Adult-onset vanishing white matter disease with the EIF2B2 gene mutation presenting as menometrorrhagia

Abstract

Background: Vanishing white matter disease (VWMD) is one of the most prevalent inherited leukoencephalopathies, which generally presents in childhood as a progressive disorder while less beginning in adulthood. The present report describes the clinical, neuroimaging, and genetic findings of a female patient with adult-onset VWMD. In addition, to provide a clearer delineation of the clinical and genetic characteristics of female adult-onset VWMD patients, 32 genetically confirmed female adult-onset EIF2B-mutated cases are summarized.

Case presentation: The patient described here suffered from long-term menometrorrhagia prior to manifesting progressive neurological impairments that included tremors, bilateral pyramidal tract injury, cerebellar ataxia, and dementia. To the best of our knowledge, this is the first female patient with adult-onset VWMD suffering from long-term menometrorrhagia attributed to the c.254 T > A and c.496A > G mutations in the EIF2B2 gene; the c.496A > G mutation has not been reported in previous studies. The patient also exhibited metabolic dysfunction. The present findings widen the spectrum of phenotypic heterogeneity observed in VWMD patients.

Conclusions: The present report summarizes 33 female patients with adult-onset VWMD to provide an overview of the clinical and genetic characteristics of this disorder and ovarioleukodystrophy. The mean age of clinical onset in female patients with adult-onset VWMD was 36.8 years and the neurological symptoms primarily included motor and cognitive dysfunction such as paraparesis, cerebellar ataxia, and executive deficits. In addition, ovarian failure occurred in all of these female patients and usually preceded the neurological symptoms. Furthermore, several patients also suffered from metabolic dysfunction. All 33 patients had mutations on EIF2B1-5, and of these, the c.338 G > A mutation in the EIF2B5 gene (p.Arg113His) was the most common. These findings suggest that clinicians should be aware of adult-onset forms of VWMD as well as its typical magnetic resonance imaging (MRI) and clinical characteristics although this pathology is usually recognized as a pediatric disorder. No curative treatment is presently available, and thus early recognition is important to prevent triggering events and to allow for genetic counseling.

Keywords: Adult-onset vanishing white matter disease; Eukaryotic translation initiation factor 2B; Late-onset vanishing white matter disease; Leukodystrophies; Ovarioleukodystrophy; Vanishing white matter disease.

Fig. 1

Neuroimaging results of the VWMD patient. a Axial T1-weighted, T2-weighted, Flair, DWI, ADC and coronal T1-weighted images showing extensive cerebral white matter abnormalities with central areas resembling signal intensity of cerebrospinal fluid surrounded by a rim of hyperintensity in the periventricular and subcortical regions. White-matter rarefaction and cystic degeneration are more evident in subcortical and periventricular regions. Obvious brain atrophy was also detected. b Brain ¹⁸F-FDG PET showed decreased FDG uptake in left frontal, parietal and temporal lobe. Compared with right side, the decline rate is 17, 12 and 17%. c Brain DTI disclosed fibrous white bundle was reduced sparsely among bilateral periventricular

Fig. 2

Genetic results of the VWMD patient. Genomic sequence chromatograms of the missense in EIF2B2 in patient’s family members: c.254 T > A and c.496A > G

Fig. 3

Function prediction and protein molecular models: a SIFT and b POLYPHEN2 online websites were used to analyze the amino acid substitutions of p.M166 V. Both programs predicted the mutation c.496A > G to be deleterious, which means they probably damage and affect protein functions. c The mutation protein E85 has a different side chain to the wild-type protein V85. The wide-type protein has a longer side chain than the mutation V166 protein