Despite the improvement in dietary therapy during the past 20 years, the overall outcome of severe forms of propionic acidaemia (PA) remains often disappointing. Good results can be obtained at a very high price in terms of medical attention, family burden and high cost. In most early onset forms of PA, the intake of natural protein must be rigidly restricted to 8-12 g/day for the first 3 years of life, and then slowly increased to 15-20 g/day by the age of 6-8 years. Supplementation with a precursor-free aminoacid mixture to provide 1.5 g/kg protein per day is generally recommended, although remains controversial. From the age of 1 year onward, these children are often severely anorectic and most of the diet must be delivered by nocturnal gastric drip feeding or gastrostomy. Metronidazole is very effective in reducing the excretion of propionate metabolites derived from the gut. L-carnitine (50 to 100 mg/kg) is systematically given to promote propionylcarnitine synthesis and excretion. We report here a retrospective study of 33 patients with PA diagnosed during the last 20 years in our hospital. Of them, 2 have been liver transplanted. In these two patients who presented frequent severe and unexpected metabolic decompensations despite good compliance with the dietary therapy, orthotopic liver transplantation (OLT) was done at 7 and 9 years respectively. One child died 15 months after transplantation due to a severe lymphoproliferative disorder; the other child now aged 13.5 years is doing well. Despite a persistent methylcitrate excretion, she is under normal moderate daily protein intake (40-50 g/day) and still on carnitine supplementation. Interestingly, another patient who filled the criteria for OLT (very frequent and severe decompensations leading to frequent admissions to the intensive care unit despite excellent dietary management) was also placed on the list for OLT. From the time he was registered onward, he experienced no further episodes of metabolic decompensation, there was almost no interruption in his daily intake and he gained height and weight and developed well. He was finally removed from the list and is still doing very well 2 years thereafter. Correction of propionylCoA carboxylase deficiency restricted to hepatic tissues seems to induce a change towards clinical normalisation and a milder biochemical phenotype. Liver transplanted PA patients still require slight protein restriction and carnitine treatment. We consider that at the moment OLT should only be performed in severe forms of PA, mostly characterised by frequent and unexpected episodes of metabolic decompensation despite good dietary therapy. However, a strict appreciation of these criteria is difficult. A more generalised indication for OLT in PA will require more information about the long-term outcome of transplanted patients. We should also await other alternatives like auxiliary partial OLT from living donors or transplantation of isolated allogenic hepatocytes, genetically modified or not.

In a retrospective study, urinary malondialdehyde concentration in 45 preterm neonates (25-35 weeks' gestation) during their first month of life was measured by HPLC. Urine was collected on different days of life as a 3-h sample. The frequency of urine collection and measurement varied between one (n = 22) and seven times (n = 8) per child. The study group was divided into three categories according to birth weight: low-birth-weight infants (LBW) (n = 16), very low-birth-weight infants (VLBW) (n = 17) and extremely low-birth-weight infants (ELBW) (n = 12). Urinary malondialdehyde concentration was highest in the ELBW group: 1.15 (0.66, 2.12) mumol/l (median and quartiles) versus 0.58 (0.34, 1.18) mumol/l in the VLBW and 0.60 (0.40, 1.06) mumol/l in the LBW groups (ELBW versus VLBW, p < 0.005; ELBW versus LBW, p < 0.02). In oxygen-treated neonates, significantly higher malondialdehyde values were found compared to those without supplementary oxygen (0.89 (0.48, 1.74) versus 0.58 (0.32, 0.89) mumol/l; p < 0.005). Likewise, a higher malondialdehyde concentration was found in infants requiring mechanical ventilation (intermittent mandatory IMV or high frequency ventilation) compared to those breathing spontaneously (intermittent mandatory ventilation: 0.80 (0.42, 1.66); p > 0.05 and high frequency ventilation: 1.20 (0.83, 2.13); p < 0.001 versus 0.57 (0.33, 0.88) mumol/l). Malondialdehyde concentrations correlated significantly with FiO2 values of the individual patients (r = 0.22; p < 0.02). Comparing urinary malondialdehyde concentrations in infants with and without bronchopulmonary dysplasia, a significantly higher malondialdehyde concentration was found in the former group (0.96 (0.51, 2.07) versus 0.60 (0.32, 0.98) mumol/l; p < 0.005)).(ABSTRACT TRUNCATED AT 250 WORDS)

Orthotopic liver transplantation (OLT) was performed in two patients with propionic acidaemia, a 7-year-old boy and a 9-year-old girl, diagnosed with a severe neonatal form with high risk of metabolic decompensation. In both cases the metabolic liver functions recovered within the 12 postoperative hours; no clinical symptoms of propionic acid toxicity, metabolic acidosis, severe hyperammonaemia, hyperglycinaemia or haematological abnormalities were observed. In both cases insulin-dependent diabetes mellitus occurred early after OLT (persisting in the boy's case). Severe post-transplantation complications were observed (acute rejection and CMV infection in both patients) which did not trigger metabolic decompensation. The boy developed chronic rejection and vanishing bile duct syndrome due to incomplete hepatic arterial thrombosis. He required permanent in-patient care with chronic hyperammonaemia and neurological sequelae involving the basal ganglia and died 15 months after OLT. The girl left hospital after 2 months and is presently leading a normal life with almost no dietary protein restriction (40 g protein per day). Urinary urea excretion and daily protein intake increased after liver transplantation. Propionyl- and tiglylglycine disappeared immediately after OLT. Urinary methylcitrate and 3-hydroxypropionate remained at concentrations corresponding to those before OLT. However, the total of all characteristic metabolites of organic acid analysis was reduced to 50-60% of the values before OLT in both patients. Propionylcarnitine was still detected at significant concentrations. Plasma odd-chain fatty acid concentrations decreased continuously after OLT only in the girl's case. Tissue of both transplanted livers showed increased odd-chain fatty acid concentrations 9 and 15 months after OLT, respectively, in both patients. We consider that at present OLT should only be performed in severe forms of propionic acidaemia.

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