EIF2AK2 variants cause symptoms akin to Pelizaeus-Merzbacher disease

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Hypomyelinating leukodystrophies (HLD) are a group of rare genetic disorders characterized by degeneration of the brain’s white matter due to inadequate development of the myelin sheath, the fatty insulator that surrounds nerve fibers. An archetype of these disorders is the Pelizaeus-Merzbacher disease (PMD), which is caused by mutations in the Proteolipid protein 1 (PLP1) gene. This is the most common type of HLD and manifests in infancy or early childhood. It is characterized by a continuum of neurological impairments from delayed motor and cognitive impairment, increased rigidity of muscles, seizures, and results in early mortality from respiratory complications during childhood. Interestingly, a significant proportion (20-40%) of patients clinically diagnosed with PMD lack any identifiable changes in the PLP1 gene. The underlying molecular cause for their neurological impairments remains a mystery.

A comprehensive analysis of two unrelated individuals now reveals that variants in Eukaryotic Initiation Factor 2 Alpha Kinase 2 (EIF2AK2) gene can result in clinical symptoms that are remarkably similar to PMD. The lead authors of this study, who are child neurologists and neuroscientists at Texas Children’s Hospital and Baylor College of Medicine, suggest that “EIF2AK2-related Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression (LEUDEN) syndrome,” a brand-new disorder that they discovered in March 2020 should be considered as a differential diagnosis for PMD and other hypomyelinating dystrophies.

Early and precise diagnosis of HLD patients is critical to facilitate access to clinical trials and could help in the development of targeted therapeutic interventions, such as neural stem cell transplantation. The study published in Neurology Genetics.

“Within a span of a few months, our neurology clinic at Texas Children’s evaluated two unrelated patients with seizures, pronounced regression in cognitive capabilities after febrile illnesses, abnormal eye movements, and muscle stiffness. Additionally, serial magnetic resonance imaging (MRI) of these patients’ brains showed persistent delays in myelination. Based on the clinical and radiographic features, we strongly suspected PMD initially. However, neither patient had any identifiable variation in the PLP1 gene, which suggested alteration(s) in other gene(s) and molecular pathways were likely responsible for their neurological impairments,” lead author Dr. Hsiao-Tuan Chao, who is an assistant professor at Baylor College of Medicine and principal investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s, said.

To pinpoint the exact molecular cause, the team sequenced the exomes (protein-coding regions of the DNA) of both patients at Baylor Genetics diagnostic laboratory and found spontaneous, protein-altering missense mutations in the EIF2AK2 gene.

Coincidentally, Chao’s team had recently discovered variants in this gene were associated with a previously unidentified neurodevelopmental disorder that presented with strikingly similar symptoms of developmental delays, febrile illness triggering neurologic regression, and, importantly, alterations in the brain’s white matter with varying degrees of severity.

“We are still at the initial stages of identifying and cataloging various pathologic syndromes that can arise from variants in this gene. Currently, there are only 14 people known in the medical literature with mutations in EIF2AK2 gene,” Chao added.

So far, 19 genes are associated with all HLDs, several of which share overlapping features with PMD. Understanding and recognizing cardinal clinical, radiographic or genetic features specific to each of these disorders is critical to guiding diagnostic testing and prognostication.

First author Dr. Daniel Calame, a child neurology resident at Texas Children’s, then performed a comprehensive functional analysis to map

out how these genes implicated in various white matter diseases interplay with one another.

“It was very interesting to observe how these genes clustered for each HLD. We think the functional and interactome-based models we have built here are going to prove very useful as we continue to evaluate candidate genes in the future and find molecular diagnosis for all HLD patients,” Calame said.

This study suggests that PMD patients who currently do not have molecular diagnosis could likely carry mutations in EIF2AK2 gene or in the pathways regulated by this gene.

“The fact that we came across two unrelated patients carrying a similar gene variant exhibiting identical symptoms within a short timespan indicates that this disease may not be rare. Also, since this gene codes for a kinase, a ‘druggable’ target, it raises the possibility of developing targeted treatments for these patients. Our hope is if we are able to diagnose these patients early enough, there might be ways we could suppress the expression of the mutant form of this protein to improve brain development and halt epilepsy and other complications,” Chao said.

Other researchers involved in the study include Meagan Hainlen, M.D., Danielle Takacs, M.D., Leah Ferrante, M.D., Kayla Pence, M.D., and Lisa T. Emrick, M.D. They are affiliated to one or more of the following institutions: Baylor College of Medicine, Texas Children’s Hospital and University of Texas Southwestern.