Short Communication Vanishing white matter disease caused by EIF2B2 mutation with the presentation of an adrenoleukodystrophy phenotype ☆ Ahmed Alsalem a , Ranad Shaheen a , Fowzan S. Alkuraya a, b, c, ⁎ a Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia b Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia c Department of Anatomy and Cell Biology, College of Medicine, Alfasial University, Riyadh, Saudi Arabia abstract article info Article history: Accepted 22 December 2011 Available online 17 January 2012 Keywords: EIF2B2 Leukomalacia Homozygosity scan Neurodegenerative disease Vanishing white matter disease (VWMD) is an autosomal recessive disorder characterized by progressive de- generation of the white matter. While variable clinical presentation is well documented, there are no reports of adrenal insufficiency. We describe a young Saudi girl with VWMD whose atypical phenotype suggested ad- renoleukodystrophy. This complicated the diagnostic workup until homozygosity scan revealed a novel mu- tation in EIF2B2.This report widens the clinical spectrum of VWMD and raises the possibility of an allele- specific association with adrenal insufficiency. © 2011 Elsevier B.V. All rights reserved. 1. Introduction Vanishing white matter disease (VWMD, OMIM 603896), also known as childhood ataxia with central nervous system hypomyelina- tion, is an autosomal recessive disease that presents classically in the first five years of life with symptoms ranging from spasticity and ataxia to coma resulting in death (Ohlenbusch et al., 2005). The disease is caused by impaired Eukaryotic Translation Initiation Factor 2B (EIF2B), a nucleotide exchange factor that executes the exchange of a GDP bound-eIF2 with a GTP to form GTP-eIF2 complex that is capable of ini- tiating translation in a rate limiting reaction. EIF2B is only functional by the interaction between its five non-identical subunits α, β, γ, δ and ε, and recessive mutations in any of these subunits have been found to cause VWM disease (Pavitt and Proud, 2009). More than 120 mutations are identified in the literature, about 50% of which are in EIF2B5 which encodes the ε subunit, while the rest are distributed unequally between EIF2B1-4 with EIF2B1 being the least common. Interestingly, most muta- tions are missense, and when truncating nonsense mutations are ob- served, they are always compound heterozygous with a missense mutation which suggests that having one partially functional copy is es- sential for survival (Pronk et al., 2006). Mutations in the regulatory sub- complex (e.g. EIF2B2) were found to cause complex instability by way of interfering with the holocomplex formation whereas mutations in the catalytical sub-complex (e.g. EIF2B5) are responsible for a decrease in the functional units present in the cells of VWMD patients. Clinical re- ports revealed direct correlation between mutation severity and the age of onset (Maletkovic et al., 2008; Pavitt and Proud, 2009). Classical VWMD presents in the second year of life, after a period of normal development, with a neurological spectrum of signs and symp- toms such as developmental delay, spasticity, seizure disorder and cere- bellar dysfunction but usually with minimal mental impairment. It is usually progressive with a relapsing and remitting nature, and episodes can be triggered by febrile illness or head trauma. Towards the severe end of the spectrum, the disease can present in the first year of life or even antenatally with broad systemic involvement in the form of intra- uterine growth restriction (IUGR), oligohydramnios, renal malformation, cataract, glaucoma, dysmorphic features and joint contractures (van der Knaap et al., 2003). Milder forms can have an onset in adolescence and present as mild neurological symptoms and amenorrhea reflecting pre- mature ovarian failure (ovarioleukodystrophy). Indeed, the existence of multiple forms of this disease stimulated the concept of EIF2B-related disorders as a more encompassing designation (Labauge et al., 2009). In this report, we add to the clinical heterogeneity of this disorder by pre- senting a young Saudi girl with this disease who was misdiagnosed with adrenoleukodystrophy owing to significant adrenal insufficiency which has not been reported in association with VWMD. 2. Clinical report Index is a three and a half years old Saudi girl. She is the product of a pregnancy complicated by premature labor (at 36 weeks) and low birth weight of 2.150 kg. Neonatal history was remarkable for poor feeding Gene 496 (2012) 141–143 Abbreviations: OMIM, Online inheritance in man; GDP, Guanosine diphosphate; GTP, Guanosine triphosphate; ACTH, Adrenocorticotropic hormone; MRI, Magnetic resonance imaging; VLCFA, Very long chain fatty acids. ☆ Authors declare no conflict of interest. ⁎ Corresponding author at: Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, MBC 03, PO Box 3354, Riyadh 11211, Saudi Arabia. Tel.: +966 1 442 7875; fax: +966 1 442 4585. E-mail address: falkuraya@kfshrc.edu.sa (F.S. Alkuraya). 0378-1119/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.gene.2011.12.047 Contents lists available at SciVerse ScienceDirect Gene journal homepage: www.elsevier.com/locate/gene