Variants in EIF2AK2 are associated with leukoencephalopathy, developmental delay, and episodic neurologic regression (LEUDEN) syndrome. EIF2AK2 regulates stress response and lymphocyte transcription factors. Presentations of LEUDEN syndrome vary and include developmental delay, abnormal myelination, tone differences, neurologic regression, seizures, and movement disorders. Neurologic regression classically follows systemic stressors such as febrile illness.
A 30-month-old boy with LEUDEN syndrome experiencing episodic neurologic regression after viruses presented to Immunology. His parents, informed through community groups, sought evaluation due to reported benefits from immunoglobulin replacement therapy (IgRT).
Around 4-5 months old, the patient experienced viral infections, requiring hospitalizations for feeding difficulty, weakness, and head lag. Despite meeting early developmental milestones, developmental delay was diagnosed at 1 year, and he began therapies. Delays improved until 22 months when he presented to the ED for parainfluenza and acute otitis media, where he was prescribed antibiotics and discharged. A few days later, he re-presented for head lag and lethargy. He received empiric antibiotics for possible meningitis. EEG showed diffuse slowing. Brain MRI showed extensive white matter abnormalities. Broad infectious and metabolic workup was unrevealing besides low IgG (478 mg/dL). Post-discharge with intensive therapy, the patient gradually improved starting 2-3 weeks after his initial illness, regaining milestones. Whole-genome sequencing identified a likely pathogenic variant in EIF2AK2 (c.1382C>G, p.Ser461Cys), confirming LEUDEN syndrome.
Immune evaluation at 30 months showed reassuring T/B/NK cell counts, IgG/IgA/IgM/IgE, and vaccine titers. The patient continued to have intermittent viruses with variable neurologic impacts. Immune re-evaluation one year later showed protective but waning titers to tetanus (0.65 IU/mL) and diphtheria (0.11 IU/mL) and poor pneumococcal protection with <50% of serotypes with titers >1.0 ug/mL. This antibody pattern with normal IgG (666 mg/dL) suggested specific antibody deficiency, and IgRT was offered.
After starting monthly IVIG (∼450 g/kg) at 4 years old, his infections decreased in frequency and severity. He showed neurological improvements without regression during viral illnesses.
This single case report highlights subtle antibody deficiencies in a patient with LEUDEN syndrome and his improvement following IgRT. Further studies are needed to characterize the immune profiles and the potential utility of IgRT in LEUDEN syndrome.
