MAPK8IP3:
What We Know So Far
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MAPK8IP3-related neurodevelopmental disorder, also called neurodevelopmental disorder with or without variable brain anomalies (NEDBA), is a rare genetic condition associated with changes in the MAPK8IP3 gene. It was established as a distinct genetic disorder in 2019. The total number of affected individuals worldwide remains uncertain because the condition is rare and genetic testing and reporting vary.
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The condition can affect development, learning, communication, movement, muscle tone, behavior, and, in some individuals, brain structure or electrical activity. Its presentation varies considerably: even people with changes in the same gene can have different developmental abilities and support needs.
What is MAPK8IP3-related neurodevelopmental disorder?
What does the MAPK8IP3 gene do?
What have researchers learned about the genetic cause?
The MAPK8IP3 gene provides instructions for making a protein called JIP3 (also known as JNK-interacting protein 3). JIP3 helps coordinate the movement of materials within nerve cells and participates in cell-signaling pathways.
Neurons depend on internal transport systems to move cellular components between the cell body and distant parts of the cell, including axons and synapses. JIP3 helps coordinate this transport with molecular motors, including kinesin and dynein, and participates in signaling involving the c-Jun N-terminal kinase (JNK) pathway. These processes are important for normal neuronal development and function.
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Researchers believe that disease-associated MAPK8IP3 variants disrupt these processes in different ways. Understanding those differences is an important part of current research. Research has identified different types of disease-associated variants, including missense variants, which change a single amino acid in the protein, and truncating or other loss-of-function variants, which can interfere with production of the normal amount of JIP3 protein.
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Most cases described in the literature resulted from de novo variants, meaning the genetic change was not detected in either parent and arose for the first time in the affected individual. However, a 2026 report documented an inherited splice-site variant in a family spanning three generations. This shows that inheritance from a parent is possible and that family members carrying the same variant may have very different clinical presentations.
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A central question is why different variants produce different effects. The evidence increasingly suggests that some variants may alter JIP3 function rather than simply reduce the amount of working protein. However, there is not yet a reliable way to predict an individual's abilities, medical needs, or future development from the variant alone.
The following features have been described in published studies and clinical reports. Not every person will have every feature, and this list should not be interpreted as a prediction of an individual child's development.
Symptoms
Development, learning, and communication
Developmental delays, intellectual disability of varying severity, delayed speech and language, and differences in learning and adaptive skills. Some individuals may have autism or ADHD.
Movement and muscle tone
Low muscle tone (hypotonia), increased muscle tone (hypertonia), spasticity, dystonia, coordination/balance difficulties, and delays in gross or fine motor skills.
Brain structure and neurological function
MRI findings can include a thin or underdeveloped corpus callosum, cortical malformations such as polymicrogyria, and cerebral or cerebellar changes. Abnormal EEG findings and seizures have also been reported in some individuals.
Other reported features
Visual impairments, microcephaly (a smaller-than-expected head circumference), short stature, scoliosis, sleep or feeding difficulties, and differences in puberty timing have been reported in some individuals.
What does research and care?
Diagnosis is generally made through genetic testing that identifies a pathogenic or likely pathogenic variant in MAPK8IP3. A genetics medical professional can help interpret the exact variant, its classification, and whether parental testing is appropriate. There is currently no established disease-modifying treatment specific to MAPK8IP3-related neurodevelopmental disorder. Care is symptom-driven and may include:
Physical Therapy
Focuses on improving gross motor skills, enhancing coordination, and addressing muscle tone differences like hypotonia or hypertonia to support mobility.
Occupational Therapy
Supports fine motor development, sensory integration, and daily living skills to promote independence in self-care and play activities.
Speech Therapy
Addresses speech delays and language difficulties, often utilizing AAC (Augmentative and Alternative Communication) strategies to enhance expressive communication.
Developmental, Educational & Behavioral Supports
Tailored support for each individual’s learning, development, communication, and behavioral needs.
Specialty Care
Assessment and monitoring by specialists to manage neurological issues, vision, feeding and swallowing, growth, muscle tone, orthopedic concerns, sleep, and other symptoms as indicated.
The latest relevant research articles
The following publications provide an overview of important clinical findings and emerging research into MAPK8IP3-related neurodevelopmental disorder.
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Disclaimer: Research and new insights into MAPK8IP3 are continuing to emerge and it is important to keep in mind that a promising laboratory result is not the same as a proven treatment, and published group findings cannot predict the future of an individual child.
Any information on our site should not constitute or replace personal medical advice. Families should always consult with a qualified medical professional for all information and treatment regarding MAPK8IP3 and MAPK8IP3-Related Neurodevelopmental Disorder. While the Foundation does its best to keep information on our website accurate, information may come out that changes our understanding of MAPK8IP3 and MAPK8IP3-Related Neurodevelopmental Disorder. Therefore, is important to check with a qualified medical professional to ensure the most accurate and up-to-date information regarding this disorder and treatment.
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1. Comprehensive Clinical Characteristics, Longitudinal Adaptive Functioning, and Electroencephalogram Activity in MAPK8IP3-Related Neurodevelopmental Disorder
Authors: Sudnawa KK et al.
Journal: Clinical Genetics, 109(2):233–242. Published online in 2025; issue dated February 2026.
This clinical study examined 32 individuals with MAPK8IP3-related neurodevelopmental disorder. Researchers investigated developmental abilities, motor function, adaptive functioning, neurological findings, and EEG activity.
The study adds to our understanding of the condition's clinical presentation and highlights the importance of standardized assessments and longitudinal research.
Why it matters: Larger clinical studies help researchers identify common features, understand developmental trajectories, and prepare for future clinical trials.
Read the article: https://pubmed.ncbi.nlm.nih.gov/40734308/
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2. Characterization of a Novel Inherited Splice-Site Variant in MAPK8IP3 Expands the Genetic and Phenotypic Spectrum of Neurodevelopmental Disorders
Journal: Biochemistry and Biophysics Reports, volume 46, 2026, article 102582.
This study investigated an inherited MAPK8IP3 splice-site variant in a family spanning multiple generations. RNA analysis demonstrated an effect on the processing of the gene's transcript. Family members carrying the variant displayed different clinical presentations.
Why it matters: This research demonstrates that inherited variants are possible and highlights the considerable variability that can occur among relatives with the same genetic change.
Read the full article: https://pmc.ncbi.nlm.nih.gov/articles/PMC13101558/
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3. Pathogenic MAPK8IP3 Variants Drive Distinct Motor and Behavioral Phenotypes in Humans and Mice
Authors: Crowder CM et al.
Posted: July 2026, on bioRxiv.
This preprint compares clinical findings in people with different MAPK8IP3 variants with findings from genetically engineered mouse models. The researchers investigate differences in motor, cognitive, and behavioral features and explore how experimental models may help explain the effects of individual variants.
Why it matters: Understanding how different variants affect the nervous system may help researchers identify disease mechanisms and develop future treatment strategies.
Important note: This publication was identified as a preprint in the literature search. Its findings should be considered preliminary until peer review and further validation.
Read the preprint: https://www.biorxiv.org/content/10.64898/2026.07.20.739682v1
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4. A Toxic Gain-of-Function Variant in MAPK8IP3 Provides Insights into JIP3 Cellular Roles
Journal: JCI Insight, 2025;10(8):e187199.
Published: April 22, 2025.
This laboratory study investigated a specific MAPK8IP3 variant, R578C. Researchers examined changes in cellular transport and signaling and explored an experimental antisense oligonucleotide approach to reduce some effects of the variant in laboratory systems.
Why it matters: The findings provide insight into how certain variants may disrupt cellular function and suggest possible directions for future therapeutic research.
Important note: These are experimental findings, not evidence of an established or approved treatment for people with MAPK8IP3-related neurodevelopmental disorder. The findings may not apply to other variants.
Read the article: https://insight.jci.org/articles/view/187199/version/2
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5. MAPK8IP3-Related Neurodevelopmental Disorder: Case Report and Therapeutic Rationale for a Truncating Variant
Authors: Crowder CM et al.
Journal: Drug Repurposing, 2025;2(1):e20250002.
Published: August 5, 2025.
This case report describes an individual with developmental delay associated with a truncating MAPK8IP3 variant. The authors discuss a potential therapeutic rationale related to the genetic finding.
Why it matters: Case reports can help identify new clinical presentations and generate hypotheses for future research.
Important note: A proposed treatment rationale is not evidence that a treatment is safe or effective. Further investigation is needed.
Read the article: https://doi.org/10.58647/DRUGREPO.25.1.0002
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6. De Novo Variants in MAPK8IP3 Cause Intellectual Disability with Variable Brain Anomalies
Authors: Platzer K et al.
Journal: American Journal of Human Genetics, 2019;104(2):203–212.
This foundational study described 13 unrelated individuals with de novo MAPK8IP3 variants and developmental delay or intellectual disability. The researchers also conducted functional studies supporting the relationship between MAPK8IP3 variants and neurodevelopmental disease.
Why it matters: This landmark publication helped establish MAPK8IP3-related neurodevelopmental disorder as a distinct genetic condition.
Read the full article: https://pmc.ncbi.nlm.nih.gov/articles/PMC6369540/
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7. Recurrent De Novo MAPK8IP3 Variants Cause Neurological Phenotypes
Authors: Iwasawa S et al.
Journal: Annals of Neurology, 2019;85(6):927–933.
This early study described individuals with recurrent MAPK8IP3 variants and neurological features that included spasticity, intellectual disability, and brain imaging abnormalities. Experimental studies also investigated the role of these variants in neuronal development.
Why it matters: This publication provides foundational evidence linking particular MAPK8IP3 variants to neurological and developmental differences.
Read the article: https://doi.org/10.1002/ana.25481
Important research questions that remain
While research has advanced significantly since 2019, several critical questions remain. Key areas for future investigation include: Variant-Specific Effects (how different genetic variations alter JIP3 behavior); Phenotypic Variability (why presentation varies among individuals with the same variant); Natural History Study (long-term developmental trajectories); Targeted Therapies (precision medicine strategies); and Biomarkers (reliable predictors of development or treatment response).
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How can families contribute to research?
Families can help advance research by participating in natural-history studies, sharing clinical information when they choose to do so, connecting with research organizations, and supporting collaboration between clinicians and scientists. By bringing together families, researchers, clinicians, and relevant organizations, the community can help accelerate understanding of MAPK8IP3-related neurodevelopmental disorder and work toward better outcomes for affected individuals.
- We closely collaborate with Wolverine Foundation, an private foundation, involved in MAPK8IP3 research to support progress for families.
- The Wolverine Foundation has built a research toolkit available for scientists that include: Mouse, zebrafish, and roundworm models for animal studies, patient-derived pluripotent stem cells or IPSCs (developed from a blood draw of participating individuals with a MAPK8IP3 gene variant), and brain organoids. They also support our Natural History Study.