Leukoencephalopathy with Vanishing White Matter and Ovarioleukodystrophy via the EIF2B1 Gene

Variants in the genes that encode the five subunits of the eukaryotic translation initiation factor 2B (EIF2B1-B5) cause a heterogeneous spectrum of white matter disorders in which MRI studies show a symmetric pattern of white matter rarefaction, cystic degeneration, and loss of oligodendrocytes by apoptosis (van der Knaap et al. Neurology 51:540-547, 1998; Bugiani et al. J Neuropath Exp Neurol 69:987-996, 2010). Over the course of the disease, white matter gradually vanishes and is replaced by cerebrospinal fluid. Age at onset varies from prenatal to adulthood, with childhood onset being the most common. The earliest-onset cases are associated with oligohydramnios, IUGR, microcephaly, contractures, and severe encephalopathy. In later-onset cases development is normal initially, followed by a progressive course with features of ataxia, spasticity, optic atrophy, and diminished mental ability. Periods of acute deterioration can be provoked by stresses such as febrile illness, minor head injury or extreme fright (Vermeulen et al. Ann Neurol 57:560-563, 2005). A severe and early-onset form of the disease, called Cree leukoencephalopathy, is found among the native Cree and Chippewa populations of northern Quebec and Manitoba (Black et al. Ann Neurol 24:490-496, 1988). The mild juvenile and adult forms are often associated with primary ovarian failure, a syndrome referred to as ovarioleukodystrophy (Schiffmann et al. Ann Neurol 41:654-661, 1997; Fogli et al. Am J Hum Genet 72:1544-1550, 2003).

The eukaryotic initiation factor, 2B, is a GTP exchange factor that regulates the rate of protein synthesis. EIF2B is a heteropentameric protein encoded by the five genes EIF2B1 – B5. The EIF2B-related leukodystrophies (OMIM 603896) are inherited in an autosomal recessive manner. Thus far, only EIF2B2, EIF2B4, and EIF2B5 have been implicated in ovarioleukodystrophy (Fogli et al. 2003). Approximately 90% of all pathogenic variants are missense variants (Fogli et al. Neurology 62:1509–517, 2004).

Sensitivity among individuals with characteristic MRI findings is ~90% (Schiffmann et al. GeneReview, 2010). Over 60% of all molecularly diagnosed patients have variants in EIF2B5 and another ~20% have variants in EIF2B2 or EIF2B4 (Schiffmann et al. 2010). Variants in EIF2B3 and EIF2B1 account for ~9% and ~2% of patients, respectively.

This test provides full coverage of all coding exons of the EIF2B1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).