Adult-onset vanishing white matter disease with novel missense mutations in a subunit of translational regulator, EIF2B4.

Content Provider	Semantic Scholar
Author	Kanbayashi, Takamichi Saito, Fumiaki Matsukawa, Takashi Hokkoku, Keiichi Hatanaka, Yuki Tsuji, Shoji Sonoo, Masahiro
Copyright Year	2015
Abstract	To the Editor: Vanishing white matter disease (VWM) is one of the most prevalent inherited leucoencephalopathies with autosomal recessive inheritance. The clinical features of VWM are episodes of rapid neurological deterioration provoked by stresses, such as fever and minor head trauma, during a chronic progressive course (1). Magnetic resonance imaging (MRI) findings that exhibit leukoencephalopathy, with lesions having cerebrospinal fluid (CSF)-like signals, are very characteristic. The phenotypic variation is broad – most cases of VWM develop in early childhood though adult-onset cases have also been reported occasionally. Severe forms start in the prenatal or early infantile period and lead to early death (2). In contrast, much milder variants start in adolescence or adulthood and are characterized by slow disease progression. VWM is caused by mutations in the genes EIF2B1-5 encoding the subunits of eukaryotic translation initiation factor 2B (eIF2B). Among them, mutations in EIF2B5 are the most common, accounting for 60–70% of all cases of VWM (3). On the other hand, mutations in EIF2B4 are 4–14% (4, 5). Here, we describe a patient with adult-onset VWM who carries novel missense mutations in EIF2B4. A 59-year-old Japanese woman presented to our hospital. She noticed gait unsteadiness and forgetfulness at the age of 56, which exacerbated slowly. She had experienced no episodes of rapid neurological symptoms evoked by stresses. Her birth and development during childhood were normal, and she had no ovarian failure. The family history was unremarkable. Her parents did not have a consanguineous marriage. Neurological examinations showed spastic paraparesis, increased bilateral patellar tendon reflexes, and bilateral extensor Babinski signs. Mini-Mental State Examination score was 16. Wechsler Adult Intelligence Scale-third edition (WAIS-III) revealed a low intelligence quotient (verbal IQ of 66, performance IQ of 59, full-scale IQ of 60). Brain MRI showed symmetric diffuse high-intensity lesions in the deep white matter on T2-weighted images. The lesions in the deep frontal white matter had CSF-like signals on fluid-attenuated inversion recovery (FLAIR) images (Fig. 1a,b). The results of routine laboratory tests were normal. CSF examination showed elevation of protein at 54 mg/dl (normal <40) and increased glycine concentrations at 11.6 μmol/l (normal 7.7± 3.5); the latter is considered a biochemical marker for VWM (6). The clinical course and MRI findings characteristic of VWM prompted us to perform genetic analyses. Sanger sequencing of all exons of the VWM causative genes, EIF2B1-5, revealed novel heterozygous missense mutations, c.617T>C (p.Met206Thr) and c.952A>G (p.Ile318Val) in EIF2B4. Furthermore, direct nucleotide sequence analysis of the plasmids, in which genomic segments containing c.617T>C and c.952A>G in EIF2B4 were cloned, revealed that the mutations, c.617T>C (p.Met206Thr) and c.952A>G (p.Ile318Val), were located on different alleles (Fig. 1c). As shown in Fig. 1d, the amino acid Ile318 of EIF2B4 is highly conserved among species, and p.Ile318Val mutation is predicted to be probably damaging and disease causing by Polyphen-2, SIFT, and Mutation Taster. On the other hand, the amino acid Met206 is highly conserved among mammals. By SIFT and Mutation Taster, p.Met206Thr is predicted to be damaging and disease causing (Fig. 1d). These mutations were not present in 276 unrelated Japanese control subjects, and not registered in the Human Genetic Variation Database (HGVD), a database of the exome sequencing of 1208 Japanese individuals. This is the second reported case of adult-onset VWM with mutations in EIF2B4 (4). The age of 56, when our case developed symptoms, is the oldest among patients with EIF2B4 mutation thus reported (5). So far, the influence of genotype on the phenotype in EIF2B4 mutation has not yet been clarified. Revealing the genotype–phenotype relationship is important as it enables clinicians and genetic counselors to provide appropriate information to patients and families. Our case indicates that the heterozygous c.617T>C (p.Met206Thr) and c.952A>G (p.Ile318Val) mutations in EIF2B4 might be related to the late-onset milder form of VWM.
File Format	PDF HTM / HTML
DOI	10.1111/cge.12554
Alternate Webpage(s)	http://www.laserwords.co.in/offprint/cge_88-4/cge_12554_web.pdf
PubMed reference number	25600065
Alternate Webpage(s)	https://doi.org/10.1111/cge.12554
Journal	Medline
Volume Number	88
Issue Number	4
Journal	Clinical genetics
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article