PT  - JOURNAL ARTICLE
AU  - Calame, Daniel G.
AU  - Hainlen, Meagan
AU  - Takacs, Danielle
AU  - Ferrante, Leah
AU  - Pence, Kayla
AU  - Emrick, Lisa T.
AU  - Chao, Hsiao-Tuan
TI  - <em>EIF2AK2</em>-related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease
AID  - 10.1212/NXG.0000000000000539
DP  - 2021 Feb 01
TA  - Neurology Genetics
PG  - e539
VI  - 7
IP  - 1
4099  - http://ng.neurology.org/content/7/1/e539.short
4100  - http://ng.neurology.org/content/7/1/e539.full
SO  - Neurol Genet2021 Feb 01; 7
AB  - Objective To demonstrate that de novo missense single nucleotide variants (SNVs) in EIF2AK2 cause a neurodevelopmental disorder with leukoencephalopathy resembling Pelizaeus-Merzbacher disease (PMD).Methods A retrospective chart review was performed of 2 unrelated males evaluated at a single institution with de novo EIF2AK2 SNVs identified by clinical exome sequencing (ES). Clinical and radiographic data were reviewed and summarized.Results 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 PLP1 copy number variants nor pathogenic SNVs were detected by chromosomal microarray and trio ES, respectively. Reanalysis of trio ES identified heterozygous de novo EIF2AK2 missense variant c.290C>T (p.Ser97Phe) in proband 1 and c.326C>T (p.Ala109Val) in proband 2.Conclusions The autosomal dominant EIF2AK2-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.ACMG=American College of Medical Genetics; EEG=electroencephalogram; HLD=hypomyelinating leukodystrophy; ISR=integrated stress response; LEUDEN=leukoencephalopathy, developmental delay, and episodic neurologic regression; OFC=occipital-frontal head circumference; OMIM=Online Mendelian Inheritance in Man; PMD=Pelizaeus-Merzbacher disease; VMW=vanishing white matter