Clinical characteristics.

PPP2R5D-related neurodevelopmental disorder (PPP2R5D-NDD) is characterized by mild-to-profound neurodevelopmental delay, pronounced hypotonia, and macrocephaly. Onset of independent walking varies widely, and ataxia and movement disorders, including early-onset parkinsonism, are reported. Almost all individuals have speech impairment, with a wide range of abilities. Autism spectrum disorder is also reported in some individuals. Seizures and ophthalmologic abnormalities are reported in fewer than half of individuals. Gastrointestinal and skeletal manifestations are reported. Endocrine, cardiac, and genitourinary issues are each reported in a few individuals. To date, more than 100 individuals with PPP2R5D-NDD have been reported.

Diagnosis.

The diagnosis of PPP2R5D-NDD is established in a proband by identification of a heterozygous pathogenic variant in PPP2R5D by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment for developmental delays, intellectual disability, neurobehavioral issues, sleep dysregulation, seizures, visual impairment, gastrointestinal and skeletal manifestations, parkinsonism, and endocrine issues. Develop transition plan to adult care; provide family any community resources.

Surveillance: Assess developmental progress and educational needs at each visit; behavior assessment as clinically indicated; ophthalmology evaluations per ophthalmologist or as needed; assess for gastrointestinal and skeletal manifestations at each visit; evaluation with neurology as needed for movement disorder; assess for impairment in fine motor, gross motor, and activities of daily living at each visit; assess for precocious puberty annually throughout early childhood; assess for cryptorchism at each visit in early childhood.

Genetic counseling.

PPP2R5D-NDD is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Rarely, an individual diagnosed with PPP2R5D-NDD has the disorder as the result of a pathogenic variant inherited from an affected, heterozygous parent. Each child of an individual with PPP2R5D-NDD has a 50% chance of inheriting the pathogenic variant. Once the PPP2R5D pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

PPP2R5D-NDD should be considered in individuals presenting with the following clinical and brain MRI findings.

Clinical findings

• Generalized hypotonia of infancy
• Mild-to-profound developmental delays and/or intellectual disability
• Autism spectrum disorder
• Macrocephaly
• Epilepsy (reported seizure types: generalized tonic-clonic, myoclonic, multifocal, complex partial, and generalized epileptic spasms)
• Early-onset parkinsonism

Brain MRI findings

• Macrocephaly or megalencephaly
• Nonspecific findings including focal cortical abnormalities (n=2), cavum septum pellucidum et vergae (n=3), mesial temporal sclerosis (n=1), plagiocephaly (n=1), white matter abnormalities (n=3) and mild ventriculomegaly (n=5), hydrocephalus (n=2), small or dysplastic corpus callosum (n=2), and cavum septum pellucidum (n=1)

Establishing the Diagnosis

The diagnosis of PPP2R5D-NDD is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in PPP2R5D by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP 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 PPP2R5D variant of uncertain significance does not establish or rule out the diagnosis.

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-NDD 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).

Clinical Description

PPP2R5D-related neurodevelopmental disorder (PPP2R5D-NDD) is characterized by mild-to-profound developmental delay and/or intellectual disability, pronounced hypotonia, and macrocephaly. Some individuals have autism spectrum disorder, seizures, coordination disorder, early-onset parkinsonism, ophthalmologic abnormalities, and skeletal, endocrine, and/or cardiac malformations. To date, more than 100 individuals with PPP2R5D-NDD have been reported [Houge et al 2015, Loveday et al 2015, Shang et al 2016, Yeung et al 2017, Levine & Chung 2023, Oyama et al 2023]. Affected individuals range in age from 22 months to 61 years.

Developmental delay and intellectual disability. All individuals reported to date have had developmental delay and/or intellectual disability. Developmental milestones are consistently delayed.

The age at which individuals walk independently varies widely, from age 18 months to nine years, with some individuals still unable to walk at age ten years. Most, but not all, individuals are able to achieve independent walking. Six individuals were reported to walk with an ataxic gait [Houge et al 2015, Shang et al 2016], and in-person assessments show individuals with gross motor difficulties, less functional mobility, and endurance limitations [Sudnawa et al 2025].

Almost 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-NDD have had issues with language development [Yeung et al 2017]. Regardless of language eventually achieved, almost all individuals experience speech delay [Biswas et al 2020, Sudnawa et al 2025].

Neurobehavioral/psychiatric manifestations. In an analysis of 72 individuals, 16% were found to have a clinical diagnosis of autism and 16% were borderline autistic. Other common behaviors included sleep problems (16/26), with delay in sleep onset (92.3%), parasomnia (61.5%), and night waking (57.7%) [Oyama et al 2023]. Additionally, individuals are reported to be withdrawn, have attention-seeking behaviors, tantrums, aggressiveness, trouble adjusting to new situations, problems with impulse control, depression, social problems, sensory integration disorder, attention-deficit/hyperactive disorder, and distractibility [Shang et al 2016, Oyama et al 2023, Sudnawa et al 2025].

Macrocephaly. Macrocephaly was reported in 48 out of 72 individuals [Oyama et al 2023]. Head occipitofrontal circumference ranged from two standard deviations (SD) above the mean to 3.8 SD above the mean in affected individuals. Congenital macrocephaly was reported in 7/10 individuals [Sudnawa et al 2025].

Seizures have been reported in 33 individuals. Seizure types observed include generalized tonic-clonic (36.4%), myoclonic (30.3%), multifocal, complex partial, and generalized epileptic spasms. The age of onset ranged from birth to 17.8 years, with a mean age of onset of 2.3 years [Oyama et al 2023]. Two individuals reported with macrocephaly also had epilepsy [Yeung et al 2017]. Further, two affected individuals 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 (27.8%) and astigmatism (16.7%) are common. Other features include amblyopia, esotropia, ptosis, cortical visual blindness, and myopia [Houge et al 2015, Shang et al 2016, Oyama et al 2023]. One individual had cataracts at age 53 years [Houge et al 2015].

Dysmorphic facial features. Many individuals have dysmorphic facial features, including mild hypertelorism, downslanted palpebral fissures, frontal bossing, and a long, hypotonic face. Midface hypoplasia, low-set ears, and plagiocephaly have also been reported. However, dysmorphic features are mild, nonspecific, and vary widely among individuals reviewed.

Gastrointestinal manifestations. Feeding difficulties are common, along with constipation/diarrhea (23.6%), gastroesophageal reflux, and food sensitivities [Levine & Chung 2023, Oyama et al 2023].

Skeletal abnormalities observed include scoliosis (4/16), 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].

Movement disorders. Uncoordinated gait seen in childhood, hand tremors reported in adolescence, and early-onset parkinsonism have been reported beginning in the mid-20s [Hetzelt et al 2021]. Neuropathologic analyses in one individual showed uneven and severe neuronal loss and gliosis in the substantia nigra pars compacta, but no Lewy bodies were observed [Kim et al 2020].

Other

• Endocrine abnormalities such as short stature (<3rd centile) were observed in three individuals [Houge et al 2015, Shang et al 2016]. However, two affected individuals with heights two SD above the mean were also reported. One individual had hypoglycemia, and another was diagnosed with poor weight gain [Houge et al 2015, Shang et al 2016]. Age of onset of these conditions was unknown. Precocious puberty has also been reported.
• Cardiac. Two of 23 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. Undescended testes have also been reported.

Genotype-Phenotype Correlations

Greater cognitive impairment has been seen in individuals with the PPP2R5D pathogenic variants p.Glu198Lys and p.Glu420Lys, whereas less cognitive impairment was observed in individuals with the pathogenic variants p.Glu197Lys and p.Glu200Lys [Biswas et al 2020].

Individuals with p.Glu200Lys have higher adaptive function compared to p.Glu198Lys and p.Glu420Lys [Sudnawa et al 2025].

Individuals with the PPP2R5D pathogenic variants p.Asp251Ala, p.Asp251Tyr, p.Asp251His, p.Asp251Val, and p.Glu200Lys pathogenic variants had better expressive language skills, personal care, and social skills compared with individuals with p.Glu198Lys and p.Trp207Arg [Oyama et al 2023].

Increased aggression was reported more often in individuals with p.Glu198Lys and p.Glu200Lys compared with individuals with pathogenic variants of amino acid residue 251 [Oyama et al 2023].

Individuals with p.Glu200Lys demonstrated increased oppositional behavior with age [Oyama et al 2023].

Seizures were commonly seen in those with pathogenic variant p.Glu198Lys (60.6%) [Oyama et al 2023].

All groups, except those with amino acid changes involving residue 251, had increased attention difficulties and hyperactivity [Oyama et al 2023].

Penetrance

The majority of the reported pathogenic variants are confirmed de novo. Parental results were not available for all reported cases.

There is one report of reduced penetrance. A proband with developmental delay (speech and social) and normal head circumference had a maternally transmitted PPP2R5D pathogenic variant c.1321C>T (p.Arg441Ter). His mother had similar cognitive issues and facial features shared with her son, including thick eyebrows, drooping eyelids, shallow orbits, blunt nasal tip, and thick, prominent vermilion of the upper and lower lips. The variant was also found in a healthy sib of the proband [Liu et al 2022].

Prevalence

The prevalence of PPP2R5D-NDD is unknown. To date, more than 100 individuals with PPP2R5D-NDD have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PPP2R5D-NDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

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.

Mode of Inheritance

PPP2R5D-related neurodevelopmental disorder (PPP2R5D-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• To date, most individuals diagnosed with PPP2R5D-NDD whose parents have undergone molecular genetic testing have the disorder as the result of a de novo PPP2R5D pathogenic variant.
• Rarely, an individual diagnosed with PPP2R5D-NDD has the disorder as the result of a pathogenic variant inherited from an affected, heterozygous parent.
  • In one family, the proband had the disorder as the result of a PPP2R5D pathogenic variant (c.1321C>T [p.Arg441Ter]) inherited from his similarly affected mother (of note, the pathogenic variant was also identified in an unaffected sib of the proband) [Liu et al 2022].
  • In another family, transmission of a PPP2R5D pathogenic variant from a mildly affected heterozygous parent to four affected sibs was reported [Oyama et al 2023].
• 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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or reduced penetrance (reduced penetrance is rare and to date has only been described in a family segregating the c.1321C>T [p.Arg441Ter] pathogenic variant). Therefore, de novo occurrence of a PPP2R5D pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the PPP2R5D 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:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * Theoretically, if the parent is the individual in whom the PPP2R5D pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected.

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

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Parent-to-child transmission of a PPP2R5D pathogenic variant has been reported in two families to date [Liu et al 2022, Oyama et al 2023].
• If the PPP2R5D pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the parents have not been tested for the PPP2R5D pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for PPP2R5D-NDD because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with PPP2R5D-NDD has a 50% chance of inheriting the PPP2R5D 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 PPP2R5D pathogenic variant, the parent's family members may be at risk.

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 the PPP2R5D pathogenic variant 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.

Molecular Pathogenesis

PPP2R5D encodes 56 kDa regulatory subunit delta isoform (B56δ), a subunit of the serine/threonine-protein phosphatase 2A (PP2A). The PP2A complex is composed of three subunits: a scaffolding subunit A, a regulatory subunit B, and a catalytic domain C. B56δ is one of the isoforms of subunit B and is highly expressed in the brain. This protein is thought to be involved in cell growth, chromatin remodeling, and transcriptional regulation. There is evidence that the PP2A-B56δ holoenzyme interacts with the PI3K/AKT growth regulatory cascade [Loveday et al 2015].

All known pathogenic variants to date are missense variants. Four variants (p.Glu197Lys, p.Glu198Lys, p.Glu200Lys, and p.Glu420Lys) alter a highly conserved negatively charged glutamic acid to a positively charged lysine and are predicted to affect protein structure. Of these, p.Glu198Lys has been frequently encountered, identified in 48% (11/23) of individuals with PPP2R5D-related neurodevelopmental disorder. With the exception of variant p.Pro53Ser, pathogenic variants showed deficient holoenzyme formation in HEK293 cells [Houge et al 2015]; p.Pro53Ser has been associated with a different phenotype, including microcephaly and short stature.

Mechanism of disease causation. The p.Glu198Lys and p.Glu200Lys disease-associated variants disrupt PP2A subunit binding and impair dephosphorylation of specific substrates [Houge et al 2015]. The p.Glu420Lys variant is positioned near an active site of the catalytic subunit and is likely to disrupt holoenzyme formation or substrate recognition [Shang et al 2016]. A dominant-negative effect is proposed, supported by biochemical evidence of B56δ-dependent PP2A dysregulation [Houge et al 2015]; however, large 6p21.1-deletion phenotypes are suggestive of a loss-of-function mechanism.

Author Notes

Dr Ghayda Mirzaa is a geneticist and researcher at the University of Washington and Seattle Children's Hospital. Her research program studies the underlying causes, natural history, and medical management of developmental brain disorders including brain growth disorders (macrocephaly and megalencephaly) and malformations of cortical development.

Dr Wendy Chung is a medical and molecular geneticist at Boston Children's Hospital / Harvard Medical School and studies the genetic basis of autism neurodevelopmental disorders, congenital anomalies, and other conditions.

Kimberly Foss, LGC, is a genetic counselor and associate professor at the University of North Carolina at Chapel Hill. She works on many research projects centered around population screening and neurogenetics. She also spends time in clinic with adult patients.

Dr Khemika Sudnawa is a developmental-behavioral pediatrician at Phramongkutklao Hospital and Phramongkutklao College of Medicine. She previously served as a research fellow at Boston Children's Hospital / Harvard Medical School. Dr Sudnawa focuses on the developmental and behavioral aspects of various childhood neurodevelopmental disorders.

Acknowledgments

We thank Jordan's Guardian Angels for supporting research on PPP2R5D-related neurodevelopmental disorder.

Author History

Wendy K Chung, MD, PhD (2019-present)
Kimberly Foss, MS, CGC (2019-present)
Ghayda Mirzaa, MD (2019-present)
Mary Nattakom, BA; Columbia University (2019-2024)
Khemika Sudnawa, MD (2025-present)

Revision History

• 9 January 2025 (sw) Comprehensive update posted live
• 24 January 2019 (sw) Review posted live
• 7 September 2018 (kf) Original submission

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