Vanishing White Matter Disease With EIF2B2 c.254T >A Variant

Abstract

Objectives

Typical MRI findings of vanishing white matter disease (VWM) include diffuse white matter lesions with cystic degeneration. However, mild cases may lack these typical features, posing diagnostic challenges.

Methods

We describe 2 of 3 individuals carrying the homozygous c.254T >A variant in EIF2B2 identified at our hospital, excluding 1 previously reported case.¹ Genetic analyses were performed using whole-genome sequence or whole-exome sequence analysis, and detected variants were confirmed by direct nucleotide sequence analysis. Brain MRI findings and clinical features were reviewed for the 2 individuals along with other cases in the literature with the same variant.

Results

A 69-year-old woman presented with recurrent transient dizziness and secondary amenorrhea. MRI of the brain revealed small T2-hyperintense lesions confined to the subcortical white matter with hyperintensities on diffusion-weighted images and mildly elevated apparent diffusion coefficient values. A 28-year-old woman presented with transient dizziness and secondary amenorrhea. MRI of the brain showed mild T2-hyperintense lesions in the cerebral white matter with frontal predominance.

Discussion

This report highlights the clinically mild cases of VWM with subtle abnormalities on brain MRI who had the homozygous c.254T >A in EIF2B2, further expanding the clinical spectrum of VWM and underscoring the importance of genetic assessments in the diagnosis of individuals with mild clinical and MRI findings.

Introduction

Vanishing white matter disease ([VWM], Mendelian Inheritance in Man (MIM) number 603896) is a neurodegenerative disorder with autosomal recessive inheritance caused by biallelic disease-causing variants of one of the 5 genes, EIF2B1–5, which encode the subunits of translation initiation factor eIF2B.^1,2 VWM is classified into 5 subtypes (VWM1–5) based on the causative genes. Regardless of the specific EIF2B gene involved, there are common clinical features across the 5 subtypes, and within each of the EIF2B1-5 genes, specific variants associated with either severe or mild disease phenotypes have been identified.^3,4 Adult-onset VWM individuals present with slowly progressive cerebellar ataxia, spasticity, cognitive decline, and psychiatric disorders, often with episodes of acute deterioration triggered by head trauma or infection. In typical cases of VWM individuals, T2-weighted images (T2WI) on brain MRI show diffuse symmetric lesions extending from the periventricular white matter to the subcortical white matter accompanying cystic degeneration that has a signal comparable with that of the CSF.² In mild cases of VWM, white matter lesions are less extensive and may lack cystic degeneration.⁵ Although diffusion restriction is not always present in nonrarefied white matter, it occurs in relatively preserved white matter in early-onset individuals with short disease duration.⁶

This report details 2 individuals with VWM2 carrying the homozygous c.254T >A (p.V85E) variant in EIF2B2, a variant previously reported to show mildly decreased enzymatic activity.⁷ Both individuals exhibited mild clinical and MRI manifestations. MRI revealed T2-hyperintense lesions in the subcortical white matter, partly accompanied by bright hyperintensity on diffusion-weighted images (DWI) without diffusion restriction. To grasp the clinical and MRI characteristics of the individuals with the homozygous c.254T >A variant in EIF2B2, we reviewed the relevant literature.

Methods

Ethics Statement

This study was approved by the institutional review board of the University of Tokyo (G1396-[64]). Written informed consents were obtained from all the individuals for genetic analyses and publication.

Genetic Studies

Genomic DNAs were extracted from the individuals' peripheral blood leukocytes. Whole-genome sequence (WGS) analysis of Individual 1 was conducted using the NovaSeq 6,000 (Illumina, San Diego, CA) platform with an average depth of 27x. Variant call and structural variant call were performed using gVCFtyper program of the Sentieon package and Manta, respectively.⁸ Whole-exome sequence (WES) analysis of Individual 2 was conducted with SureSelect Human All Exon V6 + UTRs kit (Agilent Technology, Santa Clara, CA) using Hiseq 2,500 (Illumina, San Diego, CA). Direct nucleotide sequence analysis was performed to confirm the variant using primers (5′-TCGCGTTGGCTCCTCTTATC-3′ and 5′-GCCCGTGCAAAAAGTGTCAC-3′). The primer sets and PCR conditions of the repeat-primed PCR for FMR1 and NOTCH2NLC were described before.^9,10

Results

Individual 1

A 69-year-old woman without a family history for any neurologic diseases or parental consanguinity presented with recurrent transient dizziness that resolved within a few days. She has had secondary amenorrhea since she was 15 years. Physical examination revealed no muscle weakness, ataxia, sensory disturbances, or autonomic dysfunction. Her pupils measured 4 mm bilaterally with rapid light reflexes. Tendon reflexes were within normal limits in all 4 limbs, and no abnormal pathologic reflexes were observed. Cognitive function was well preserved with a Mini-Mental State Examination score of 29. MRI of the brain, performed to evaluate the recurrent dizziness, revealed scattered T2-hyperintense lesions in the subcortical white matter of the bilateral frontal lobes, partly accompanied by bright hyperintensity on DWI and mildly elevated apparent diffusion coefficient (ADC) values (Figure 1). Some of these lesions showed hypointense signals on T1-weighted images (T1WI). These MRI findings remained stable over 7 years. Prominent hyperintensities on DWI confined to the frontal subcortical white matter initially provoked the differential diagnosis of neuronal intranuclear inclusion disease (NIID) or fragile X-associated tremor/ataxia syndrome (FXTAS). However, repeat-primed PCR analysis excluded NIID and FXTAS. WGS analysis revealed a known disease-causing variant c.254T >A, p.V85E in EIF2B2 (NM_014239.4) in the homozygous state, which was further confirmed by direct nucleotide sequence analysis of the PCR products.⁷ No additional exonic variants associated with leukoencephalopathy were detected in WGS data with allele frequencies of less than 0.005 in gnomAD, except for the EIF2B2 variant (eTable 1). The Manta structural variant caller detected no deletions involving EIF2B2.

Figure 1. MRI of the Brain of Individual 1 at Age 69 Years, 7 Years After Her Initial Visit to Our Hospital.

Scattered T2-hyperintense lesions were observed deep in the cerebral sulci of the bilateral frontal lobes, accompanied by bright hyperintensity on diffusion-weighted images and mildly elevated apparent diffusion coefficient values (orange arrowheads). On T2-weighted images, the lesions showed slight hyperintensity compared with the CSF. The lesions showed marked hypointensity on T1-weighted images. No hemorrhage or calcification was observed on T2 star-weighted images.

Individual 2

A 28-year-old woman without a family history for any neurologic diseases or parental consanguinity presented with transient dizziness. She had no neurologic abnormalities on examination but had secondary amenorrhea. MRI of the brain revealed T2-hyperintense white matter lesions with frontal predominance, accompanied by hypointense signals on T1WI (Figure 2). DWI showed hyperintensities in these lesions with mildly elevated ADC values. WES analysis revealed a variant c.254T >A in EIF2B2 in the homozygous state, which was confirmed by direct nucleotide sequence analysis. A heterozygous c.2288C >T, p.A763V in LAMA2 (NM_000426.4) was also found in WES, which has conflicting classifications in ClinVar. As LAMA2-related muscular dystrophy is autosomal recessive and no second variant was found, and given the absence of elevated creatin kinase, muscle weakness, or cardiac involvement, we considered it unrelated to the phenotype. Based on these findings, a diagnosis of VWM2 was made. At the age of 34, she remained neurologically asymptomatic except for transient dizziness, and her MRI findings remained unchanged.

Figure 2. MRI of the Brain of Individual 2 When She Was 28 Years.

Hyperintense lesions on T2-weighted images with reduced signals on T1-weighted images were observed from the subcortical white matter with frontal predominance. Hyperintensity on DWI with mildly elevated apparent diffusion coefficient values was observed in these lesions. DWI = diffusion-weighted image.

Discussion

We report 2 VWM2 individuals with the homozygous c.254T >A variant in EIF2B2, presenting with mild clinical manifestations and MRI findings. Especially, Individual 1 showed T2-hyperintense lesions confined to the frontal subcortical white matter, with DWI hyperintensity and elevated ADC values. While reduced N-acetylaspartate signals on magnetic resonance (MR) spectroscopy are potentially useful for early diagnosis of VWM,¹¹ MR spectroscopy was not performed in the 2 cases.

To better define the clinical spectrum of individuals carrying homozygous c.254T >A variant in EIF2B2, we reviewed the relevant literature. Four Japanese cases of VWM2, including the 2 described here, and 1 Korean case of VWM2 carried this variant (Table 1).^7,12,13 Individual 3 is a previously reported patient from our hospital.⁷ The allele frequency of c.254T >A in EIF2B2 in the Japanese population (0.001718, ToMMo 60KJPN¹⁴) and that in the East Asian population (0.001317, gnomAD v4.1.0¹⁵) is relatively high, while the variant has not been detected in Finnish or non-Finnish European population (gnomAD v4.1.0s). This may explain why all reported cases with the homozygous c.254T >A variant were from individuals of East Asian descent. Clinically, Individual 3 progressively deteriorated and became bedridden, and Individual 4 exhibited intellectual disability from the age of 3 and experienced an episode of worsening symptoms due to an infection. Individual 5 also had progressive movement disorder, with symptoms ranging from hand tremors to upper-extremity and lower-extremity weakness. By contrast, Individuals 1 and 2 presented only with transient dizziness and amenorrhea, without other neurologic manifestations. MRI findings also differed: Individuals 3 and 4 exhibited diffuse T2-hyperintense lesions extending from the periventricular white matter to the subcortical white matter, with cystic lesions in Individual 3. By contrast, Individuals 1 and 2 had smaller white matter lesions (Figures 1 and 2). Individual 5 also exhibited relatively mild white matter lesions compared with Individuals 3 and 4. It is well known that VWM exhibits the genotype-phenotype correlation.⁵ Previously, a functional study of the EIF2B2 with the p.V85E variant demonstrated a mild but significant (approximately 20%) decrease in the guanine nucleotide exchange activity.⁷ The disease course of VWM is strongly influenced by stress factors such as fever or trauma.¹ In fact, Individual 3 developed gait disturbance at age 43 years, which worsened intermittently after minor trauma, and Individual 4 became drowsy after an infection at age 7 years.^7,12 Thus, the homozygous c.254T >A variant is likely to lead to milder clinical and MRI manifestations compared with other pathogenic EIF2B2 variants, while trauma and/or infection can deteriorate the disease course. Because both Individuals 1 and 2 had recurrent dizziness, this symptom may represent an early symptom of VWM, as previously reported.¹⁶ Given the broad ranges of clinical presentations including the cases presenting subtle symptom, this study emphasizes the role of genetic testing for cases presenting with mild white matter lesions on MRI.

Table 1.

Clinical and MRI Characteristics of the Individuals With Homozygous c.254T >A Variant in EIF2B2 Reported in This Study and Previous Reports

	Individual 1	Individual 2	Individual 3	Individual 4	Individual 5
Reference	This study	This study	Ref 1 case 2	Ref 12 patient 2	Ref 13
Age	69	34	73	8	29
Sex	F	F	F	F	F
Population	Japanese	Japanese	Japanese	Japanese	Korea
Genes	EIF2B2	EIF2B2	EIF2B2	EIF2B2	EIF2B2
Variant	c.254T >A	c.254T >A	c.254T >A	c.254T >A	c.254T >A
Inheritance	Homozygous	Homozygous	Homozygous	Homozygous	Homozygous
Consanguinity	—	—	+	—	—
Family history	—	—	—	—	—
Age at onset	62	28	43	3	5
Follow-up	7 y	6 y	30 y	5 y	24 y
Disease course	Asymptomatic	Asymptomatic	Progressive	Progressive	Progressive
Provoking factors	—	—	Trauma, infection	Infection	—
Cognitive decline	—	—	+	+	—
Seizures	—	—	+	+	—
Walking	Normal gait	Normal gait	Bedridden	Walk without aid	Muscle weakness in limbs
Ovarian functions	Secondary amenorrhea	Secondary amenorrhea	Secondary amenorrhea	NA	Ovarian failure
MRI hyperintense lesions on T2WI	Subcortical area	From periventricular to subcortical white matter	Diffuse	Diffuse	Frontotemporal white matter
MRI hyperintense lesions on DWI	+	+	+	NA	+
ADC values in hyperintense lesions on DWI	Elevated	Elevated	Elevated	NA	Elevated
MRI lesions with CSF-like signals	—	—	+	+	—

Abbrevitions: ADC = apparent diffusion coefficient; DWIs = diffusion-weighted images; NA = not available; T2WI = T2-weighted images.

MRI of Individual 1 showed hyperintensities on DWI with mildly elevated ADC values, confined to subcortical white matter. In VWM, white matter lesions with hyperintensities on DWI with mildly elevated ADC values are typically observed in affected individuals with later-onset and prolonged duration.⁶ Individual 1, a 69-year-old woman, showed only recurrent dizziness. Although the extent of white matter lesions on DWI may vary among individuals carrying the homozygous p.V85E variant, these lesions consistently exhibit high DWI signals with elevated ADC values (Table 1).⁷ WGS excluded the involvement of other potentially pathogenic variants with allele frequencies of less than 0.5% in gnomAD in Individual 1 (eTable 1). Thus, the MRI findings in Individual 1 likely represent a very mild form of VWM.

In conclusion, we report 2 individuals with the homozygous c.254T >A variant in EIF2B2. This variant is associated with mild clinical phenotypes with subtle abnormalities on brain MRI, presumably due to its mildly decreased enzymatic activity of EIF2B2. This report further expands the phenotypic spectrum of VWM2 associated with the homozygous c.254T >A variant in EIF2B2.

Author Contributions

T. Kakumoto: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. T. Matsukawa: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. R. Tokimura: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. Y. Tsuboyama: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. Y. Hayashi: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. A. Mitsutake: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. A. Iwata: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. M.H. Maeda: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. J. Shimizu: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. W. Gonoi: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. H. Ishiura: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. J. Mitsui: drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data. S. Tsuji: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. T. Toda: drafting/revision of the manuscript for content, including medical writing for content; study concept or design.

Study Funding

This work was supported in part by the Japan Agency for Medical Research and Development (AMED) (JP20ek0109491, JP21ek0109491, JP22ek0109491, and JP23ek0109673) (S.T.), and KAKENHI (JP22K07413 and JP23K27514) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.K. and H.I).

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/NG for full disclosures.