Journal of Inherited Metabolic Disease

, Volume 31, Supplement 2, pp 293–297

Wolcott–Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome

Short Report

Summary

Wolcott-Rallison syndrome (WRS) (OMIM 226980) is a rare, autosomal recessive disorder with infancy-onset diabetes mellitus, multiple epiphyseal dysplasia, osteopenia, mental retardation or developmental delay, and hepatic and renal dysfunction as main clinical findings. Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3. We report a female patient who developed insulin-requiring diabetes at 2.5 months of age. Multiple epiphyseal dysplasia was diagnosed at age 2 years. At age 5.5 years she developed a Reye-like syndrome with hypoketotic hypoglycaemia and renal and hepatic insufficiency and died. A partial autopsy showed fat infiltration in the liver and kidneys. Examination of urine by gas chromatography and mass spectrometry showed large amounts of C6-dicarboxylic acid (adipic acid), 3-hydroxy-C8-dicarboxylic acid, 3-hydroxy-C10-dicarboxylic acid, and 3-hydroxydecenedioic acid. Acetoacetate and 3-hydroxybutyrate were absent. The findings suggested a metabolic block in mitochondrial fatty acid oxidation, but lack of material precluded enzyme analyses. The clinical diagnosis of WRS was suggested in retrospect, and confirmed by sequencing of DNA extracted from stored autopsy material. The patient was compound heterozygous for the novel EIF2AK3 mutations c.1694_1695delAT (Y565X) and c.3044T > C (F1015S). Our data suggest that disruption of the EIF2AK3 gene may lead to defective mitochondrial fatty acid oxidation and hypoglycaemia, thus adding to the heterogeneous phenotype of WRS.

Abbreviations

eIF2α

eukaryotic translation initiation factor 2-alpha

PERK

eukaryotic translation initiation factor 2-alpha kinase 3

WRS

Wolcott–Rallison syndrome

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Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • O. Søvik
    • 1
    • 2
  • P. R. Njølstad
    • 1
    • 2
  • E. Jellum
    • 3
  • A. Molven
    • 4
    • 5
  1. 1.Section for Pediatrics, Department of Clinical MedicineUniversity of BergenBergenNorway
  2. 2.Department of PediatricsHaukeland University HospitalBergenNorway
  3. 3.Institute of Clinical BiochemistryUniversity of OsloOsloNorway
  4. 4.Section for Pathology, The Gade InstituteUniversity of BergenBergenNorway
  5. 5.Department of PathologyHaukeland University HospitalBergenNorway

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