EIF2AK3 – Wolcott-Rallison syndrome

Wolcott-Rallison syndrome is a rare autosomal recessive disorder characterized by permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia, and recurrent acute liver failure. Patients often present with diabetes within the first six months of life and develop skeletal dysplasia and growth retardation within the first two years of life. Additional variable features include intellectual disability, hepatic and renal dysfunction, hypothyroidism, and neutropenia. Clinical suspicion should be raised in infants with non-autoimmune diabetes and early signs of skeletal abnormality, particularly in consanguineous families (PMID:9185226; PMID:21050479).

Pathogenic variants in EIF2AK3 underlie the syndrome. More than 100 affected individuals from over 60 unrelated families have been reported, with biallelic loss-of-function and missense mutations segregating with disease in consanguineous pedigrees. A recurrent nonsense variant, c.1563G>A (p.Trp521Ter), abolishes the kinase domain and has been identified in multiple unrelated kindreds (PMID:23933668).

Segregation analysis across 12 consanguineous families demonstrated co-segregation of EIF2AK3 variants with clinical disease in at least 18 additional affected relatives, confirming autosomal recessive inheritance and high penetrance in homozygous or compound heterozygous states (PMID:15220213).

Functional studies reveal that PERK (the protein encoded by EIF2AK3) is essential for phosphorylation of eukaryotic initiation factor 2α (eIF2α) during endoplasmic reticulum stress. Disease-associated missense and truncating mutations completely abrogate kinase activity, leading to failure of the unfolded protein response, β-cell apoptosis, and impaired bone development in cellular and animal models (PMID:10932183; PMID:15220213).

Mechanistically, loss of PERK function disrupts endoplasmic reticulum homeostasis, causing unmitigated stress, upregulation of CHOP, and cell death in pancreatic islet cells and chondrocytes. Rescue experiments in PERK-deficient models restore eIF2α phosphorylation and improve survival, supporting haploinsufficiency as the primary pathogenic mechanism (PMID:12086964).

Genetic testing for EIF2AK3 is recommended in any infant presenting with permanent neonatal diabetes before six months of age, especially with skeletal dysplasia or family history of consanguinity. Early molecular diagnosis enables anticipatory management of hepatic crises and guides genetic counseling and prenatal diagnosis. Key take-home: EIF2AK3 mutation analysis is critical for confirming Wolcott-Rallison syndrome, informing prognosis, and optimizing multidisciplinary care.

References

• Pediatric pathology & laboratory medicine • 1997 • Autopsy findings in the Wolcott-Rallison syndrome. PMID:9185226
• Orphanet journal of rare diseases • 2010 • Wolcott-Rallison syndrome. PMID:21050479
• Nature genetics • 2000 • EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. PMID:10932183
• Diabetes • 2004 • Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. PMID:15220213
• Diabetes • 2002 • Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. PMID:12086964
• Diabetes • 2002 • Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. PMID:12086964
• Diabetes • 2002 • Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. PMID:12086964
• Diabetes • 2002 • Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. PMID:12086964
• Diabetes • 2002 • Loss of kinase activity in a patient with Wolcott-Rallison syndrome caused by a novel mutation in the EIF2AK3 gene. PMID:12086964

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