus, pulmonic stenosis, atrial septal defect, bicuspid aortic valve, mild ventricular hypertrophy, and aberrant left subclavian artery. It should be noted that these data may represent an underestimate (particularly of minor cardiac abnormalities that may not manifest obvious signs of disease), as not all individuals had an echocardiogram as a matter of course.

Heart rhythm abnormalities reported occasionally include unexplained tachycardia/bradycardia and increased QTc interval in which a contribution of other (genetic) causes is possible.

Other

  • Neonatal hypothermia (38% [24/63]; minimum prevalence: 11%). Although difficulties in regulating body temperature in the neonatal period appear to occur frequently, descriptions of them are limited.
  • Excessive hiccups in utero, which are rarely reported in the published medical literature, are frequently disclosed on direct questioning. Excessive hiccups may be present in the neonatal period and can sometimes persist [D Hunt, personal observation].

5q31.3 Deletion Syndrome

To date, 18 individuals with 5q31.3 deletion syndrome have been reported. Features of these individuals that overlap with those of individuals with PURA syndrome include neonatal hypotonia, feeding difficulties, hypersomnolence, and respiratory difficulties as well as severe intellectual disability and epilepsy [Shimojima et al 2011, Hosoki et al 2012, Brown et al 2013, Bonaglia et al 2015, Bonaglia et al 2015, Choi et al 2021, Dai et al 2023].

Individuals with 5q31.3 deletion syndrome that encompasses multiple genes in addition to PURA show a more severe neurodevelopmental phenotype than individuals with PURA syndrome [Brown et al 2013, Dai et al 2023, Kofoed et al 2024]. The meta-analysis performed by Taniguchi et al [2025] indicates that congenital malformations, respiratory difficulties, and non-ambulation are more likely to be present in individuals with a 5q31.3 deletion than in individuals with PURA syndrome.

Genotype-Phenotype Correlations

Current data suggest that PURA pathogenic variants in the region encoding the PUR III repeat cause a more severe phenotype than variants in the regions that encode PUR I or PUR II repeats [Taniguchi et al 2025].

Penetrance

The penetrance of all PURA pathogenic variants appears to be complete. To date, there are no reports of clinically unaffected individuals with pathogenic PURA variants.

Differential Diagnosis

PURA syndrome. Genetic disorders in the differential diagnosis of PURA syndrome are listed in Table 2.

Table 2.

PURA Syndrome: Genetic Differential Diagnosis

Gene / Genetic MechanismDisorderMOISelected Features Similar to PURA SyndromeSelected Features Distinct from PURA Syndrome
AMT
GLDC
(GCSH) 1		Nonketotic hyperglycinemia (NKH)AR
  • Prenatal & neonatal hiccups
  • Neonatal lethargy
  • Hypotonia
  • Apnea
  • Poor feeding
  • Myoclonic jerks
  • DD
  • Pharmacoresistant seizures
  • Abnormal movements
  • Elevation of glycine concentration in plasma & CSF; abnormal CSF-to-plasma glycine ratio
  • Burst suppression pattern on EEG is often seen in NKH & not typical in PURA syndrome.
DMPK Congenital myotonic dystrophy 1 (See Myotonic Dystrophy Type 1.)AD
  • Hypotonia & weakness at birth
  • Respiratory insufficiency
  • ID
  • Fast runs of single-fiber discharges on EMG in infants
  • Hypersomnolence, hypothermia, & exaggerated startle are not typical.
DYNC1H1 DYNC1H1-NDD (See DYNC1H1-Related Disorders.)AD
  • Hypotonia
  • Neurodevelopmental delay
  • Epilepsy
  • Not assoc w/hypersomnolence, hypothermia, hypoventilation, & exaggerated startle in neonatal period
  • EMG/NCS indicate axonal neuropathy.
GLRA1
GLRB
SLC6A5 		Hereditary hyperekplexia (HPX)AD
AR		Exaggerated startle in utero & in infancy
  • Exaggerated startle is often followed by prolonged stiffening.
  • Glabellar tap reflex is typically positive in HPX & negative in PURA syndrome.
IGHMBP2 Distal autosomal recessive spinal muscular atrophy 1 (OMIM 604320)AR
  • Respiratory distress in infants
  • Swallow dysfunction
  • Muscle weakness
  • Eventration of diaphragm not seen in PURA syndrome.
  • Weakness predominantly involves upper limbs & distal muscles, whereas in PURA syndrome axial hypotonia is most prominent.
MECP2 MECP2 disorders (incl Error! Hyperlink reference not valid. [primarily females] & severe neonatal encephalopathy [males])XLIn MECP2-related severe neonatal encephalopathy:
  • Hypotonia
  • Feeding difficulties
  • Movement disorder
  • Central hypoventilation
  • Sleep apnea
  • Epilepsy
  • DD
  • Reflux
  • Abnormal EEG
Microcephaly, regression, & stereotypical hand movements are common.
NALCN Congenital contractures of limbs & face, hypotonia, & DD (OMIM 616266)AD
  • Global DD, ID
  • Seizures
  • Hypotonia
  • Abnormal breathing patterns incl apneas
Contractures are a defining feature.
PHOX2B Congenital central hypoventilation syndrome AD
(AR)		Neonatal presentation w/hypoventilation, altered temperature regulation, & possible seizures
  • Abnormal pupillary response to light
  • Hypersomnolence & hypotonia are not typical.
Abnormal DNA methylation w/in PWCR at 15q11.2-q13 Prader-Willi syndrome Depends on underlying genetic mechanism
  • Neonatal hypotonia
  • Feeding difficulties in early infancy
  • DD
  • Temperature instability
  • Central & obstructive sleep apnea
  • DD/ID are typically milder.
  • Excessive eating & development of obesity in childhood are not typical of PURA syndrome.
RNU2-2 Developmental & epileptic encephalopathy 119 (OMIM 621304)AD
  • Global DD w/most persons remaining non-speaking; ID
  • Autistic traits
  • Seizures
  • Hypotonia
  • Microcephaly is present in vast majority (OFC is in normal range in most persons w/PURA syndrome).
  • Hyperventilation is reported in significant minority.
SLC2A1 Glucose transporter type 1 deficiency syndrome AD
(AR)
  • Hypoglycorrhachia
  • DD/ID
  • Pharmacoresistant seizures
  • Paroxysmal events, movements disorders, abnormal eye movements
Hypotonia, hypothermia, & hypoventilation are not typical.
TCF4 (intragenic PV or 18q21.2 deletion encompassing TCF4) Pitt-Hopkins syndrome AD
  • Apnea
  • Hypotonia
  • DD/ID
  • Seizures
  • Dysregulation of body temperature
  • Characteristic facial features (may be less obvious in infancy)
  • Hyperventilation (PURA syndrome is assoc w/hypoventilation.)
UBE3A (deficient expression/function of maternally inherited UBE3A allele) Angelman syndrome Depends on underlying genetic mechanism
  • Hypotonia & feeding problems in infancy
  • Severe DD/ID typically w/no speech
  • Movement or balance disorder
  • Epilepsy
  • Nonepileptic myoclonus
  • Microcephaly is common.
  • Happy demeanor & fascination w/water
  • Most affected persons become ambulatory.
~30 genes incl:
CHAT
CHRNE
COL13A1
COLQ
DOK7
RAPSN		 Congenital myasthenic syndromes AD
AR
  • Neonatal episodic apnea or respiratory insufficiency
  • Feeding difficulties
  • Decremental EMG response of CMAP evoked on low-frequency stimulation.
Hypersomnolence & hypothermia are not typical.
>40 genes incl:
AHI1
CPLANE1
CC2D2A
CEP290
CSPP1
INPP5E
KIAA0586
MKS1
NPHP1
RPGRIP1L
TCTN2
TMEM67
TMEM216		 Joubert syndrome AR 2
AD
  • Hypotonia
  • Abnormal eye movements
  • Respiratory disturbance
  • Cognitive impairment
  • Ataxia
  • MRI shows cerebellar vermian hypoplasia w/molar tooth sign.
  • Retinal dystrophy
  • Renal cysts
  • Polydactyly

AD = autosomal dominant; AR = autosomal recessive; CMAP = compound muscle action potential; CSF = cerebrospinal fluid; EMG = electromyography; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; NCS = nerve conduction studies; NDD = neurodevelopmental disorder; OFC = occipitofrontal circumference; PV = pathogenic variant; PWCR = Prader-Willi critical region; XL = X-linked

1.

Although two individuals homozygous for a GCSH pathogenic variant were reported (as an abstract at a meeting), to date no proof of pathogenicity has been provided. No other instances of nonketotic hyperglycinemia caused by GCSH deficiency have been identified.

2.

Joubert syndrome (JS) is predominantly inherited in an autosomal recessive manner. OFD1-related JS is inherited in an X-linked manner. SUFU-related JS is inherited in an autosomal recessive or autosomal dominant manner.

5q31.3 deletion syndrome. The differential diagnosis of 5q31.3 deletion syndrome includes disorders characterized by severe intellectual disability and epilepsy in addition to the disorders listed in Table 2.

Management

No clinical practice guidelines for PURA-related neurodevelopmental disorders (PURA-NDDs) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a PURA-NDD (PURA syndrome or 5q31.3 deletion syndrome), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 3.

PURA-Related Neurodevelopmental Disorders: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Neurologic Neurologic eval
Brain MRIIndicated in child w/seizures &/or hypoventilation &/or abnormal vision or eye movements who has not previously had a brain MRI
EEG & video EEGIf seizures are suspected video EEG monitoring may help distinguish epileptic from nonepileptic events (e.g., dystonia, dyskinesia, dysconjugate eye movements).
EMG/NCS
  • Indicated in those w/severe hypotonia & recurrent apneas
  • Consider SF-EMG w/repetitive stimulation in those w/fluctuating tone, as evidence of NMJ dysfunction has been reported in some persons.
Respiratory Assess pulmonary function.Consider screening for hypercapnia in neonates.
Development Developmental assessment
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Speech, language, & communication Speech-language pathologist assessmentIncl eval of speech (verbal, non-speaking) & receptive & expressive language abilities
Gastrointestinal / Feeding difficulties Gastroenterology / nutrition / feeding team eval
  • To incl eval of possible GERD & constipation
  • In persons w/dysphagia &/or aspiration risk, consider eval for gastrostomy tube placement.
Ophthalmologic Ophthalmology eval
  • To assess for reduced vision, abnormal ocular movement, best corrected visual acuity, refractive errors, strabismus, & more complex findings that may require referral for subspecialty care &/or low vision services
  • Electrodiagnostic tests may be indicated, esp if CVI is suspected.
Musculoskeletal Orthopedics / physical medicine & rehab / physiatry / PT & OT / orthotics evalsTo incl assessment of:
  • Gross motor & fine motor skills
  • Hip dysplasia & scoliosis
  • Mobility, ADL, & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Cardiovascular Consider echocardiogram.To determine if congenital heart defect is present
Genital anomaly Exam of external genitaliaMales: referral to pediatric urologist as needed
CAKUT Abdominal ultrasound examTo determine whether congenital anomalies of kidneys &/or urinary tract are present
Endocrine Measure serum vitamin D concentrations.To check for vitamin D deficiency
Assess bone density.If osteoporosis or osteopenia is suspected
Evaluate anterior pituitary hormones.If necessary
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of PURA-NDDs to facilitate medical & personal decision making
Family support
& resources 		By clinicians, wider care team, & family support organizationsAssessment of family & social structure to determine need for:

ADL = activities of daily living; CAKUT = congenital anomalies of the kidney or urinary tract; CVI = cerebral visual impairment; EMG = electromyography; GERD = gastrointestinal reflux disease; MOI = mode of inheritance; NCS = nerve conduction studies; NDD = neurodevelopmental disorder; NMJ = neuromotor junction; OT = occupational therapy; PT = physical therapy; SF-EMG = single-fiber electromyography

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

PURA-NDDs are incurable genetic disorders that are managed supportively and symptomatically. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields that may include but not limited to a pediatrician, clinical geneticist, child neurologist, pulmonologist, ophthalmologist, orthopedic surgeon, physical therapist, occupational therapist, and speech-language therapist (see Table 4).

Table 4.

PURA-Related Neurodevelopmental Disorders: Treatment of Manifestations

Manifestation/ConcernTreatmentConsiderations/Other
Epilepsy Mgmt by experienced neurologist/epileptologist
  • Seizure control can be very difficult to achieve. To date, no robust studies have been performed to determine relative ASM efficacy in PURA syndrome. Monotherapy is rarely effective; thus, most persons require polytherapy. However, no combination of ASMs has been proven to be particularly effective. Thus, in practice, many different ASMs are tried. A further complication is that seizure types typically evolve over time.
  • Although ketogenic diet has been used effectively in some persons, there is currently only 1 report of a significant positive response to treatment. 1
  • The efficacy of neither vagus nerve stimulation nor cannabidiol has been established. There is no proven role for conventional epilepsy surgery.
  • Education of parents/caregivers is recommended. 2
Movement disorders Mgmt by neurologist experienced w/movement disordersMay need medications to manage dystonia &/or hyperkinetic movements
Developmental delay /
Intellectual disability 		See Developmental Delay / Intellectual Disability Educational Issues.
Speech, language, & communication Mgmt by speech-language pathologist experienced in rare genetic disease or AAC
  • Most persons will require AAC.
  • Speech-language pathologist input should be in collaboration w/PT or OT to optimize AAC selection & use. 3
  • AAC can be unaided (i.e., relying on gesture & body movement) &/or aided (i.e., picture-based communication systems or eye gaze tablet devices).
Hypotonia Mgmt by experienced neurologist 4
Hypoventilation
  • Supplementary oxygen (at night) & (rarely) tracheostomy
  • Some infants require short periods of intubation & mechanical ventilation, esp during acute illness. 5
  • Ambulatory peripheral saturation monitoring may be required.
  • Due consideration should be given to additional respiratory risks posed by general anesthesia. 6
Gastrointestinal Feeding issues Feeding therapy for those w/dysphagiaLow threshold for clinical feeding eval &/or radiographic swallowing study when showing manifestations of dysphagia
GERD
  • Medical mgmt
  • Consider Nissen fundoplication if medical treatment is not sufficient
Referral to gastroenterologst may be required when severe.
Constipation Routine mgmtReferral to gastroenterologist may be required when severe.
Musculoskeletal/ADL Physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
  • Consider need for positioning & mobility devices, disability parking placard.
  • Ankle-foot orthoses may improve stability, allowing for better standing & transferring ability.
Scoliosis
  • Requires clinical & radiographic surveillance by specialist.
  • Progression can be rapid; thus, intervention may be warranted w/in 1-2 yrs of onset.
  • Options incl bracing/casting or surgery (growing rods or spinal fusion, depending on skeletal maturity).
Adequate surgical instrumentation should be considered in persons w/low bone density.
Hip dysplasia, progressive subluxation, & dislocation
  • Hip surveillance via interval radiographs of pelvis
  • Hip reconstructions w/proximal femoral varus derotational osteotomies plus or minus pelvic osteotomies should be considered.
Generalized joint laxity & continued inability to walk may cause relapsing hip subluxation even after surgical reconstruction.
Ophthalmologic
  • Correction of refractive errors
  • Vision support
  • Standard treatment for strabismus & exophoria
Cerebral visual impairment No specific treatmentEarly intervention program to stimulate visual development
Congenital heart defects Mmt per current practice for specific congenital heart defect
Genital anomalies Mgmt per current practice for specific genital anomaly
CAKUT Mgmt per usual practice by nephrologist &/or urologist
Osteoporosis/
Osteopenia 		Standard mgmt
Vitamin D deficiency Vitamin D supplementationConsider DXA scan in those w/additional risk factors for low bone density.
Anterior pituitary hormone deficiencies Standard treatment as directed by endocrinologist
Transition to adult care Develop realistic plans for adult life (see American Epilepsy Society Transitions from Pediatric Epilepsy to Adult Epilepsy Care).Starting by age ~16 yrs
Family/Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

AAC = augmentative and alternative communication; ADL = activities of daily living; ASM = anti-seizure medication; CAKUT= congenital anomalies of the kidney or urinary tract; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease

1.
2.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.

3.

M St John & A Morgan, unpublished data

4.

There are published reports that hypotonia may improve with medications including oral albuterol (salbutamol) and pyridostigmine [Qashqari et al 2022, Wyrebek et al 2022]; however, it is important to stress that the evidence is anecdotal at best, and it should be noted that pyridostigmine was associated with worsening respiratory status in one individual, prompting the commencement of noninvasive positive pressure ventilation, and no clinical benefit in another despite having evidence of neuromotor junction dysfunction on single-fiber electromyography [Qashqari et al 2022]. The use of oral albuterol, however, may be associated with some improvement in general vigor [LD Sanchez, personal experience], but this observation is not yet supported by any robust data collected through a prospective clinical trial.

5.

There are published reports that apnea and hypoventilation may improve with medications including caffeine citrate, oral albuterol (salbutamol), and pyridostigmine [Qashqari et al 2022, Wyrebek et al 2022]. However, it is important to stress that the evidence is anecdotal at best, and it should be noted that pyridostigmine was associated with worsening respiratory status in one individual, prompting the commencement of noninvasive positive pressure ventilation, and no clinical benefit in another despite having evidence of neuromotor junction dysfunction on single-fiber electromyography [Qashqari et al 2022]. The use of caffeine citrate in conjunction with oral albuterol, however, may be associated with some improvement in apneas [LD Sanchez, personal experience], but this observation is not yet supported by any robust data collected through a prospective clinical trial.

6.

Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine the services and therapies needed and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Speech, language, and communication issues. Speech-language evaluation should be considered early in development for children who have delayed communication milestones or who are not yet talking. Evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) is appropriate for individuals who have speech or receptive and expressive language difficulties. An AAC evaluation should be completed by a speech-language pathologist who has expertise in the area. This evaluation typically takes into account cognitive abilities, sensory impairments, and motor skills to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development. Many children will continue to require AAC into later childhood and adulthood, while some may use their AAC for a shorter time to help aid speech and language development.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Table 5.

PURA-Related Neurodevelopmental Disorders: Recommended Surveillance

System/ConcernEvaluationFrequency
Neurologic
  • Clinically monitor those w/seizures as indicated.
  • Assess for new manifestations such as seizures, changes in tone, & movement disorders.
At each visit
Development Monitor developmental progress & educational needs.
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
Speech, language, & communication Monitor for speech & language progress & changes, incl reassessment of AAC systems as needs change.At each visit (reassessment yearly)
Respiratory Monitor for evidence of aspiration & respiratory insufficiency.During infancy, when prevalence of apneas is highest, cardiorespiratory sleep study at least every 6 mos is considered prudent. Thereafter, an annual sleep study would be advisable, unless any specific concerns are raised, in which case more frequent assessment may be indicated.
Musculoskeletal Physical medicine & OT/PT assessment of mobility, self-help skills, & musculoskeletal complications incl hip dysplasia & scoliosisClinical assessment at each visit, with radiographs annually or every 6 mos if emerging clinical concerns
Ophthalmologic involvement
  • Assessment of visual acuity, refraction, & fundus
  • Orthoptic assessment
Per treating ophthalmologist(s)
Genital anomalies Per treating cliniciansPer treating clinicians
CAKUT No specific surveillance is advised unless abnormality identified on screening at diagnosis or if prone to recurrent UTIs.
Endocrine
  • Clinical assessment for signs of precocious or delayed puberty
  • Periodic assessment for vitamin D deficiency &/or evidence of low bone density
At each visit
Family/Community Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

CAKUT = congenital anomalies of the kidney or urinary tract; OT = occupational therapy; PT = physical therapy

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PURA-related neurodevelopmental disorders (PURA-NDDs) – including PURA syndrome (caused by an intragenic pathogenic variant in PURA) and 5q31.3 deletion syndrome (caused by a 5q31.3 deletion encompassing all or part of PURA) – are autosomal dominant disorders typically caused by a de novo genetic alteration. Rarely, individuals with a PURA-NDD have the disorder as the result of a pathogenic variant inherited from a heterozygous or mosaic parent.

PURA Syndrome – Risk to Family Members

Parents of a proband

  • Almost all individuals diagnosed with PURA syndrome have the disorder as the result of a de novo constitutional PURA pathogenic variant.
  • Rarely, individuals diagnosed with PURA syndrome have the disorder as the result of a postzygotic somatic mosaic PURA pathogenic variant. A child with PURA syndrome had triple somatic mosaic variants in PURA including one nonsense and two missense variants all shown to be present on the same chromosome by long-read sequencing [Fujita et al 2025]. The child presented with hypotonia, sucking and respiratory difficulty, developmental delay, precocious puberty, facial dysmorphism, and stagnated growth.
  • Rarely, individuals diagnosed with PURA syndrome have the disorder as the result of a PURA pathogenic variant inherited from a parent.
    • A child with PURA syndrome inherited a PURA pathogenic variant from her unaffected father, who had low-level somatic mosaicism [D Hunt, personal observation].
    • A child with a mild form of PURA syndrome inherited a PURA pathogenic missense variant from her heterozygous affected mother [Hildebrand et al 2024]. The child had dysarthria, phonologic disorder, severe receptive and expressive language impairment, borderline intellectual disability, attention difficulties, oropharyngeal dysmotility, and dysmorphic facial features. Her mother had dysarthria, moderate receptive language impairment, and borderline intellectual disability. Both the proband and her mother completed mainstream schooling with classroom support.
  • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. De novo occurrence of a PURA pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the PURA pathogenic variant.
  • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the parents:

Offspring of a proband. Each child of an individual with PURA syndrome has a 50% chance of inheriting the PURA pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the PURA pathogenic variant, the parent's family members may be at risk.

5q31.3 Deletion Syndrome – Risk to Family Members

Parents of a proband

  • To date, all reported 5q31.3 deletions have been de novo.
  • Evaluation of the parents by genomic testing that will detect the 5q31.3 deletion identified in the proband is recommended. In addition, karyotype of the parents is recommended to determine if a parent has a predisposing chromosomal anomaly.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the parents:

  • If neither parent has a detected 5q31.3 deletion or a chromosomal rearrangement, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the possibility of parental gonadal mosaicism.
  • If a predisposing balanced chromosome rearrangement is identified in a parent, the risk to sibs may be significant and depends on the specific chromosomal rearrangement and the possibility of other variables.

Offspring of a proband. To date, individuals with 5q31.3 deletion syndrome are not known to reproduce. However, the theoretic risk to offspring of an affected individual is 50%. (Note: Very few adults have been identified with 5q31.3 deletion syndrome.)

Other family members. Given that all probands reported to date with 5q31.3 deletion syndrome have had a de novo deletion, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once an intragenic pathogenic variant in PURA or a 5q31.3 chromosomal deletion encompassing all or part of PURA has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

PURA-Related Neurodevelopmental Disorders: Genes and Databases

GeneChromosome LocusProteinHGMDClinVar
PURA5q31​.3Transcriptional activator protein Pur-alphaPURAPURA

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for PURA-Related Neurodevelopmental Disorders (View All in OMIM)

600473PURINE-RICH ELEMENT-BINDING PROTEIN A; PURA
616158NEURODEVELOPMENTAL DISORDER WITH NEONATAL RESPIRATORY INSUFFICIENCY, HYPOTONIA, AND FEEDING DIFFICULTIES; NEDRIHF

Molecular Pathogenesis

PURA encodes a highly conserved 322-amino acid protein, transcriptional activator protein Pur-alpha [Lalani et al 2014]. The functionality of Pur-alpha depends on three PUR repeat motifs: PUR I, PUR II, and PUR III [Graebsch et al 2009, Weber et al 2016, Wang et al 2025].

PUR-alpha is a sequence-specific, DNA-/RNA-binding protein with an important role in DNA replication, DNA transcription, mRNA trafficking, and unwindase activity [White et al 2009, Weber et al 2016]. Pur-alpha is a multifunctional protein that has an important role in normal postnatal brain development in animal models [Khalili et al 2003, Hokkanen et al 2012]. Note: Interestingly, PURA had de novo loss-of-function variants in a neurodevelopmental disorder cohort significantly exceeding any plausible ascertainment by disease. The authors concluded this is consistent with the known function of PURA in regulating replication and transcription control [Seplyarskiy et al 2025].

Mechanism of disease causation. Although effects of PURA pathogenic variants at functional levels are not yet clear, such variants presumably cause functional haploinsufficiency of the protein [Hunt et al 2014]. In vitro studies with cell lines suggest PURA pathogenic variants impair DNA-binding PUR domains of the Pur-alpha protein and its colocalization with processing bodies (P-bodies) that are cytoplasmic structures critical in post-transcriptional gene regulation, particularly mRNA decay and translational repression [Proske et al 2024]. The PURA pathogenic variants destroyed the folding integrity, RNA binding, or dimerization of Pur-alpha. The protein was particularly susceptible to even conservative PURA pathogenic variants impairing its structural integrity, potentially explaining the full penetrance of manifestations in individuals with PURA syndrome.

A specific episignature for individuals with PURA syndrome was identified by genome-wide DNA methylation analysis [Xiao et al 2024]. This distinctive methylation profile was used to reclassify PURA variants of uncertain significance. A haploinsufficiency mechanism was supported by individuals with PURA syndrome heterozygous for either haploinsufficient or missense PURA variants sharing comparable DNA methylation profiles with consistent Pur-alpha downregulation. The PURA episignature is not available for clinical testing on the current EpiSign v5 (https://episign.com) classifier but may be added in the future.

PURA-specific laboratory technical considerations. Individuals with 5q31.3 deletion syndrome have nonrecurrent chromosomal deletions of varying sizes; thus, genetically, they represent a comparatively heterogeneous group. PURA is one of two genes located within the minimum critical deleted region associated with 5q31.3 deletion syndrome [Dai et al 2023]. To date, the smallest microdeletion encompassing PURA was reported by Bonaglia et al [2015].

Chapter Notes

Author History

Mel Anderson, BEd, PGDip (2026-present)
Diana Baralle, MBBS, MD, FRCP (2017-present)
Michael S Hildebrand, PhD (2026-present)
David Hunt, MBBS, PhD, MRCP (2017-present)
Bo Hoon Lee, MD (2017-present)
Richard J Leventer, MBBS, BMedSci, PhD, FRACP (2017-present)
Angela T Morgan, BSpPath (AudHons), PhD (2026-present)
Alex R Paciorkowski, MD, FACMG (2017-present)
Margot RF Reijnders, MD, PhD (2017-present)
L Dengle Sanchez, MD (2026-present)
Paulo Selber, MD, SBOT, FRACS (2017-present)
Miya St John, BSc, MAppLing, MspPath, PhD (2026-present)

Revision History

  • 25 March 2026 (bp) Comprehensive update posted live
  • 27 April 2017 (bp) Review posted live
  • 13 May 2016 (dh) Original submission

References

Literature Cited

  • Aaltio J, Etula A, Ojanen S, Brilhante V, Lönnqvist T, Isohanni P, Suomalainen A. Genetic etiology of progressive pediatric neurological disorders. Pediatr Res. 2024;95:102-11. [PMC free article: PMC10798881] [PubMed: 37563452]
  • Ben Issa A, Ben Ayed I, Jallouli O, Souissi A, Bouchaalla W, Ben Said M, Mallouli S, Masmoudi S, Charfi Triki C, Hadj Kacem H, Kammoun F. A new case with the recurrent PURA p.(Phe233del) pathogenic variant: expansion of the phenotype and review of the literature. Int J Dev Neurosci. 2023;83:383-95. [PubMed: 37204304]
  • Boczek NJ, Macke EL, Kemppainen J, Klee EW, Renaud DL, Gavrilova RH. Expansion of PURA-related phenotypes and discovery of a novel PURA variant: a case report. Child Neurol Open. 2020;7:2329048X20955003. [PMC free article: PMC7573717] [PubMed: 33117858]
  • Bonaglia MC, Zanotta N, Giorda R, D'Angelo G, Zucca C. Long-term follow-up of a patient with 5q31.3 microdeletion syndrome and the smallest de novo 5q31.2q31.3 deletion involving PURA. Mol Cytogenet 2015:8:89. [PMC free article: PMC4650292] [PubMed: 26582469]
  • Borlot F, de Almeida BI, Combe SL, Andrade DM, Filloux FM, Myers KA. Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability. Epilepsia. 2019;60:1661-9. [PubMed: 31273778]
  • Brown N, Burgess T, Forbes R, McGillivray G, Kornberg A, Mandelstam S, Starl Z. 5q31.3 Microdeletion syndrome: clinical and molecular characterization of two further cases. Am J Med Genet A 2013;161A:2604-8. [PubMed: 23950017]
  • Cerón SM, Pérez DA, Montaño JH, Acosta MA. First report of PURA syndrome in a Colombian patient with de novo missense variant c.692T>C (p.Phe231Ser). Biomedica. 2024;44:441-50. [PMC free article: PMC11781598] [PubMed: 39531550]
  • Choi SA, Lee HS, Park TJ, Park S, Ko YJ, Kim SY, Lim BC, Kim KJ, Chae JH. Expanding the clinical phenotype and genetic spectrum of PURA-related neurodevelopmental disorders. Brain Dev. 2021;43:912-8. [PubMed: 34116881]
  • Cinquina V, Ciaccio C, Venturini M, Masson R, Ritelli M, Colombi M. Expanding the PURA syndrome phenotype: a child with the recurrent PURA p.(Phe233del) pathogenic variant showing similarities with cutis laxa. Mol Genet Genomic Med. 2021;9:e1562. [PMC free article: PMC7963414] [PubMed: 33275834]
  • Colombo RB, Maxit C, Martinelli D, Anderson M, Masone D, Mayorga L. PURA and GLUT1: sweet partners for brain health. Biochim Biophys Acta Mol Basis Dis. 2024;1870:167261. [PubMed: 38777099]
  • Crippa ACS, Bacheladenski EP, Rodrigues DCB, Ferreira LP, Meira AT, Franklin GL. Movement disorders in PURA syndrome: a video case series. Mov Disord Clin Pract. 2023;10:1542-6. [PMC free article: PMC10585970] [PubMed: 37868916]
  • Dai W, Sun Y, Fan Y, Gao Y, Zhan Y, Wang L, Xiao B, Qiu W, Gu X, Sun K, Yu Y, Xu N. A 25 Mainland Chinese cohort of patients with PURA-related neurodevelopmental disorders: clinical delineation and genotype-phenotype correlations. Eur J Hum Genet. 2023;31:112-21. [PMC free article: PMC9822978] [PubMed: 36376392]
  • Falsaperla R, Sortino V, Schinocca MA, Fusto G, Rizzo R, Barberi C, Ruggieri M, Pappalardo XG. PURA-related neurodevelopmental disorders with epilepsy treated with ketogenic diet: a case-based review. Genes (Basel). 2024;15:848. [PMC free article: PMC11276249] [PubMed: 39062627]
  • Fujita A, Suenaga Y, Takeshita E, Takahashi Y, Suzuki Y, Ohori S, Tsuchida N, Uchiyama Y, Koshimizu E, Miyatake S, Mizuguchi T, Matsumoto N. Triple mosaic variants of PURA in a patient with multiple congenital anomalies. J Hum Genet. 2025;70:227-30. [PubMed: 39809889]
  • Fukuda Y, Kudo Y, Saito M, Kaname T, Oota T, Shoji R. Expanding the PURA syndrome phenotype with manifestations in a Japanese female patient. Hum Genome Var. 2022;9:11. [PMC free article: PMC9019084] [PubMed: 35440576]
  • Graebsch A, Roche S, Niessing D. X-ray structure of Pur-alpha reveals a Whirly-like fold and an unusual nucleic-acid binding surface. Proc Natl Acad Sci U S A 2009;106:18521-6. [PMC free article: PMC2765457] [PubMed: 19846792]
  • Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z, Li S, Tang S, Helbig I. Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med. 2016;18:898-905. [PubMed: 26795593]
  • Hildebrand MS, Braden RO, Lauretta ML, Kaspi A, Leventer RJ, Anderson M, Goel H, Bahlo M, Scheffer IE, Amor DJ, Janowski R, Niessing D, Morgan AT. Inherited PURA pathogenic variant associated with a mild neurodevelopmental disorder. Neurol Genet. 2024;10:e200181. [PMC free article: PMC11309559] [PubMed: 39131487]
  • Hokkanen S, Feldmann HM, Ding H, Jung CK, Bojarski L, Renner-Müller I, Schüller U, Kretzschmar H, Wolf E, Herms J. Lack of Pur-alpha alters postnatal brain development and causes megalencephaly. Hum Mol Genet 2012;21:473-84 [PubMed: 22010047]
  • Hosoki K, Ohta T, Natsume J, Imai S, Okumura A, Matsui T, Harda N, Bacino CA, Scaglia F, Jones JY, Niikawa N, Saitoh S. Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome. Am J Med Genet A 2012;158A:1891-6 [PubMed: 22711443]
  • Hunt D, Leventer RJ, Simons C, Taft R, Swoboda KJ, Gawne-Cain M, Study DDD, Magee AC, Turnpenny PD, Baralle D. Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability. J Med Genet 2014;51:806-13. [PMC free article: PMC4251168] [PubMed: 25342064]
  • Jezela-Stanek A, Ciara E, Jurkiewicz D, Kucharczyk M, Jędrzejowska M, Chrzanowska KH, Krajewska-Walasek M, Żemojtel T. The phenotype-driven computational analysis yields clinical diagnosis for patients with atypical manifestations of known intellectual disability syndromes. Mol Genet Genomic Med. 2020;8:e1263. [PMC free article: PMC7507388] [PubMed: 32337850]
  • Johannesen KM, Gardella E, Gjerulfsen CE, Bayat A, Rouhl RPW, Reijnders M, Whalen S, Keren B, Buratti J, Courtin T, Wierenga KJ, Isidor B, Piton A, Faivre L, Garde A, Moutton S, Tran-Mau-Them F, Denommé-Pichon AS, Coubes C, Larson A, Esser MJ, Appendino JP, Al-Hertani W, Gamboni B, Mampel A, Mayorga L, Orsini A, Bonuccelli A, Suppiej A, Van-Gils J, Vogt J, Damioli S, Giordano L, Moortgat S, Wirrell E, Hicks S, Kini U, Noble N, Stewart H, Asakar S, Cohen JS, Naidu SR, Collier A, Brilstra EH, Li MH, Brew C, Bigoni S, Ognibene D, Ballardini E, Ruivenkamp C, Faggioli R, Afenjar A, Rodriguez D, Bick D, Segal D, Coman D, Gunning B, Devinsky O, Demmer LA, Grebe T, Pruna D, Cursio I, Greenhalgh L, Graziano C, Singh RR, Cantalupo G, Willems M, Yoganathan S, Góes F, Leventer RJ, Colavito D, Olivotto S, Scelsa B, Andrade AV, Ratke K, Tokarz F, Khan AS, Ormieres C, Benko W, Keough K, Keros S, Hussain S, Franques A, Varsalone F, Grønborg S, Mignot C, Heron D, Nava C, Isapof A, Borlot F, Whitney R, Ronan A, Foulds N, Somorai M, Brandsema J, Helbig KL, Helbig I, Ortiz-González XR, Dubbs H, Vitobello A, Anderson M, Spadafore D, Hunt D, Møller RS, Rubboli G; PURA study group. PURA-related developmental and epileptic encephalopathy: phenotypic and genotypic spectrum. Neurol Genet. 2021;7:e613. [PMC free article: PMC8592566] [PubMed: 34790866]
  • Kaspi A, Hildebrand MS, Jackson VE, Braden R, van Reyk O, Howell T, Debono S, Lauretta M, Morison L, Coleman MJ, Webster R, Coman D, Goel H, Wallis M, Dabscheck G, Downie L, Baker EK, Parry-Fielder B, Ballard K, Harrold E, Ziegenfusz S, Bennett MF, Robertson E, Wang L, Boys A, Fisher SE, Amor DJ, Scheffer IE, Bahlo M, Morgan AT. Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development. Mol Psychiatry. 2023;28:1647-63. [PMC free article: PMC10208970] [PubMed: 36117209]
  • Khalili K, Del Valle L, Muralidharan V, Gault WJ, Darbinian N, Otte J, Meier E, Johnson EM, Daniel DC, Kinoshita Y, Amini S, Gordon J. Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse. Mol Cell Biol 2003;23:6857-75. [PMC free article: PMC193944] [PubMed: 12972605]
  • Kobak J, Szczupak M, Czerkiewicz K, Bielocerkowski S, Krupa-Nurcek S. PURA syndrome-a genetic cause of a neurodevelopmental disorder-case report. Front Pediatr. 2025 Jul 10;13:1607213. [PMC free article: PMC12286935] [PubMed: 40708900]
  • Kofoed AWS, Kristiansen SS, Miranda MJ, Rubboli G, Johannesen KM. Differences in manifestations of epilepsy and developmental delay in PURA syndrome and 5q31 microdeletions. Clin Genet. 2024;106:386-93. [PubMed: 38923490]
  • Kwong AK, Tsang MH, Fung JL, Mak CC, Chan KL, Rodenburg RJT, Lek M, Huang S, Pajusalu S, Yau MM, Tsoi C, Fung S, et al. Exome sequencing in paediatric patients with movement disorders. Orphanet J Rare Dis. 2021;16:32. [PMC free article: PMC7809769] [PubMed: 33446253]
  • Lalani SR, Zhang J, Schaaf CP, Brown CW, Magoulas P, Tsai AC, El-Gharbawy A, Wierenga KJ, Bartholomew D, Fong CT, Barbaro-Dieber T, Kukolich MK, Burrage LC, Austin E, Keller K, Pastore M, Fernandez F, Lotze T, Wilfong A, Purcarin G, Zhu W, Craigen WJ, Mcguire M, Jain M, Cooney E, Azamian M, Bainbridge MN, Muzny DM, Boerwinkle E, Person RE, Niu Z, Eng CM, Lupski JR, Gibbs RA, Beaudet al Yang Y, Wang MC, Xia F. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome. Am J Hum Genet 2014;95:579-83. [PMC free article: PMC4225583] [PubMed: 25439098]
  • Lee BH, Reijnders MRF, Abubakare O, Tuttle E, Lape B, Minks KQ, Stodgell C, Bennetto L, Kwon J, Fong CT, Gripp KW, Marsh ED. Expanding the neurodevelopmental phenotype of PURA syndrome. Am J Med Genet A. 2018;176:56-67. [PMC free article: PMC5821266] [PubMed: 29150892]
  • Lee S, Kim SH, Kim HD, Lee JS, Ko A, Kang HC. Genetic diagnosis in neonatal encephalopathy with hypoxic brain damage using targeted gene panel sequencing. J Clin Neurol. 2024;20:519-28. [PMC free article: PMC11372210] [PubMed: 39227335]
  • Lin SJ, Lin YF, Tsai CH, Huang CH, Ho F, Tsai SF, Lin WS. Complex movement disorders in a boy with PURA syndrome. Mov Disord Clin Pract. 2021;8:1137-9. [PMC free article: PMC8485615] [PubMed: 34631953]
  • Liu SN, Chi CS, Lee HF, Tsai CR, Yang YL, Wu PY. Genotype-phenotype variations in PURA syndrome: Asian and non-Asian perspectives from a systematic review. Orphanet J Rare Dis. 2025;20:376. [PMC free article: PMC12297800] [PubMed: 40713824]
  • Liu Y, Liu R, Xu T, Zhou YX, Zhang SC. Neonatal PURA syndrome: a case report and literature review. Transl Pediatr. 2021;10:194-203. [PMC free article: PMC7882292] [PubMed: 33633953]
  • López-Rivera JJ, Rodríguez-Salazar L, Soto-Ospina A, Estrada-Serrato C, Serrano D, Chaparro-Solano HM, Londoño O, Rueda PA, Ardila G, Villegas-Lanau A, Godoy-Corredor M, Cuartas M, et al. Structural protein effects underpinning cognitive developmental delay of the PURA p.Phe233del mutation modelled by artificial intelligence and the hybrid quantum mechanics-molecular mechanics framework. Brain Sci. 2022;12:871. [PMC free article: PMC9313109] [PubMed: 35884678]
  • Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, Massingham LJ, Miller D, Yu TW, Hisama FM; ACMG Board of Directors. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23:2029-37. [PubMed: 34211152]
  • Mayorga L, Gamboni B, Mampel A, Roqué M. A frame-shift deletion in the PURA gene associates with a new clinical finding: hypoglycorrhachia. Is GLUT1 a new PURA target? Mol Genet Metab. 2018;123:331-6. [PubMed: 29307761]
  • Mishra S, Girisha KM, Shukla A. Expanding the phenotype of PURA-related neurodevelopmental disorder: a close differential diagnosis of infantile hypotonia with psychomotor retardation and characteristic facies. Clin Dysmorphol. 2021;30:1-5. [PMC free article: PMC9944571] [PubMed: 33229923]
  • Mora-Martinez S, Castaño-Giraldo N, Nati-Castillo HA, Barahona Machado L, Mora Arbeláez T, Gordillo-Gonzalez G, Izquierdo-Condoy JS. Case report: expanding the phenotypic spectrum of PURA syndrome in South America with the first presentation of concurrent vitiligo. Front Pediatr. 2024;12:1323014. [PMC free article: PMC11007168] [PubMed: 38606370]
  • Mroczek M, Zafeiriou D, Gurgel-Gianetti J, Vilela Morais de Azevedo B, Roos A, Bartels E, Kohlschmidt N, Phadke R, Feng L, Duff J, Töpf A, Straub V. Three individuals with PURA syndrome in a cohort of patients with neuromuscular disease. Neuropediatrics. 2021;52:390-3. [PubMed: 33352606]
  • Noda Y, Kido J, Misumi Y, Sugawara K, Ohori S, Fujita A, Matsumoto N, Ueda M, Nakamura K. Heterozygous c.175C>T variant in PURA gene causes severe developmental delay. Clin Case Rep. 2023;11:e7779. [PMC free article: PMC10483498] [PubMed: 37692153]
  • Nogueira M, Melo C, Grangeia A, Magalhães T, Soares C, Dias R, Fonseca J, Sampaio M, Sousa R. PURA syndrome in a child with severe developmental delay: a challenging diagnosis. Rev Neurol. 2022;74:170-3. [PMC free article: PMC11502210] [PubMed: 35211951]
  • Okamoto N, Nakao H, Niihori T, Aoki Y. Patient with a novel purine-rich element binding protein A mutation. Congenit Anom (Kyoto). 2017;57:201-4. [PubMed: 28164378]
  • Proske M, Janowski R, Bacher S, Kang HS, Monecke T, Koehler T, Hutten S, Tretter J, Crois A, Molitor L, Varela-Rial A, Fino R, Donati E, et al. PURA syndrome-causing mutations impair PUR-domain integrity and affect P-body association. Elife. 2024;13:RP93561. [PMC free article: PMC11042805] [PubMed: 38655849]
  • Qashqari H, McNiven V, Gonorazky H, Mendoza-Londono R, Hassan A, Kulkarni T, Amburgey K, Dowling JJ. PURA syndrome: neuromuscular junction manifestations with potential therapeutic implications. Neuromuscul Disord. 2022;32:842-4. [PubMed: 36210261]
  • Qiao Y, Bagheri H, Tang F, Badduke C, Martell S, Lewis SME, Robinson W, Connolly MB, Arbour L, Rajcan-Separovic E. Exome sequencing identified a de novo mutation of PURA gene in a patient with familial Xp22.31 microduplication. Eur J Med Genet. 2019;62:103-8. [PubMed: 29908350]
  • Reijnders MRF, Janowski R, Alvi M, Self JE, van Essen TJ, Vreeburg M, Rouhl RPW, Stevens SJC, Stegmann APA, Schieving J, Pfundt R, van Dijk K, et al. PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature. J Med Genet. 2018;55:104-13. [PMC free article: PMC5800346] [PubMed: 29097605]
  • Rezkalla J, Von Wald T, Hansen KA. Premature thelarche and the PURA syndrome. Obstet Gynecol. 2017;129:1037-9. [PubMed: 28486374]
  • Richa S, Dwivedi A, Shaw SC, Singh D. NEDRIHF syndrome or PURA syndrome: a rare cause of central hypotonia. Med J Armed Forces India. 2024;80:S325-S328. [PMC free article: PMC11670646] [PubMed: 39734905]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Rodríguez-García ME, Cotrina-Vinagre FJ, Arranz-Canales E, Aragón AM, Hernández-Sánchez L, Rodríguez-Fornés F, Carnicero-Rodríguez P, Morales-Conejo M, Martín-Hernández E, Martínez-Azorín F. A novel de novo mutation in the PURA gene associated with a new clinical finding: large brainstem. J Genet. 2020;99:7. [PubMed: 32089526]
  • Rosenfeld JA, Drautz JM, Clericuzio CL, Cushing T, Raskin S, Martin J, Tervo RC, Pitarque JA, Nowak DM, Karolak JA, Lamb AN, Schultz RA, Ballif BC, Bejjani BA, Gajecka M, Shaffer LG. Deletions and duplications of developmental pathway genes in 5q31 contribute to abnormal phenotypes. Am J Med Genet A. 2011;155A:1906-16. [PubMed: 21744490]
  • Seplyarskiy V, Moldovan MA, Koch E, Kar P, Neville MDC, Rahbari R, Sunyaev S. Hotspots of human mutation point to clonal expansions in spermatogonia. Nature. 2025;647:429-35. [PMC free article: PMC12714578] [PubMed: 41062699]
  • Shimojima K, Isidor B, Le Caignec C, Kondo A, Sakata S, Ohno K, Yamamoto T. A new microdeletion syndrome of 5q31.3 characterized by severe developmental delays, distinctive facial features, and delayed myelinisation. Am J Med Genet A 2011;155A:732-6. [PubMed: 21594995]
  • Shimojima K, Okamoto N, Ohmura K, Nagase H, Yamamoto T. Infantile spasms related to a 5q31.2-q31.3 microdeletion including PURA. Hum Genome Var. 2018;5:18007. [PMC free article: PMC5874397] [PubMed: 29619234]
  • Sinisterra-Díaz SE, Vasquez-Forero DM, Ordoñez L, Prieto LE, Pachajoa H. A Colombian boy with a novel de novo PURA variant: a case report. Mol Syndromol. 2025;16:278-82. [PMC free article: PMC12136552] [PubMed: 40475166]
  • Solazzi R, Fiorini E, Parrini E, Guerrini R, Bernardina BD, Nardocci N, Cantalupo G. Early-onset bradykinetic rigid syndrome and reflex seizures in a child with PURA syndrome. Epileptic Disord. 2021;23:745-8. [PubMed: 34583915]
  • Spangenberg L, Guecaimburú R, Tapié A, Vivas S, Rodríguez S, Graña M, Naya H, Raggio V. Novel frameshift mutation in PURA gene causes severe encephalopathy of unclear cause. Mol Genet Genomic Med. 2021;9:e1622. [PMC free article: PMC8172205] [PubMed: 33750045]
  • Tanaka AJ, Bai R, Cho MT, Anyane-Yeboa K, Ahimaz P, Wilson AL, Kendall F, Hay B, Moss T, Nardini M, Bauer M, Retterer K, Juusola J, Chung WK. De novo mutations in PURA are associated with hypotonia and developmental delay. Cold Spring Harb Mol Case Stud. 2015;1:a000356 [PMC free article: PMC4850890] [PubMed: 27148565]
  • Taniguchi N, Watanuki K, Nakato D, Takenouchi T, Kosaki K, Koga H. PURA-related neurodevelopmental disorders: a systematic review on genotype-phenotype correlations. J Med Genet. 2025;62:191-8. [PubMed: 39824548]
  • Trau SP, Pizoli CE. PURA syndrome and myotonia. Pediatr Neurol. 2020;104:62-3. [PubMed: 31911028]
  • van der Sanden BPGH, Schobers G, Corominas Galbany J, Koolen DA, Sinnema M, van Reeuwijk J, Stumpel CTRM, Kleefstra T, de Vries BBA, Ruiterkamp-Versteeg M, Leijsten N, Kwint M, Derks R, Swinkels H, den Ouden A, Pfundt R, Rinne T, de Leeuw N, Stegmann AP, Stevens SJ, van den Wijngaard A, Brunner HG, Yntema HG, Gilissen C, Nelen MR, Vissers LELM. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur J Hum Genet. 2023;31:81-8. [PMC free article: PMC9822884] [PubMed: 36114283]
  • Wang Y, Wang P, He J, Wang H, Liu S. PURA protein mislocalisation in the nucleus: mechanistic basis for transcriptional dysregulation and DNA unwinding deficits in a model of the p.L148Wfs*77 PURA variant. J Med Genet. 2025;62:812-821. [PMC free article: PMC12703310] [PubMed: 41130720]
  • Weber J, Bao H, Hartlmüller C, Wang Z, Windhager A, Janowski R, Madl T, Jin P, Niessing D. Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha. Elife. 2016;5:e11297. [PMC free article: PMC4764581] [PubMed: 26744780]
  • White MK, Johnson EM, Khalili K. Multiple roles for Puralpha in cellular and viral regulation. Cell Cycle. 2009;8:1-7. [PMC free article: PMC2683411] [PubMed: 19182532]
  • Wyrebek R, DiBartolomeo M, Brooks S, Geller T, Crenshaw M, Iyadurai S. Hypotonic infant with PURA syndrome-related channelopathy successfully treated with pyridostigmine. Neuromuscul Disord. 2022;32:166-9. [PubMed: 35094889]
  • Xiao B, Dai W, Zhan Y, Qiu W, Zhang H, Liu D, Xu N, Yu Y. Genome-wide epigenetic signatures facilitated the variant classification of the PURA gene and uncovered the pathomechanism of PURA-related neurodevelopmental disorders. Genet Med. 2024;26:101167. [PubMed: 38770750]
  • Zhang D, Gao J. Neonatal PURA syndrome mimicking cervical spinal cord injury after a cesarean section for a breech presentation: a case report. Int J Gynaecol Obstet. 2023;163:1033-5. [PubMed: 37724818]
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