Clinical And EIF2B Gene Mutations In Patients With Vanishing White Matter

Vanishing White Matter disease (VWM), also called childhood ataxia with central nervous system hypomyelination (CACH) syndrome (OMIM 603896),is an autosomal recessive transmitted leukoencephalopathy. It is characterized by chronic progressive neurological deterioration with cerebellar ataxia,spasticity,variable optic atrophy or seizures. Episodes of major and rapid deterioration following minor head trauma and febrile infections is the typical presentation of this disorder. During these episodes, patients rapidly lose motor abilities and even become coma or die. Magnetic resonance imaging (MRI) shows specific abnormality of the white matter, almost all cerebral white matter and some cerebellar became demyelination with partial replacement by cerebrospinal fluid (CSF). This typical change is easy seen in fluid-attenuated inversion recovery (FLAIR) images. According to the clinical features (mainly the onset age), there are five phenotypes, including prenatal/congenital form, subacute infantile form, early childhood-onset form, late childhood/juvenile-onset form and adult-onset form according to. In 2001-2002,VWM was found to be caused by mutation in any of the five genes (EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5) which encoding the subunits of eukaryotic translation initiation factor eIF2B (eIF2Bα,eIF2Bβ,eIF2Bγ,eIF2Bδ,eIF2Bε),this is the first disease caused by mRNA translation Dysfunction. Ye Wu et al from Pediatrics department of Peking University First Hospital reported the first domestic case with VWM in 2006. Objective To analysis the five genes(EIF2B5, EIF2B4, EIF2B2, EIF2B3, EIF2B1) in 11 patients which had been collected in the Peking University First Hospital, to make a definite diagnosis and set up the basis of genetic counseling and prenatal diagnosis.Methods To analyze patients'information including clinical manifestations, cranial MRI and laboratory tests results in 11 patients with the diagnosis of VWM. PCR assays followed by DNA sequencing were used to analyse the five genes. All these data works had been done in Pediatrics Department of Peking University First Hospital.Results1. Clinical manifestations:10 patients had the neurologic symptoms and signs, 1 patient only showed abnormal cranial MRI with no clinical abnormalities. The onset age ranged from 1 year 4 months to 6 years 5 months, average 3 years 10 months. All patients had normal psychomotor development before the onset of the disease. The initial symptom was usually movement disorder with predominant involvement of lower limbs. The rapid deterioration of the disease happened after respiratory tract infection in 5 patients and trauma in 4 patients, respectively. Seizures were found in 4 patients, and 1 patient had positive family history. Pyramidal signs were found in 10 patients and ataxia in 5 patients. All patients fit the clinical diagnose criteria for VWM.2. Cranial MRI: MRI findings were diffuse and symmetrical involvement of white matter surrounding the ventricle with long T1 and T2 signal. Subcortical white matter was also involved with predominance in frontal and parietal lobes. FLAIR image showed symmetrical high signal intensity in cerebral white matter with low signal intensity similar to CSF in partial area or low signial in most area of white matter with only meshwork of higher signal preserved. Corpus callosum in 5 patients'had abnormal signal and in 1 patient was thinner than that of normal person. Brain stem and pons had punctiform long T2 signal in 2 patients. 6 Patients took the cranial MRI serially,only 1 patient's MRI deteriorated significantly compared with the MRI in 2 years ago.3. Laboratory test: routine biochemistry lab tests and inborn error screening were normal.4. Gene test: Mutations were found in 9 out of 11 patients. EIF2B3 mutations were found in 4 patients', and EIF2B5 mutations were found in the other 5 patients. 3 patients had homozygosis mutation, and 5 patients had heterozygous compound mutations. One patient has only found 1 mutation up to now. There were12 kinds of mutations were found in these 9 patients,including 5 novel missense mutations: c.1126 A>G (p.N376D), c.1004 G>C (p.C335S), c.185 A>T (p.D62V), c.140 G>A (p.G47E), c.1037 T>C (p.I346T). 5 kinds of reported missense mutations: c.943 C>T (p.R315C), c.1340 C>T (p.S447L), c.674 G>A (p.R225Q), c.1016 G>C (p.R339P), c.1157 G>C (p.G386V), one novel nonsense mutation: c.805 C>T (p.R269X), one novel deletion mutation: c.1827₁838del (p.S610_D613del). All mutations found in the patients with DNA of their parents had been proved inherited from their patients. All parents were carrier with normal phenotype. Among the cases with clinical diagnosis of VWM , only 95 percent can be found with gene mutations, other 5 percent patients may have some mutations in intron, 5'noncoding region, and 3'noncoding region in these genes . More investigations are required for this.Conclusion This work established the gene mutation detecting method of EIF2B1-5 for VWM. That helped us to make a definite diagnosis for 9 domestic patients. This is the first time to confirm the diagnosis of this disease in China. Totally 12 kinds of mutations has been found, with 7 novel mutations. All these mutations inherited from their patients who were carrier with normal phenotype. These may help us to do the precise diagnosis, and will be very important for genetic counseling and prenatal diagnosis for the involved families. It is also the basis of EIF2B's function study in the future.