Pura-Related Neurodevelopmental Disorders
Summary
Clinical characteristics.
PURA-related neurodevelopmental disorders include PURA syndrome, caused by a heterozygous pathogenic sequence variant in PURA, and 5q31.3 deletion syndrome, caused by a genomic 5q31.3 deletion encompassing all or part of PURA. PURA-related neurodevelopmental disorders are characterized by moderate-to-severe neurodevelopmental delay with absence of speech in most and lack of independent ambulation in many. Early-onset problems 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 a PURA-related neurodevelopmental disorder is established in a proband with either a heterozygous PURA pathogenic sequence variant (90% of affected individuals) or a nonrecurrent deletion of 5q31.3 that encompasses all or part of PURA (10%).
Management.
Treatment of manifestations: Ongoing routine care by a multidisciplinary team. Treatment and/or therapy for developmental delays; neurologic findings (hypotonia, seizures, abnormal movements); feeding difficulties; apnea; visual impairment; and malformations of the heart, urogenital tract, and skeleton.
Surveillance: Long-term follow up to assess psychomotor development, seizures or suspected seizures, vision, feeding for dysphagia, and musculoskeletal complications (hip dysplasia and scoliosis).
Genetic counseling.
PURA-related neurodevelopmental disorders, caused by either a heterozygous PURA pathogenic sequence variant or a 5q31.3 deletion encompassing all or part of PURA, are inherited in an autosomal dominant manner. In almost all probands with a PURA pathogenic sequence variant the sequence variant is de novo; to date, all reported 5q31.3 deletions have been de novo. For parents of an affected child, the risk to future pregnancies is presumed to be low, as a de novo genetic alteration involving PURA is most likely in the proband. However, parents of an affected child may wish to consider prenatal testing or preimplantation genetic testing, as risk may be greater than in the general population owing to the possibility of parental germline mosaicism (estimated empirically at <1%).
Diagnosis
No formal clinical diagnostic criteria have been published for PURA-related neurodevelopmental disorders, which comprise PURA syndrome (caused by a heterozygous PURA pathogenic sequence variant) and 5q31.3 deletion syndrome (caused by a nonrecurrent 5q31.3 deletion encompassing all or part of PURA).
Suggestive Findings
A PURA-related neurodevelopmental disorder should be suspected in infants and older individuals with the following clinical findings.
Infants
- Hypotonia
- Neonatal hypoventilation
- Hypothermia
- Hypersomnolence
- Feeding difficulties, including gastroesophageal reflux disease (GERD)
Older individuals
- Hypotonia
- Moderate-to-severe intellectual disability, including absent speech
- Seizures
- Abnormal nonepileptic movements (e.g., dystonia, dyskinesia, and dysconjugate eye movements)
Establishing the Diagnosis
The diagnosis of a PURA-related neurodevelopmental disorder is established in a proband with one of the following genetic findings (see Table 1):
- A heterozygous PURA pathogenic sequence variant (90% of affected individuals)
- Nonrecurrent deletion of 5q31.3 that encompasses all or part of PURA (10%)
Molecular genetic testing approaches can include a combination of genomic testing (chromosomal microarray analysis, comprehensive genomic sequencing) and gene-targeted testing (multigene panel and single-gene testing).
Gene-targeted testing requires the clinician to determine which specific gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many genetic intellectual disability disorders overlap, most children with a PURA-related neurodevelopmental disorder are diagnosed by one of the following.
Recommended Testing
A multigene panel that includes PURA and other genes of interest (see Differential Diagnosis). 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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 this disorder, a multigene panel that also includes copy number analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Chromosomal microarray analysis (CMA) to detect large, nonrecurrent 5q31.3 deletions that include PURA which cannot readily be detected by sequence analysis of PURA.
Testing to Consider
Comprehensive genomic sequencing (when available) includes exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Note: Single-gene testing (sequence analysis of PURA, followed by gene-targeted deletion/duplication analysis) may be helpful in some circumstances – for example, when clinical suspicion in a neonate is considerable and a rapid diagnosis would be beneficial.
Table 1.
Molecular Genetic Testing Used in PURA-Related Neurodevelopmental Disorders
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| PURA | Sequence analysis 3 | 71/79 4 |
| Gene-targeted deletion/duplication analysis 5 | Unknown 6 | |
| CMA 7 | 8/79 8 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic 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 small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
n=11 [Lalani et al 2014], n=4 [Hunt et al 2014], n=6 [Tanaka et al 2015], n=1 [Okamoto et al 2017], n=49 [Author, personal observation]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
- 7.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 5q31.3 region.
- 8.
n=2 [Shimojima et al 2011], n=3 [Hosoki et al 2012], n=2 [Brown et al 2013], n=1 [Bonaglia et al 2015]
Clinical Characteristics
Clinical Description
PURA-related neurodevelopmental disorders comprise PURA syndrome (caused by a heterozygous PURA pathogenic sequence variant) and 5q31.3 deletion syndrome (caused by a nonrecurrent 5q31.3 deletion encompassing all or part of PURA). PURA-related neurodevelopmental disorders are characterized by moderate-to-severe neurodevelopmental delay; most affected individuals are nonverbal, and many do not achieve independent ambulation.
Early-onset problems are wide ranging and can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements, and visual problems.
Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur, but are less common [Hunt et al 2014; Lalani et al 2014; Tanaka et al 2015; Okamoto et al 2017; Author, personal observation].
The figures given for the following clinical features are based on observed frequencies in individuals with PURA syndrome. Individuals with 5q31.3 deletions encompassing PURA have not been included here as they have nonrecurrent chromosomal deletions of varying sizes; thus, genetically, they represent a comparatively heterogeneous group.
Development. All 71 individuals with PURA syndrome reported to date have had moderate-to-severe neurodevelopmental delay.
Speech is absent in most; however, the use of augmentative and alternative communication aids has proved beneficial in some children. Many children have relatively good receptive language skills and may follow simple instructions, despite having no overt expressive language.
Motor development is delayed, but with variable severity. Some individuals never achieve independent ambulation. In those who do, the age ranges from 22 months to seven years. The gait of affected children is typically broad-based.
Many individuals have poor fine-motor skills, which can hinder the use of some types of communication aids.
Neurologic. Severe hypotonia and hypersomnolence are common at birth.
Epilepsy has been reported in at least 50% of the individuals (42/71) and usually starts with myoclonic jerks progressing to other seizure types including generalized tonic-clonic seizures, tonic seizures, and epileptic spasms. In some instances, the seizure disorder progresses to the Lennox-Gastaut syndrome.
The age of seizure onset ranges between the neonatal period and 16 years, although most of those who develop epilepsy do so in the first five years, many in infancy.
The seizures are often drug resistant.
Nonepileptic movements that may be seen include dystonia, dyskinesia, and dysconjugate eye movements.
Nonepileptic exaggerated startle response is present in several children.
Nystagmus is present in 17/71 individuals.
MRI findings include the following:
- Delayed myelination or nonspecific subtle white matter hyperintensities, which constitute the most frequently reported brain abnormalities (23/71)
- Excessive extra-axial fluid spaces (7/71)
- Volume loss of the corpus callosum (4/71)
- Cerebellar tonsillar ectopia (1/71)
- Possible cerebral atrophy (1/71)
- Absent septum pellucidum (1/71)
Ophthalmologic. Strabismus, Brown syndrome, and exophoria are the most frequently reported abnormalities (21/71).
Early cortical visual impairment (7/71), hypermetropia (6/71), and optic nerve pallor (1/71) have also been reported.
Respiratory. Apnea and hypoventilation are present in more than 50% of affected individuals (42/71).
For the majority of affected individuals, the episodes of apnea and hypoventilation resolve after the first year of life; however, in a minority, apnea may persist or recur during an acute respiratory illness.
Aspiration pneumonia due to hypotonia and dysphagia has been reported.
Cardiovascular. Structural heart defects, present in a minority of affected individuals, include ventricular septal defect (3/71), persistent foramen ovale (2/71), persistent ductus arteriosus (1/71), pulmonic stenosis (1/71), atrial septal defect (1/71), bicuspid aortic valve (1/71), and aberrant left subclavian artery (1/71). However, it should be borne in mind that these figures may represent an underestimate (particularly of minor cardiac abnormalities that may not be manifesting obvious signs of disease) as not all individuals will have had an echocardiogram as a matter of course.
Gastrointestinal. A significant number of neonates have severe feeding difficulties and/or gastroesophageal reflux disease (GERD) (56/71).
Dysphagia often persists throughout life. Drooling is common; however, the cause (either excessive salivation or oromotor dyspraxia / swallowing problems) requires further investigation.
Constipation has been reported in the majority of individuals [Tanaka et al 2015; Author, personal observation].
Urogenital. In four affected individuals, renal and genital defects including cryptorchidism (3/71), kidney stones (3/71), congenital hydronephrosis (2/71), prolapsed uterus (1/71), and urinary reflux (1/71) have been reported.
Skeletal. Scoliosis (13/71), hip dysplasia (11/71), and osteoporosis/osteopenia (7/71) are the most frequently reported skeletal abnormalities.
Endocrine. Anterior pituitary dysregulation may be within the spectrum of PURA-related neurodevelopmental disorders [Hunt et al 2014] based on the following observations:
- Disturbed levels of gonadotropins (2/71) and medical treatment for precocious puberty (3/71)
- A blunted cortisol response (2/71)
- Hypothyroidism (2/71)
- Elevated prolactin levels (1/71)
Although low vitamin D levels (7/71) and anemia and/or low iron levels (4/71) have been reported, the true prevalence may be higher as vitamin D and iron levels are often not measured routinely and deficiency may not be obvious clinically.
Other
- Neonatal hypothermia. Difficulties in regulating body temperature in the neonatal period have not yet been reported in the literature, but appear to occur frequently [Author, personal observation].
- Excessive hiccups in utero and in the neonatal period have been observed in a significant proportion of the individuals [Author, personal observation].
Genotype-Phenotype Correlations
Current data suggest that PURA 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 (see Molecular Genetics, Normal gene product). However, the functional effect at a molecular level is not yet clear and requires further investigation [Hunt et al 2014].
PURA-related neurodevelopmental disorders encompass both PURA syndrome and the 5q31.3 deletion syndrome. It has been suggested that PURA haploinsufficiency contributes to the neurodevelopmental phenotype of individuals with a 5q31.3 deletion [Brown et al 2013].
The features of individuals with a 5q31.3 deletion that overlap with those of individuals with a PURA pathogenic variant include neonatal hypotonia, feeding difficulties, 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].
Of note, individuals with a deletion that also includes the neighboring gene NRG2 – as well as those with larger deletions that encompass multiple genes in addition to PURA and NRG2 – show a more severe phenotype (including distinct facial dysmorphisms) than individuals with an intragenic PURA pathogenic variant. It has been suggested that deletion of NRG2 contributes to the more severe phenotype observed in individuals with a large 5q31.3 deletion [Brown et al 2013].
Penetrance
To the authors' knowledge, the penetrance of all intragenic PURA pathogenic variants and 5q31.3 deletions encompassing PURA is complete.
Nomenclature
The OMIM designation for PURA-related neurodevelopmental disorders – "mental retardation, autosomal dominant 31" (OMIM 616158) – is no longer in use.
Prevalence
To date, 71 individuals are known to have PURA syndrome [Hunt et al 2014; Lalani et al 2014; Tanaka et al 2015; Okamoto et al 2017; Author, personal observation]. Eight individuals with the 5q31.3 deletion syndrome have been reported.
Based on the study of Hunt et al [2014], the estimated frequency of PURA syndrome as a cause of intellectual disability is 3:1,133 (0.3%).
Lalani et al [2014] and Tanaka et al [2015] estimated a higher frequency (0.5%) based on their cohorts of 11:2,117 and 6:1,098, respectively.
Differential Diagnosis
Disorders in the differential diagnosis of PURA-related neurodevelopmental disorders are:
- Congenital central hypoventilation syndrome
- Prader-Willi syndrome
- Lower extremity-predominant autosomal dominant spinal muscular atrophy 1 (OMIM 158600) / distal autosomal recessive spinal muscular atrophy 1 (OMIM 604320)
- Myotonic dystrophy in the newborn (see Myotonic Dystrophy Type 1)
- Neurotransmitter disorder [Pearl et al 2007]
- Rett syndrome
- Pitt-Hopkins syndrome
- Angelman syndrome
See Mental retardation, autosomal dominant: OMIM Phenotypic Series to view genes associated with this phenotype in OMIM.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a PURA-related neurodevelopmental disorder, the following evaluations are recommended.
Table 2.
Recommended Evaluations Following Initial Diagnosis
| System/Concern | Evaluation | Comment |
|---|---|---|
| Cognitive | Developmental assessment | |
| Neurologic | Neurologic eval | |
| Brain MRI | Indicated in a child w/a PURA-related neurodevelopmental disorder w/seizures &/or hypoventilation &/or abnormal vision or eye movements who has not previously had a brain MRI | |
| EEG & video EEG | If seizures are suspected | |
| Eyes | Ophthalmology exam | Electrodiagnostic tests may be indicated. |
| Cardiovascular | Consider echocardiogram | |
| Respiratory | Assessment of pulmonary function | As needed |
| Gastrointestinal |
| As needed |
| Genitourinary | Consider ultrasound of the urinary tract. | |
| Musculoskeletal | Appropriate radiographs | If hip dysplasia &/or scoliosis is suspected |
| Endocrine | Assessment of serum vitamin D levels | |
| Assessment of bone density | If osteoporosis or osteopenia is suspected | |
| Eval of anterior pituitary hormones | If necessary | |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor |
Treatment of Manifestations
Individuals often benefit when management is provided by a multidisciplinary team including relevant specialists, which may include, but is not limited to, a pediatrician, clinical geneticist, child neurologist, pulmonologist, ophthalmologist, orthopedic surgeon, physiotherapist, occupational therapist, and speech and language therapist.
Table 3.
Treatment of Manifestations in Individuals with PURA-Related Neurodevelopmental Disorders
| Manifestation/Concern | Treatment | Considerations/Other |
|---|---|---|
| Cognitive/ Developmental delay | See Developmental Delay/ Intellectual Disability Educational Issues. | |
| Seizures | Mgmt by a neurologist | May include video EEG monitoring to help distinguish epileptic from nonepileptic events (e.g., dystonia, dyskinesia, dysconjugate eye movements) |
| Vision deficits | Correction of refractive errors; vision support; standard treatment for strabismus & exophoria | |
| Hypoventilation | Supplementary oxygen (at night) & rarely tracheostomy; some infants require short periods of intubation & mechanical ventilation, esp during acute illness. | Ambulatory peripheral saturation monitoring may be required. |
| Congenital heart defect | Mgmt per current practice for specific congenital heart defect | |
| Frequent aspiration (or high risk of aspiration) | A percutaneous endoscopic gastrostomy tube may be considered. | |
| Gastroesophageal reflux disease | Medical mgmt; consideration of Nissen fundoplication if medical treatment not sufficient | |
| Constipation | Routine mgmt | Referral to gastroenterologist may be required in severe cases. |
| Congenital urogenital defect | Mgmt per current practice for specific urogenital defect | |
| Scoliosis | Standard mgmt | Progressive neuropathic scoliosis may require spinal fusion. |
| Osteoporosis/ Oosteopenia | Standard mgmt | |
| Instability in standing position | Ankle foot orthoses may improve stability, allowing for better standing & transferring ability. | |
| Neuropathic hip dysplasia, progressive subluxation, & dislocation | Consideration of hip reconstructions w/varus derotational proximal femoral osteotomies | Generalized joint laxity & continued inability to walk may cause relapsing hip subluxation even after previous femoral osteotomies. |
| Vitamin D deficiency | Vitamin D supplementation | |
| Anterior pituitary hormone deficiencies | Standard treatment as directed by endocrinologist |
Developmental Delay / Intellectual Disability Educational Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States (US); 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. In the US, early intervention is a nationwide, federally funded program available in all states.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. An evaluation will occur before placement to determine needed services and therapies and will be subsequently written into an individualized education plan (IEP).
Ages 5-21 years
- In the US, an IEP should be developed by the local public school district based on each individual's level of function. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure that appropriate community, state, and educational agencies are involved and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a 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.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).
- Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
- For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of medications or orthopedic procedures.
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function (e.g., feeding, grooming, dressing).
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC] for individuals who have expressive language difficulties.
Surveillance
Table 4.
Recommended Surveillance for Individuals with PURA-Related Neurodevelopmental Disorders
| System/Concern | Evaluation | Frequency/Comment |
|---|---|---|
| Cognitive | Monitoring by developmental pediatrician | Long-term |
| Neurologic | EEG & video EEG monitoring | If seizures suspected |
| Eyes | Ophthalmologic & vision evals | Routine |
| Gastrointestinal | Monitoring for dysphagia & constipation | |
| Musculoskeletal | Monitoring for musculoskeletal complications incl hip dysplasia & scoliosis |
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.