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Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

AIAN-27-467
10.4103/aian.aian_257_24
Letters to the Editor
LEUDEN Syndrome: A Novel Hypomyelinating Leukoencephalopathy in a 1-Year-Old Girl
Bhanudeep Singanamalla
Koneti Bramhini Bhargavi 1
Department of Pediatrics, Apollo Institute of Medical Sciences and Research, Hyderabad, Telangana, India
1 Department of Dermatology, Kaya Clinic, Hyderabad, Telangana, India
Address for correspondence: Dr. Singanamalla Bhanudeep, Department of Pediatrics, Apollo Institute of Medical Sciences and Research, Apollo Health City Campus, Jubilee Hills, Hyderabad - 500 090, Telanagana, India. E-mail: singanamalabhanudeep0@gmail.com
Jul-Aug 2024
16 8 2024
27 4 467469
03 4 2024
29 5 2024
21 6 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
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pmcDear Editor,

A 13-month-old female child, first-born to a third-degree consanguineously married couple, was brought to us with concerns of motor development delay. She achieved neck control at 6 months and now can sit with support. She can babble (both mono and polysyllables), comprehend individual words, but cannot follow one-step command either with or without gestures and cannot say mama/dada. She has eye contact, stranger anxiety, and can wave bye-bye (developmental age: 7–8 months). There was no history of acute episodic regression with fever, minor head trauma, or acute fright. There was no history of seizures, head bobbing episodes, or horizontal eye movements. Her birth and family history were unremarkable. Examination revealed no facial dysmorphism, right lateral rectus palsy (squint), microcephaly (45 cm: -3.34 Z score), spasticity, brisk deep tendon reflexes, and upgoing plantars. There were no extrapyramidal or other abnormal movements. Fundoscopic examination was normal. The child was imaged at age 13 months [Figure 1] and 19 months [Figure 2]. The findings were suggestive of significantly delayed myelination at age 13 months. By 19 months, the myelination has not progressed on T1 or T2 sequences, suggestive of hypomyelination. Additional findings included white matter loss due to cortical atrophy, cystic changes in the white matter, thinning of corpus callosum, and Chiari-1 malformation. Metabolic studies including serum ammonia, lactate, acylcarnitine profile, and urine organic acids were normal. Whole exome sequencing revealed a likely pathogenic heterozygous nonsense variant, c. 712A>T (p.Lys238Ter) in exon 9 of EIF2AK2 gene. Parental testing and Sanger sequencing were not performed due to financial constraints.

Figure 1 (a) Axial T1. (b) Axial FLAIR weighted. (c) Sagittal T2. (d-f) Axial T2- weighted. Myelination at 13 months delayed along with periventricular white matter hyperintensities in T2 and FLAIR sequences (black arrows), thinning of CC (black thick arrow) and mild cerebral atrophy (black thin arrow)

FLAIR = Fluid-attenuated inversion recovery

Figure 2 (a) Axial T1. (b) Axial FLAIR weighted. (c) Sagittal T2. (d-f) Axial T2-weighted. At 19 months, myelination has minimally progressed along with herniation of cerebellar tonsils (white arrows)

FLAIR = fluid-attenuated inversion recovery

Leukoencephalopathy, developmental delay, and episodic neurologic regression (LEUDEN) syndrome is a novel autosomal dominant neurodevelopmental disorder characterized by development delay, delayed or hypomyelination, hypertonia or hypotonia, ataxia, neurologic regression precipitated by stress with or without epilepsy, autistic traits, and movement disorders.[1] It is caused by de novo missense or nonsense variants in EIF2AK2, a member of the eukaryotic translation initiation factor 2-alpha kinase family.[123] EIF2AK2 activates cytoprotective integrated stress response (ISR) by phosphorylating eukaryotic translation initiation factor 2 subunit 1 (EIF2S1), which prevents translation of mRNA, leading to the transient suppression of protein synthesis.[4] In addition, the phosphorylation of EIF2S1 converts EIF2S1 into a competitive inhibitor of EIF2B. In case of missense or nonsense mutations of EIF2AK2, the phosphorylation of EIF2S1 is impaired, and hence EIF2B-mediated ISR leads to neurologic decompensation.[14]

LEUDEN syndrome and vanishing white matter disease (caused by pathogenic variants in the genes encoding EIF2B protein complex: EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5) share a common pathogenetic mechanism. Hence, both of these disorders have overlap of certain symptoms, but can be distinguished radiologically.[56] Magnetic resonance imaging in vanishing white matter disease (VWM) shows diffuse symmetrical white matter T1 hypointensities, T2 hyperintensities, and sparing outer rim of the corpus callosum, subcortical U fibers, internal capsule, and anterior commissure. In addition, there may be diffuse white matter cysts, ventricular dilatation, absent contrast enhancement, and radiating stripes (fluid-attenuated inversion recovery hyperintense) within the abnormal cerebral white matter. In contrast, the imaging findings in LEUDEN syndrome range from delayed/hypomyelination to focal leukoencephalopathy pattern with T1 hyper- or isointensities and T2 hyperintensities involving the periventricular white matter and dorsal upper cervical cord.[26]

Compared to the previous patients with LEUDEN syndrome,[123] our patient did not have nystagmus, epilepsy, head bobbing, neurologic decompensation to febrile illness, and hypotonia. Long-term follow-up is necessary to better delineate the phenotype and genotype severity in these cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
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REFERENCES

1. Mao D Reuter CM Ruzhnikov MRZ Beck AE Farrow EG Emrick LT De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation Am J Hum Genet 2020 106 570 83 32197074
2. Calame DG Hainlen M Takacs D Ferrante L Pence K Emrick LT EIF2AK2-related neurodevelopmental disorder with leukoencephalopathy, developmental delay, and episodic neurologic regression mimics Pelizaeus-Merzbacher disease Neurol Genet 2020 7 e539 33553620
3. Macintosh J Thiffault I Pastinen T Sztriha L Bernard G A recurrent de novo variant in EIF2AK2 causes a hypomyelinating leukodystrophy Child Neurol Open 2023 10 2329048X231176673
4. Wek RC Jiang HY Anthony TG Coping with stress: eIF2 kinases and translational control Biochem Soc Trans 2006 34 7 11 16246168
5. Schiffmann R van der Knaap MS Invited article: An MRI-based approach to the diagnosis of white matter disorders Neurology 2009 72 750 9 19237705
6. van der Knaap MS Schiffmann R Mochel F Wolf NI Diagnosis, prognosis, and treatment of leukodystrophies Lancet Neurol 2019 18 962 72 31307818
