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• W2059172581 abstract "Glycerol kinase deficiency (GKD, MIM 307030) is an X-linked disorder caused by impaired ability to metabolize glycerol resulting in elevated levels of glycerol in blood and urine (1). Glycerol kinase catalyzes the phosphorylation of glycerol to glycerol-3-phosphate, an important intermediate in both lipid and carbohydrate metabolism. Glycerol kinase deficiency can be found as an isolated enzyme deficiency or as part of an Xp21 contiguous gene syndrome resulting in a so-called complex form involving NR0B1 (DAX1, the locus associated with adrenal hypoplasia congenita) and the Duchenne muscular dystrophy gene. Isolated GKD may in some cases be present without symptoms; however, in other cases children with isolated GKD may present with vomiting, metabolic acidosis, ketotic hypoglycemia, lethargy, and unconsciousness. These crises can be associated with infections or strenuous physical activity (2). The patients have high concentrations of glycerol in blood and urine (3). Most laboratories determine triglyceride concentration by measuring glycerol after hydrolysis of triglycerides and make the assumption that the glycerol concentration is equal to the triglyceride concentration. This can lead to misinterpretation of the laboratory results and consequently a high level of free glycerol (before hydrolysis) in the case of GKD results in a false report of high triglyceride concentration. We describe the critical clinical course in a patient with isolated GKD who had not received a diagnosis when he acquired a fulminant Epstein-Barr virus (EBV) infection, which resulted in the development of acute liver failure. The reported elevated triglyceride levels were initially interpreted as an indication of hemophagocytic lymphohistiocytosis (HLH), which possibly complicated the clinical course. Molecular genetic investigations revealed a previously undescribed microdeletion of 4 nucleotides in the GK gene, resulting in the exclusion of 3 exons in the mRNA and an abolished enzyme activity. CASE REPORT Patient's History and Clinical Course The patient, a 9-year-old boy, had normal growth, weight 2 standard deviation scores (SDS) and height 1 SDS. His psychomotor development was considered normal, but he needed extra assistance at school. The boy had been admitted to hospital care on 2 previous occasions, the first time at 5 years of age with gastroenteritis and elevated temperature. He was dehydrated after 2 days of frequent vomiting without diarrhea and had lost 8% of body weight and had a pulse of 160 beats per minute. Despite the dehydration he had good diuresis. The results of a neurological examination were normal. Blood hemoglobin concentration was 158 g/L, C-reactive protein (CRP) was <10 (ref <10) mg/L, pH 7.21, pCO2 1.98 kPa, base excess −20.9 mmol/L. No low blood glucose was recorded. The possibility of intoxication (eg, with ethylene glycol) was discussed but discarded. The boy received glucose infusion for 2 days and recovered. Six months later he had another hospital admittance with elevated temperature, lymphadenitis, and elevated CRP (116 mg/L). He was treated with intravenous antibiotics and fluids for 1 week. At 9 years of age the boy was hospitalized because of acute abdominal pain and elevated temperature. The results of routine blood tests were normal, but CT of the abdomen could not exclude appendicitis, and he underwent appendectomy. The removed appendix was histologically normal. Within the first 24 hours postoperatively, he had continuously elevated temperature, he became lethargic and pale, and signs of liver failure developed: aspartate aminotransferase 125 (ref 0.4–0.8) μkat/L, alanine aminotransferase 21 (ref <0.8) μkat/L, γ-glutamyl transferase 6 (ref <1.0) μkat/L, bilirubin 56 (ref <26) μmol/L, prothrombin time international normalized ratio 2.0 (ref <1.2), low fibrinogen 1.3 (ref 2–4) g/L, albumin 16 (ref 34–47) g/L, and CRP 20 (ref <10) mg/L. The liver was moderately enlarged, but there was no splenomegaly and no ascites. The cervical lymph nodes were moderately enlarged. Virological investigations, including serology and polymerase chain reaction, showed that the patient had a primary EBV infection. The combination of acute liver failure, pancytopenia (hemoglobin 93–78 g/L, leukocyte count 2.6 × 109/L including neutrophils 0.95 × 109/L, and platelet count 32 × 109/L), an extremely elevated triglyceride concentration 11.7 (ref <1.2) mmol/L (4), and ferritin 10,422 (30–350) μg/L (5) suggested the diagnosis of HLH, presumably associated with the EBV infection. Bone marrow investigation could not detect phagocytic cells. However, the patient received chemotherapy combined with high doses of glucocorticoids according to the treatment strategies for HLH (6). In addition, antiviral drugs were given. The further course was complicated by multiple organ involvement. The patient experienced encephalopathy, severe cholestatic jaundice with bilirubin >700 (ref <26) μmol/L, and a bleeding tendency. The ammonia level was initially 96 (ref 15–45) μmol/L, but subsequent measurements were all below 55 umol/L. Polyuria was followed by oliguria with concomitant severe electrolyte (Na+, K+, Ca2+, phosphate) disturbances, and high blood pressure. He required hemoperfusion during a period of 1 week. The multiorgan failure in combination with encephalopathy prompted investigation of the urinary organic acid profile, and an extremely elevated urinary excretion of glycerol was detected (Table 1). The elevated glycerol level, compatible with GKD, led us to question the HLH diagnosis, and after 1 dose of treatment the chemotherapy was interrupted.TABLE 1: Triglyceride concentration in serum analyzed with glycerol blanked (TGGB) and unblanked (TG) methodsThe patient's condition deteriorated further, and he required mechanical ventilation. He experienced weakness of the left side, and CT showed a small area of cerebral hemorrhage on the corresponding side. During his time in the intensive care unit he acquired pneumonia, septicemia, and a fungal infection. He had continuous elevated temperature of 39° to 41°C for several weeks, but when the temperature decreased he recovered rapidly. During 3 years of follow-up the liver function tests returned to normal. The patient has gradually returned to normal activity and attends school full time but has a slight left-sided weakness. He has attention difficulties affecting his school performance to some degree. The first year after the illness there was definite growth impairment but he subsequently experienced good catch-up growth. Confirmation of GKD Diagnosis The glycerol kinase enzyme activity was measured in fibroblasts from the patient, as described earlier (3). Reverse transcription polymerase chain reaction and subsequent sequencing of the cDNA was performed on RNA from the patient. The deletion was verified with amplification and sequencing of the relevant exons in DNA from the patient and from close relatives (Table 1) as previously described (3,7). RESULTS The glycerol kinase activity in fibroblasts from the patient was 1% of that of the control (0.01 nkat/g protein vs 0.87 nkat/g protein), and the glycerol oxidation rate was 5% (0.1 pmol/hour vs 2.02 pmol/hour). The analysis by reverse transcription polymerase chain reaction showed that exon 8 was spliced directly to exon 11 in the mRNA (Fig. 1). Genomic amplification of exon 8 to 10 resulted in fragments with the expected length. Sequencing identified a deletion of 4 nucleotides, tagG, in the splice-site junction of exon 10 (Fig. 1).FIG. 1: Sequence showing that exon 8 was spliced directly to exon 11 in mRNA from the glycerol kinase gene.The mother and 2 of the patient's 3 sisters were shown to be carriers of the tagG deletion (Table 1). The biochemical findings showed that the concentration of glycerol in the urine was 2 times higher than the reference level in 2 of 3 carriers. In a similar manner, the serum glycerol was slightly elevated in 2 carriers but not the third carrier, compared with the healthy noncarrier individuals. The glycerol levels in the patient were considerably higher than in the carriers. Different methods to determine the triglyceride concentration were used. As seen in Table 1, a glycerol-blanked method resulted in a normal triglyceride concentration (1.45 mmol/L) in serum from the patient, and the routine unblanked method gave a false high value (7.5 mmol/L). DISCUSSION It is well established that children with GKD may present with serious episodes of hypoglycemia, metabolic acidosis, and seizures elicited by bacterial or viral infections (1). Glycerol from triglycerides is an important gluconeogenic substrate in catabolic situations (8). During even mild infections, the young patient with GKD often requires additional glucose because the liver glucose production is in the same range as the brain glucose consumption (2), whereas in the adult patient the liver glucose production is about twice as large as the brain glucose consumption. Hence, the need for extra glucose in catabolic situations is less critical in adults. In this patient, the episode at 5 years of age when gastroenteritis resulted in dehydration and pronounced metabolic acidosis is typical for children with GKD (9). The second episode of hospitalization may also have been caused by catabolism precipitated by the infection in combination with GKD and was clinically reversed with intravenous fluid. During the described episode with a fulminant EBV infection, the inability to use glycerol for gluconeogenesis may have contributed to the severity of the clinical course (eg, the encephalopathy). It should be noted that even high concentrations of glycerol are nontoxic. Diagnostic guidelines have been formulated (4) for virus-associated HLH, which is often triggered by an EBV infection (10). The proposed diagnostic criteria are elevated temperature, hepatosplenomegaly, leukopenia, thrombocytopenia, anemia, hypofibrinogenemia, and hypertriglyceridemia. Hemophagocytic cells detected in 1 or more affected organs (ie, often bone marrow) confirms the diagnosis. Early in the disease, documenting hemophagocytosis on the first bone marrow specimen may be difficult. However, inability to demonstrate hemophagocytosis on the initial specimen should not preclude the prompt institution of treatment, provided other clinical criteria are fulfilled, as in this case (11). The degree of liver disease may vary considerably, and the development of acute liver failure has been described (12). Increased concentration of triglycerides was reported to occur in 87% to 100% of cases of HLH, and high concentrations of ferritin have also been reported (5). The reported high concentration of triglycerides in this patient was presumably, at least in part, a laboratory error resulting from a high concentration of free glycerol. This presumed “high concentration of triglycerides” in combination with several other findings was considered indicative of HLH, and aggressive treatment was initiated. In addition, elevated triglycerides may result in erroneous diagnosis of the lipid disorder hypertriglyceridemia and unnecessary treatment with statins (1,3). When a high triglyceride concentration is obtained with a method not corrected for free glycerol, the presence of free glycerol should be excluded to avoid the risk of erroneous diagnosis and treatment. The GKD was caused by a 4-nucleotide deletion (tagG) in the border between the intron and exon 10 in the GK gene, not previously described. This resulted in the splicing of exon 8 to exon 11. The mother and 2 of the 3 sisters were carriers of the mutation. Only the mother and 1 of the sisters had glycerol concentrations in serum and urine slightly above the reference level, confirming previous observations that glycerol levels cannot be relied upon for identification of carriers. Mutation analysis is required to establish carrier status and to determine the risk for a future child having the disease. Liver failure develops only in an extremely small portion of children with EBV infection (13,14). In retrospect, we can only speculate about the extent to which his GKD contributed to the dramatic clinical course of the EBV infection and whether knowledge of his GKD would have led to a different handling of the clinical problems. Our case indicated that GKD had a synergistic effect with the EBV infection in triggering the liver failure in our patient. The initially repeatedly low serum albumin levels could have indicated a preexisting chronic liver disease. If so, then the GKD in combination with the EBV infection could have precipitated an acute-on-chronic liver failure. However, the long-term follow-up of the boy indicates that this is not the case, inasmuch as the liver function normalized. We conclude that knowledge of the diagnosis of GKD, as of any underlying metabolic disorder, is important to prevent misinterpretation of dramatic episodes, as in the present case. It is suggested at least that boys presenting in a similar way as this patient should be examined for urinary glycerol before specific treatment for HLH is started." @default.
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• W2059172581 title "Acute Liver Failure in a Child With Epstein-Barr Virus Infection and Undiagnosed Glycerol Kinase Deficiency, Mimicking Hemophagocytic Lymphohistiocytosis" @default.
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