Last updated:
1/24/2025
Years published: 2021, 2025
NORD gratefully acknowledges Wendy Chung, MD, PhD, Clinical and Molecular Geneticist, Mary Ellen Avery Professor of Pediatrics and Chief of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Alexa Geltzeiler, ScM, CGC, Department of Pediatrics, Boston Children’s Hospital and the Wolverine Foundation for the preparation of this report.
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Summary
MAPK8IP3-related neurodevelopmental disorder is a rare genetic condition caused by changes (variants) in the MAPK8IP3 gene, leading to neurodevelopmental disease. There is a spectrum of severity ranging from mild developmental delays to intellectual disability and physical impairments. Treatment of affected individuals is typically symptom-driven and supportive, focusing on speech, physical and social development.
Individuals with MAPK8IP3-related disorder have a spectrum of neurodevelopmental disabilities. All affected individuals experience some level of global developmental delay including problems with muscle tone (both hypertonia and hypotonia have been reported), coordination, impaired development of skills, and poor or absent speech. Some individuals have brain abnormalities visible on an MRI. EEG abnormalities including slow waves with spikes have also been reported. Other reported features include:
MAPK8IP3-related neurodevelopmental disorder is caused by variants in the MAPK8IP3 gene. To date, almost all cases have been due to de novo genetic changes that were not inherited from a parent. Both missense and truncating variants in the MAPK8IP3 gene have been reported. Specific symptoms have not yet been associated with particular genetic variants.
Defective transport of cargo along the axons of neurons underlies a variety of rare genetic neurodevelopmental disorders. MAPK8IP3 (mitogen-activated protein kinase 8 interacting protein 3) is highly expressed in brain cells and encodes for the JIP3 protein (JNK-interacting protein 3) which functions as a scaffold/adapter protein that links cargos to the dynein and kinesin motors. JIP3 is important for multiple cellular processes in the developing brain, including axon guidance and the development of the brain (thalamus, hippocampus and cortical plate).
The number of individuals with MAPK8IP3-related disorder is unknown, due to the newly described nature of this condition and variable access to genetic testing. To date, there are less than 100 affected individuals reported in the published medical literature.
MAPK8IP3-related disorder is diagnosed with molecular genetic testing that identifies a disease-causing variant in the MAPK8IP3 gene.
Occupational, physical, speech and feeding therapies may be utilized to address specific developmental delays.
Genetic counseling is recommended for affected individuals and their families.
Research into the natural history, cellular mechanisms and potential treatment of MAPK8IP3-related disorder is ongoing. Please visit www.wolvfdn.com if you are interested in participating in research or if you are a provider looking to refer a patient to the current MAPK8IP3 natural history study. If you are a family interested in connecting with other affected families, please visit https://curemapk8ip3.org/
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Iwasawa S, Yanagi K, Kikuchi A, et al. Recurrent de novo MAPK8IP3 variants cause neurological phenotypes. Ann. Neurol. 2019;85: 927-933.
Platzer K, Sticht H, Edwards SL, et al. De novo variants in MAPK8IP3 cause intellectual disability with variable brain anomalies. Am. J. Hum. Genet. 2019;104: 203-212.
Kelkar N, Gupta S, Dickens M, Davis RJ. Interaction of a mitogen-activated protein kinase signaling module with the neuronal protein JIP3. Molec. Cell. Biol. 2000;20: 1030-1043.
Ito M, Yoshioka K, Akechi M, et al. SAP1, a novel Jun N-terminal protein kinase (JNK)-binding protein that functions as a scaffold factor in the JNK signaling pathway. Molec. Cell. Biol. 1999;19: 7539-7548.
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