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Eukaryotic initiation factor 2B (eIF2B) GEF activity as a diagnostic tool for EIF2B-related disorders
Laetitia Horzinski1, Aurélia Huyghe, Marie-Céleste Cardoso
1INSERM U931-CNRS 6247- Université Clermont, GReD, Clermont-Ferrand, France.
Plos One
|December 18, 2009
Summary
Measuring eukaryotic initiation factor 2B (eIF2B) Guanine nucleotide Exchange Factor (GEF) activity in cells aids in diagnosing eIF2B-related disorders, offering high specificity and sensitivity for this challenging leukodystrophy diagnosis.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- eIF2B-related disorders encompass a spectrum of leukodystrophies, previously known as Childhood Ataxia with Central Hypomyelination/Vanishing White Matter disorder (CACH/VWM).
- Clinical presentations vary widely, from severe antenatal forms to milder adult-onset cognitive impairment, challenging traditional diagnostic criteria.
- Diagnostic difficulties arise as typical MRI patterns may be absent in adult forms, and non-eIF2B mutations can mimic CACH/VWM.
- Existing biochemical markers for eIF2B-related disorders are limited, with asialotransferrin/transferrin ratio being the only recently validated marker in cerebrospinal fluid.
Purpose of the Study:
- To evaluate the diagnostic utility of eukaryotic initiation factor 2B Guanine nucleotide Exchange Factor (eIF2B GEF) activity as a biochemical marker.
- To validate eIF2B GEF activity measurements in a larger patient cohort for specific diagnosis of eIF2B-related disorders.
Main Methods:
- Performed eIF2B GEF activity assays in lymphoblastoid cell lines from 63 patients with various clinical forms and eIF2B mutations.
- Included control groups and patients with leukodystrophies or CACH/VWM-like diseases without eIF2B mutations for comparison.
- Assessed diagnostic performance using specificity and sensitivity calculations based on a defined activity threshold.
Main Results:
- A significant decrease in eIF2B GEF activity was observed in cells from patients with eIF2B mutations.
- The assay demonstrated 100% specificity and 89% sensitivity for diagnosing eIF2B-related disorders when the activity threshold was set at <=77.5%.
- These findings highlight the potential of eIF2B GEF activity as a reliable diagnostic biomarker.
Conclusions:
- Measurement of eIF2B GEF activity in transformed lymphocytes is validated as a crucial tool for diagnosing eIF2B-related disorders.
- This biochemical marker aids in differentiating eIF2B-related leukodystrophies, especially in complex or atypical cases.
