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Translation initiation factor eIF-2B subunit epsilon (eIF-2B GDP-GTP exchange factor subunit epsilon) [EIF2BE]


Mendelian adult-onset leukodystrophy genes in Alzheimer's disease: critical influence of CSF1R and NOTCH3.

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant-based and single-gene-based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation.

MeSH Terms

  • Aged
  • Aged, 80 and over
  • Aging
  • Alzheimer Disease
  • Animals
  • Cerebral Cortex
  • Cohort Studies
  • European Continental Ancestry Group
  • Female
  • Genetic Association Studies
  • Hippocampus
  • Humans
  • Leukodystrophy, Metachromatic
  • Male
  • Mice
  • Middle Aged
  • Mutation
  • Receptor, Notch3
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Risk Factors


  • Alzheimer's disease
  • CSF1R
  • Mendelian leukodystrophies
  • NOTCH3

Infantile onset Vanishing White Matter disease associated with a novel EIF2B5 variant, remarkably long life span, severe epilepsy, and hypopituitarism.

Vanishing White Matter disease (VWM) is an inherited progressive leukoencephalopathy caused by mutations in the genes EIF2B1-5, which encode for the 5 subunits of the eukaryotic initiation factor 2B (eIF2B), a regulator of protein synthesis. VWM typically presents with acute neurological decline following febrile infections or minor head trauma, and subsequent progressive neurological and cognitive regression. There is a varied clinical spectrum of VWM, with earlier onset associated with more severe phenotypes. Brain magnetic resonance imaging is usually diagnostic with diffusely abnormal white matter, progressing over time to cystic degeneration. We are reporting on a patient with infantile onset VWM associated with three heterozygous missense variants in EIF2B5, including a novel missense variant on exon 6 of EIF2B5 (D262N), as well as an interstitial duplication at 7q21.12. In addition, our case is unusual because of a severe epilepsy course, a novel clinical finding of hypopituitarism manifested by hypothyroidism and adrenal insufficiency, and a prolonged life span with current age of survival of 4 years and 11 months.

MeSH Terms

  • Abnormalities, Multiple
  • Child, Preschool
  • Epilepsy
  • Eukaryotic Initiation Factor-2B
  • Genetic Association Studies
  • Hereditary Central Nervous System Demyelinating Diseases
  • Humans
  • Hypopituitarism
  • Life Expectancy
  • Male


  • Vanishing White Matter (VWM)
  • adrenal insufficiency
  • childhood ataxia with central nervous system hypomyelination (CACH)
  • endocrine dysfunction
  • epilepsy
  • eukaryotic initiation factor 2B (eIF2B)
  • hypopituitarism
  • hypothyroidism
  • infantile Vanishing White Matter (VWM)
  • leukodystrophy