Wolcott–Rallison syndrome with 3-hydroxydicarboxylic aciduria and lethal outcome
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- Søvik, O., Njølstad, P.R., Jellum, E. et al. J Inherit Metab Dis (2008) 31: 293. doi:10.1007/s10545-008-0866-1
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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.
eukaryotic translation initiation factor 2-alpha
eukaryotic translation initiation factor 2-alpha kinase 3
Wolcott–Rallison syndrome (WRS) (Wolcott and Rallison 1972; 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 (Iyer et al 2004). Additional findings reported are central hypothyroidism (Bin-Abbas et al 2002), pancreatic hypoplasia and exocrine pancreas deficiency (Castelnau et al 2000; Thornton et al 1997), congenital malformations (Senée et al 2004; Stewart et al 1996; Thornton et al 1997), and neutropenia (Senée et al 2004). To date, only around 40 cases of WRS have been reported in the literature.
Patients with WRS have mutations in the EIF2AK3 gene, which encodes the pancreatic eukaryotic translation initiation factor 2-alpha kinase 3 (PERK) (Delépine et al 2000). The mutated kinase is unable to phosphorylate its natural substrate, the eukaryotic translation initiation factor 2-alpha (eIF2α) (Biason-Lauber et al 2002). Loss of Eif2ak3 expression in Perk−/− mice leads to severe pancreatic dysfunction by apoptosis, development of diabetes mellitus and a phenotype similar to WRS (Harding et al 2001; Zhang et al 2002).
We here report a WRS patient who died at the age of 5.5 years during a metabolic crisis (Reye-like syndrome) with renal and hepatic insufficiency. Analysis of urinary organic acids revealed 3-hydroxydicarboxylic aciduria, suggesting a metabolic block in mitochondrial fatty acid oxidation. We conclude that disrupted PERK function may cause inhibition of fatty acid oxidation, as part of hepatic dysfunction.
The female patient was the only child of non-consanguineous parents of Norwegian ethnicity. She was born at term (2960 g/48 cm). At birth she was pale and had a weak cry and frequent respiration. She was transferred to the neonatal intensive care unit and treated with antibiotics. At the age of 2.5 months she was hospitalized with hyperglycaemia (32 mmol/L) and metabolic acidosis. She was diagnosed with type 1 diabetes mellitus, but anti-GAD, IA2 or insulin antibodies were not measured. On insulin treatment she recovered rapidly and showed longitudinal catch-up growth during the following months. However, from the age of 6 months her height centiles decreased, reaching the 2.5 centile at age 5 years. This was attributed to poorly regulated diabetes. When she was 21 months old, an abnormal and stiff gait was noted. A subsequent radiograph showed multiple epiphyseal dysplasia. At age 5 years her left hip was treated surgically. At age 5.5 years, three days after onset of an upper respiratory tract infection, the patient developed the clinical picture of Reye syndrome, with vomiting, somnolence and hypoglycaemia (1.8 mmol/L) in spite of discontinued insulin therapy. She was not ketoacidotic. She had hepatomegaly with elevated levels of alanine aminotransferase (10 700 U/L, reference <40 U/L), aspartate aminotransferase (26 150 U/L, reference <40 U/L), lactic dehydrogenase (36 300 U/L, reference <570 U/L), γ-glutamyl transferase (88 U/L, reference <20 U/L), ammonia (105 U/L, reference <65 U/L) and creatinine (268 U/L, reference <60 U/L). Serum levels of free fatty acids were moderately elevated (1.8 mmol/L, reference <1.5 mmol/L). She became rapidly hypotensive (60/40) with total anuria, and died 36 h after admission, probably from cerebral oedema. The parents gave permission to a partial autopsy, which showed diffuse fat infiltration in the kidney parenchyma and in the liver, confirmed by electron microscopy. The patient did not receive supplemental lipids, neither during long-term follow-up nor during the terminal illness. There were no signs of diabetic nephropathy. Urine, obtained during the acute illness, showed excretion of organic acids as described below.
Organic acid analyses
Molecular genetic analyses
Wolcott-Rallison syndrome in this patient was recognized retrospectively and post mortem. During the initial upper respiratory tract infection, leading to the terminal illness, no salicylates were ingested, and a Reye-like syndrome and hypoketotic hypoglycaemia were totally unexpected. A simultaneous occurrence of diabetes mellitus and Reye syndrome has to our knowledge not been reported in the literature.
Having established a 3-hydroxydicarboxylic aciduria, the primary diagnostic possibility was a defect of mitochondrial fatty acid oxidation. Such a diagnosis was supported by hypoketotic hypoglycaemia, elevated serum free fatty acids, and fatty infiltration of the liver. Excretion of large amounts of several dicarboxylic and hydroxydicarboxylic acids pointed towards a deficiency of long-chain 3-hydroxyacyl-CoA-dehydrogenase (LCHAD), which is part of the trifunctional protein (TFP) complex. TFP deficiency presents with three different clinical phenotypes (Spiekerkoetter et al 2003): (1) A lethal neonatal form with a Reye-like picture, (2) a less severe, infancy-onset type, characterized by recurrent hypoketotic hypoglycaemia and lethargy during illness or fasting, and (3) a neuromyopathic phenotype occurring in 1–6-year-old children. The clinical picture of our patient was thus intermediate between types 1 and 2. Enzymatic confirmation of TFP deficiency was precluded since adequate biological material was not available. However, the postmortem diagnosis of WRS made an additional diagnosis of TFP deficiency unlikely, but instead raised the problem how to reconcile 3-hydroxydicarboxylic aciduria with a mutation of EIF2AK3.
3-Hydroxydicarboxylic aciduria may in general be classified as specific and non-specific, the specific form being associated with LCHAD, whereas non-specific forms are seen in various genetic and metabolic disorders (Bennett et al 1994; Bergoffen et al 1993; Mize et al 1997; Okajima et al 2002). Our case most likely belongs to the latter category. One may speculate that 3-hydroxyacyl-CoA-dehydrogenase activities are reduced in various states of hepatic dysfunction (Bergoffen et al 1993).
The observation of hepatic fatty infiltration in our case is at variance with another report of autopsy findings in WRS, where the liver showed only minor histological abnormalities (Thornton et al 1997). However, some patients with WRS have had unexplained hypoglycaemic episodes, probably related to impaired liver function, as summarized by Brickwood and colleagues (2003). Hepatic impairment and renal failure, which have been described in cases of WRS, are not seen in Perk-deficient mice models (Harding et al 2001; Zhang et al 2002). Interestingly, Scheuner and colleagues (2001) generated mice with a homozygous mutation at the eIF2α phosphorylation site (Ser51Ala). These mice, harbouring only the non-phosphorylated version of eIF2α, died shortly after birth due to reduced gluconeogenesis and severe hypoglycaemia. It is therefore possible that some cases of human PERK deficiency have metabolic changes reminiscent of defective murine eIF2α phosphorylation.
We conclude that a search for WRS mutations should be included in the molecular-genetic diagnosis of patients with autoantibody-negative, neonatal diabetes mellitus. With a diagnosis of WRS established, hepatic and renal complications are anticipated, allowing adequate prophylactic and therapeutic measures.
We are grateful to Ms. Solrun Steine for expert assistance with DNA sequencing.
The study was partly funded by the University of Bergen, Haukeland University Hospital and the Research Council of Norway.