<i>EIF2AK2</i> -related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease

Abstract

<h3>Objective</h3> To demonstrate that de novo missense single nucleotide variants (SNVs) in <i>EIF2AK2</i> cause a neurodevelopmental disorder with leukoencephalopathy resembling Pelizaeus-Merzbacher disease (PMD). <h3>Methods</h3> A retrospective chart review was performed of 2 unrelated males evaluated at a single institution with de novo <i>EIF2AK2</i> SNVs identified by clinical exome sequencing (ES). Clinical and radiographic data were reviewed and summarized. <h3>Results</h3> Both individuals presented in the first year of life with concern for seizures and developmental delay. Common clinical findings included horizontal and/or pendular nystagmus during infancy, axial hypotonia, appendicular hypertonia, spasticity, and episodic neurologic regression with febrile viral illnesses. MRI of the brain demonstrated severely delayed myelination in infancy. A hypomyelinating pattern was confirmed on serial imaging at age 4 years for proband 1. In proband 2, repeat imaging at age 13 months confirmed persistent delayed myelination. These clinical and radiographic features led to a strong suspicion of PMD. However, neither <i>PLP1</i> copy number variants nor pathogenic SNVs were detected by chromosomal microarray and trio ES, respectively. Reanalysis of trio ES identified heterozygous de novo <i>EIF2AK2</i> missense variant c.290C&gt;T (p.Ser97Phe) in proband 1 and c.326C&gt;T (p.Ala109Val) in proband 2. <h3>Conclusions</h3> The autosomal dominant <i>EIF2AK2</i>-related leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome should be considered in the differential diagnosis for PMD and other hypomyelinating leukodystrophies (HLDs). A characteristic history of developmental regression with febrile illnesses may help distinguish it from other HLDs.

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