Ppp2r5d-Related Neurodevelopmental Disorder
Summary
Clinical characteristics.
PPP2R5D-related neurodevelopmental disorder is characterized by mild to severe neurodevelopmental delay. Pronounced hypotonia with delay in gross motor skills is common. Onset of independent walking varies widely and ataxia is reported. All reported individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is reported in six individuals. Macrocephaly is common. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Additional anomalies include skeletal, endocrine, and cardiac malformations, each reported in a few individuals. To date, 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported.
Diagnosis.
The diagnosis of PPP2R5D-related neurodevelopmental disorder is established in a proband by identification of a heterozygous pathogenic variant in PPP2R5D on molecular genetic testing.
Management.
Treatment of manifestations: Standard treatment for seizures, visual impairment, and developmental delays.
Surveillance: Monitor for seizures, vision issues, developmental progress, and educational needs.
Genetic counseling.
PPP2R5D-related neurodevelopmental disorder is inherited in an autosomal dominant manner. All probands reported to date with PPP2R5D-related neurodevelopmental disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo PPP2R5D pathogenic variant. Risk to future pregnancies is presumed to be low, as the proband most likely has a de novo PPP2R5D pathogenic variant; however, given the theoretic possibility of parental germline mosaicism, recurrence risk to sibs is estimated at 1%, and thus prenatal and preimplantation genetic testing may be considered.
Diagnosis
Formal diagnostic criteria for PPP2R5D-related neurodevelopmental disorder have not been established.
Suggestive Findings
PPP2R5D-related neurodevelopmental disorder should be considered in individuals presenting with the following clinical and brain MRI findings.
Clinical findings
- Macrocephaly
- Generalized hypotonia of infancy
- Mild-to-profound developmental delays or intellectual disability
- Autism spectrum disorder
- Epilepsy (reported seizure types: generalized tonic-clonic, multifocal, complex partial, and generalized epileptic spasms)
Brain MRI findings
- Megalencephaly
- Nonspecific MRI findings include: hydrocephalus (2 individuals), mild-to-moderate ventricular dilatation (4 individuals), small or dysplastic corpus callosum (2), cavum septum pellucidum (1), cavum septum pellucidum et vergae (1), and white matter abnormalities (1) [Houge et al 2015, Shang et al 2016].
Establishing the Diagnosis
The diagnosis of PPP2R5D-related neurodevelopmental disorder is established in a proband by identification of a heterozygous pathogenic variant in PPP2R5D by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (typically exome sequencing).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of PPP2R5D -related neurodevelopmental disorder is nonspecific and indistinguishable from many other inherited disorders, it is most likely to be diagnosed by either a multigene panel (see Option 1) or genomic testing (see Option 2).
Option 1
An intellectual disability, macrocephaly, or epilepsy multigene panel that includes PPP2R5D and other genes of interest (see Differential Diagnosis) 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. 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. Of note, given the rarity of PPP2R5D-related neurodevelopmental disorder and the recent identification of the condition, most panels for intellectual disability may not include this gene. (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, and/or other non-sequencing-based tests (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of PPP2R5D-related neurodevelopmental disorder has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in PPP2R5D-Related Neurodevelopmental Disorder
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| PPP2R5D | Sequence analysis 3 | 23/23 (100%) 4 |
| Gene-targeted deletion/duplication analysis 5 | 0/23 (0%) None reported |
- 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.
Houge et al [2015], Loveday et al [2015], Shang et al [2016], Yeung et al [2017]
- 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.
Clinical Characteristics
Clinical Description
To date 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported [Houge et al 2015, Loveday et al 2015, Shang et al 2016, Yeung et al 2017]. Affected individuals range in age from 22 months to 53 years. Developmental delay and/or mild-to-severe intellectual disability has been reported in all individuals. Published clinical information is currently limited; it is likely that understanding of the phenotypic spectrum will evolve as additional affected individuals are identified.
The following are the most common clinical features of PPP2R5D-related neurodevelopmental disorder.
Psychosocial and cognitive development. All individuals reported to date have had developmental delay and/or intellectual disability. Developmental milestones are consistently delayed.
Although children were reported to have pronounced hypotonia, feeding difficulties were not reported as a major issue for most children. Gastric reflux was reported in one affected child [Houge et al 2015].
The age at which individuals walk independently varied widely – from age 18 months to nine years, with some individuals still unable to walk at age ten years. Six individuals were reported to walk with an ataxic gait [Houge et al 2015, Shang et al 2016].
All reported individuals had speech impairment, with a wide range of abilities. Seven individuals, ranging in age from two to 53 years, remained nonverbal. Eleven individuals were able to use words, although this ranged from two words with poor articulation at age ten years to 100-200 words and the ability to form short sentences at age 15 years. All individuals with PPP2R5D-related neurodevelopmental disorder have had issues with language development [Yeung et al 2017].
Evaluations for autism spectrum disorder (ASD) were done in eight children with PPP2R5D-related disorder. ASD was diagnosed in six of the eight children evaluated and suspected in one child who met some but not all of the DSM-IV criteria for ASD [Shang et al 2016, Yeung et al 2017]. Four children displayed behavioral issues such as tantrums, aggressiveness, trouble adjusting to new situations, and problems with impulse control [Shang et al 2016].
Macrocephaly/megalencephaly. Macrocephaly was reported in 18 of 23 individuals. Megalencephaly was specifically mentioned in two individuals. Head occipitofrontal circumference ranged from >2 to >3.8 SD above the mean in affected individuals. Congenital macrocephaly was reported in one individual [Loveday et al 2015]. The onset of macrocephaly has not been reported in most other affected individuals.
Hypotonia was reported in 17 individuals. Onset and severity were not reported.
Seizures have been reported in six individuals. Seizure types observed include generalized tonic-clonic, multifocal, complex partial, and generalized epileptic spasms. The age of onset ranged from four days to four years. Both individuals reported with megalencephaly also had epilepsy [Yeung et al 2017]. Further, two patients with epilepsy were described to have mild ventricular dilatation [Houge et al 2015] and one individual with complex partial seizures had cavum septum pellucidum (a nonspecific finding) on brain imaging [Shang et al 2016].
Ophthalmologic abnormalities such as strabismus, astigmatism, esotropia, rotational nystagmus, ptosis, and myopia were reported in seven of the 18 individuals assessed [Houge et al 2015, Shang et al 2016]. One individual had cataracts at age 53 years [Houge et al 2015].
Dysmorphic facial features. Many individuals have dysmorphic facial features including hypertelorism, downslanting palpebral fissures, frontal bossing, and a long, hypotonic face. Midface hypoplasia, low-set ears, and plagiocephaly have also been reported. Two patients with heights 2 SD above the mean were reported. However, dysmorphic features are mild, nonspecific, and vary widely among individuals reviewed.
Other
- Skeletal abnormalities observed in seven individuals include scoliosis, hip dysplasia, camptodactyly of the fourth toe, and middle 2/3 and 3/4 finger syndactyly [Houge et al 2015, Loveday et al 2015, Shang et al 2016].
- Endocrine abnormalities such as short stature (<3rd percentile) were observed in three individuals [Houge et al 2015, Shang et al 2016]. One individual had hypoglycemia and another was diagnosed with failure to thrive [Houge et al 2015, Shang et al 2016]. Age of onset of these conditions was unknown.
- Cardiac. Two individuals had significant cardiac abnormalities with atrial and ventricular septal defects and a bicuspid aortic valve in one individual and ventricular septal defect and patent foramen ovale in the other.
- Genital anomalies. One individual had hypospadias.
Genotype-Phenotype Correlations
There are no clear genotype-phenotype correlations as only 23 affected individuals have been reported to date.
Penetrance
There is no evidence of reduced penetrance; the majority of the reported pathogenic variants (22/23) are confirmed de novo. Parental results were not available for one affected individual.
Prevalence
The prevalence of PPP2R5D-related neurodevelopmental disorder is unknown. To date, 23 individuals with PPP2R5D-related neurodevelopmental disorder have been reported.
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of PPP2R5D-Related Neurodevelopmental Disorder
| Differential Diagnosis Disorder | Gene(s) | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/PPP2R5D-related ND | Distinguishing from PPP2R5D-related ND | |||
| PTEN hamartoma tumor syndrome | PTEN | AD |
|
|
| MTOR-related disorders (e.g., Smith-Kingsmore syndrome; OMIM 616638) | MTOR | AD |
|
|
| Sotos syndrome | NSD1 | AD |
|
|
| Megalencephaly-capillary malformation syndrome (see PIK3CA-Related Segmental Overgrowth) | PIK3CA | AD |
|
|
| Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome | PIK3R2 AKT3 CCND2 | AD |
|
|
| 16p11.2 deletion syndrome | See footnote 1 | AD |
| Obesity in adolescence & later in life |
| Kleefstra syndrome | EHMT1 | AD |
|
|
AD = autosomal dominant; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; ND = neurodevelopmental disorder
- 1.
The 16p11.2 recurrent deletion involves the loss of one chromosome segment harboring 25 annotated genes or transcripts [Kumar et al 2008, Marshall et al 2008, Weiss et al 2008]. The recurrent deletion is flanked by segmental duplications that contain four additional genes.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PPP2R5D-related neurodevelopmental disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with PPP2R5D-Related Neurodevelopmental Disorder
| System/Concern | Evaluation | Comment |
|---|---|---|
| Gastrointestinal/ Feeding | Nutrition eval if feeding difficulties present | Incl feeding assessment related to hypotonia & eval for gastroesophageal reflux. |
| Neurologic | Neurologic eval | Incl EEG if seizures are suspected. |
| Psychiatric/ Behavioral | Neuropsychiatric eval | Screen individuals age >12 mos for behavior concerns &/or traits suggestive of ASD. |
| Eyes | Ophthalmologic eval & vision assessment | |
| Cardiac | Full cardiac eval if audible murmurs present | True prevalence of cardiac malformation in this syndrome not yet known |
| Miscellaneous/ Other | Developmental assessment | Incl motor, speech/language eval, general cognitive, & vocational skills. |
| Consultation w/clinical geneticist &/or genetic counselor |
ASD = autism spectrum disorder
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with PPP2R5D-Related Neurodevelopmental Disorder
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Seizures | Standardized treatment w/AEDs by experienced neurologist | Many different AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder. |
| Education of parents regarding common seizure presentations | For information on non-medical interventions & coping strategies for parents or caregivers of children diagnosed w/epilepsy, see Epilepsy & My Child Toolkit. | |
| Abnormal vision &/or strabismus | Standard treatment(s) as recommended by ophthalmologist |
AEDs = antiepileptic drugs
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. In the US, early intervention is a federally funded program available in all states.
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 needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion of 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 the involvement of appropriate community, state, and educational agencies 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.
- Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
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.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one-on-one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
Table 5.
Recommended Surveillance for Individuals with PPP2R5D-Related Neurodevelopmental Disorder
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Neurologic | Monitor those w/seizures | As clinically indicated |
| Psychiatric | Behavior assessment for anxiety, attention, & aggressive or self-injurious behavior | As clinically indicated |
| Eyes | Ophthalmologic eval | At time of diagnosis & subsequently as needed depending on findings |
| Miscellaneous/ Other | Monitor developmental progress & educational needs | As clinically indicated |
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.