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Last updated:
3/20/2023
Years published: 2023
NORD gratefully acknowledges Cathy Abbott, PhD and Richard Chin, MD, PhD, Muir Maxwell Epilepsy Centre, University of Edinburgh, for the preparation of this report.
EEF1A2-related neurodevelopmental disorder is a very rare disorder caused by harmful variants in the EEF1A2 gene that have arisen spontaneously. There are many different types of these variants, and the effects are very variable, sometimes even in children with the same variant. Most children, but not all, will have epilepsy, developmental delay and intellectual disability. Some also have challenging behaviours and/or movement disorders.
EEF1A2-related neurodevelopmental disorder has a variable presentation but almost always involves epileptic seizures, developmental delay and intellectual disability. Most children, but not all, will have onset of epileptic seizures of different types within the first four months of life. The most common seizure type are myoclonic seizures, with most children developing other seizure types. The seizures can be difficult to control, but in some children, the seizures respond well to treatment. Significant global developmental delay will be seen in most but not all. Early concerns about low muscle tone, even within the first month of life, are often reported. There are no consistent characteristic features on magnetic resonance imaging (MRI) imaging studies. There have been reports that some children have a broad nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth but this is not seen in all affected children.
EEF1A2-related neurodevelopmental disorder is usually caused by harmful heterozygous variants (called missense mutations); heterozygous means that each affected individual has one normal copy of the gene and one mutant copy. These harmful variants lead to changes in the eEF1A2 protein in nerve cells and muscles. In almost every child reported so far, the variants in the EEF1A2 gene are categorised as de novo, meaning they have arisen in either an egg or sperm cell. This means the variant has not been inherited and the risk of recurrence in future children of the same parents is low. Numerous different variants in the EEF1A2 gene have been reported, and many have only been seen once, so it is not easy to make associations between specific variants and specific symptoms, although some patterns are emerging.
The frequency of EEF1A2-related neurodevelopmental disorder has been estimated to be 2.92/100,000. Prevalence in specific populations is likely to be consistent since most cases have not been inherited but arisen de novo.
A diagnosis can only be confirmed through molecular genetic testing. This testing can be done on a blood sample and may be included in a panel test that looks for variants in many different genes that cause epilepsy. There are also other methods for genetic testing such as trio-based sequencing. This is when the child and both biological parents are tested to look for gene variants.
Any child with seizures and/or developmental delay should be considered for testing for EEF1A2. This includes children with seizures that are well controlled on medication and/or have mild developmental delay. There have been some reports of children with EEF1A2-related neurodevelopmental disorder whose early development was normal but degenerative changes emerged later in life.
Multidisciplinary health, educational and social support is needed. No consistently effective antiseizure medication has been identified although there have been reports of good response with levetiracetam, clobazam and valproate. Similarly, treatment of movement disorders can be challenging but good response with tetrabenazine has been reported. Children with behavioural problems will often benefit from learning disability support/psychology intervention.
Genetic counseling is recommended for families with an affected child.
Research into the mechanisms by which different harmful variants in EEF1A2 result in epilepsy and intellectual disability is ongoing, alongside preclinical studies of drug and genetic therapies.
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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Nakajima J, Okamoto N, Tohyama J, et al. De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability, autistic behaviors and epilepsy. Clin Genet 2015;87(4):356-61 doi: 10.1111/cge.12394.
Lam WWK, Millichap JJ, Soares DC, et al. Novel de novo EEF1A2 missense mutations causing epilepsy and intellectual disability. Molecular genetics & genomic medicine 2016;4(4):465-74 doi: 10.1002/mgg3.219.
Cao S, Smith LL, Padilla-Lopez SR, et al. Homozygous EEF1A2 mutation causes dilated cardiomyopathy, failure to thrive, global developmental delay, epilepsy and early death. Hum Mol Genet 2017;26(18):3545-52 doi: 10.1093/hmg/ddx239.
Lance EI, Kronenbuerger M, Cohen JS, Furmanski O, Singer HS, Fatemi A. Successful treatment of choreo-athetotic movements in a patient with an EEF1A2 gene variant. SAGE Open Med Case Rep 2018;6:2050313X18807622 doi: 10.1177/2050313X18807622.
Carvill GL, Helbig KL, Myers CT, et al. Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy. Human Mutation 2020;41(7):1263-79 doi: 10.1002/humu.24015.
López-Rivera JA, Pérez-Palma E, Symonds J, et al. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants. Brain: A Journal of Neurology 2020;143(4):1099-105 doi: 10.1093/brain/awaa051.
Kaneko M, Rosser T, Raca G. Dilated cardiomyopathy in a patient with autosomal dominant EEF1A2-related neurodevelopmental disorder. Eur J Med Genet 2021;64(1):104121 doi: 10.1016/j.ejmg.2020.104121.
INTERNET
Developmental and epileptic encephalopathy, 33. NIH National Library of Medicine. Developmental and epileptic encephalopathy, 33 – NIH Genetic Testing Registry (GTR) – NCBI Accessed March 9, 2023.
EEF1A2. Online Mendelian Inheritance in Man (OMIM). Updated: 04/05/2022. https://www.omim.org/entry/602959 Accessed March 9, 2023.
eEF1A2 and epilepsy website. https://eef1a2epilepsy.com/ Accessed March 9, 2023.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/No patient organizations found related to this disease state.