Last updated:
August 18, 2021
Years published: 2021
NORD gratefully acknowledges Wendy Chung, MD, PhD, Clinical and Molecular Geneticist, Kennedy Family Professor of Pediatrics and Medicine, Columbia University Medical Center and Alexa Geltzeiler, ScM, CGC, Department of Pediatrics, Columbia University Medical Center, and the Wolverine Foundation for the preparation of this report.
Summary
MAPK8IP3-related neurodevelopmental disorder is a rare genetic condition caused by harmful changes (pathogenic 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) and walking, impaired intellectual development, and poor or absent speech. Some individuals have brain abnormalities visible on a MRI. EEG abnormalities including slow waves with spikes have also been reported. Other reported features include:
MAPK8IP3-related neurodevelopmental disorder is caused by harmful changes (pathogenic variants) in the MAPK8IP3 gene. To date, almost all cases have been due de novo gene changes that were not inherited. There have been rare patients with two types of egg or sperm cells (gonadal mosaicism) with and without the genetic variant in MAPK8IP3 in one parent. Both missense and truncating variants in the MAPK8IP3 gene have been reported. Specific symptoms have not yet been associated with particular gene variants. (No clear phenotype-genotype correlation).
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 18 affected individuals in the published literature.
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 families with this mutation 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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