Vanishing white matter leukodystrophy due to novel EIF2B4 mutation in an adult female
How to cite this article: Goyal S, Mudabbir M, Taallapalli AV, Nashi S, Kulkarni GB. Vanishing white matter leukodystrophy due to novel EIF2B4 mutation in an adult female. J Neurosci Rural Pract 2023;14:191-2.
The vanishing white matter leukodystrophy (VWM) is an autosomal recessive leukodystrophy which can present in childhood (1–5 years) as well as adulthood (15%). They present with behavioral changes, dementia, migraine, and seizures. Premature ovarian insufficiency and stress (fever, trauma, and infections) related clinical worsening are the characteristic features. Mutation in the genes encoding eukaryotic translation initiation factor 2B (EIF2B1-EIF2B5) is the culprit. The EIF2B5 mutation accounts for the majority of cases.[2-5] To the best of our knowledge, there are no genetically proven cases of adult-onset VWMD with EIF2B4-related mutations reported from India.
A 52-year-old lady, born out of non-consanguineous parents, presented with 2-year history of slowly progressive dragging of the right foot, 1-year history of bladder urgency, 6-month history of the right-sided abnormal posturing of limbs, swaying, and behavioral disturbances. Two months before presentation, she had high-grade fever followed by which she became bed-bound and double incontinent. She attained menopause at the age of 35 years. No significant family history.
On examination, she was opening eyes spontaneously, but could not obey simple commands. Cognitive examination revealed perseveration, repetition, echolalia, and emotional incontinence. There was a relative paucity of the right upper and lower limb with contractures and bilateral spasticity. Deep tendon reflexes were exaggerated with extensor plantar response bilaterally.
On evaluation, she was detected to have anemia (8.1 g/dl). Liver and kidney function tests, and thyroid function test, lactate, and ammonia were normal. Her urine for abnormal metabolites, serum aryl-sulfatase levels, and tandem mass spectrometer were negative. Serology for human immunodeficiency virus and venereal disease research laboratories tests were negative. Nerve conduction studies and cerebrospinal fluid study were unremarkable. Magnetic resonance imaging (MRI) brain demonstrated diffuse white matter involvement with radiating strips of preserved white matter [Figure 1a]. External capsule involvement and sparing of the basal ganglia and thalamus [Figure 1b] were seen. Cysts were present in both anterior frontal regions [Figure 1c] with no diffusion restriction [Figures 1d and e] and no contrast enhancement [Figure 1f]. Thinning of the corpus callosum [Figure 2a], selective involvement of posterior limb of the internal capsule [Figure 2b], central tegmental tract hyperintensities [Figure 2c], and mineralization of globus pallidus [Figure 2d] were seen. Based on clinical and imaging characteristics, diagnosis of adult-onset VWM was made.
Genetic testing revealed a homozygous missense mutation in exon-12 of the EIF2B4 gene.
The eIF2B is the guanine exchange factor for eIF2 and helps in translation initiation and regulation of protein synthesis under different conditions, including cell stress. Mutations in EIF2B genes alter the cellular response to stress and thus lead to worsening of clinical symptoms. Mutations in EIF2B5 are the most common (60%) followed by EIF2B2 mutation.[2,9,10] In 1997, van der Knaap introduced the term “vanishing white matter disease.” Since then, multiple isolated cases have been reported. In 2001, Japanese authors reported the first Asian girl with vanishing white matter disease. The disease presents in young children with cerebellar ataxia and less prominent spasticity. Optic atrophy with loss of vision and epilepsy may occur rarely.[6,11,13] In adults, it presents with behavioral changes, dementia, migraine, and seizures. Premature ovarian failure is reported in females and can precede the neurological symptoms by decade. Both childhood and adult-onset forms witness stress-related exacerbations. MRI shows diffuse and symmetric involvement of the cerebral white matter that spares U-fibers, the outer part of the corpus callosum, the internal capsule, and anterior commissure. Gradually cystic degeneration occurs. Our patient has cystic degeneration of the white matter, sparing U fibers, and no contrast enhancement.
There is no specific treatment for VWM. The avoidance of stressful events may help in prolonged survival. These measures include avoiding contact sports, liberal use of antipyretics, and antibiotics for suspected infections. Patients must be vaccinated up-to-date.
Possibility of VWMD needs to be considered in adult patients who present with features of leukodystrophy and stress-related neurological worsening and associated with premature ovarian failure. Imaging features of progressive rarefaction, cyst formation, and shrinkage of the white matter support the diagnosis. Genetic testing helps in prognostication and initiation of preventive measures.
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