Andrea Bartuli

I148M patatin‐like phospholipase domain‐containing 3 gene variant and severity of pediatric nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in children. Genetic variability, which is a main player in NAFLD, is especially characterized by polymorphisms in genes involved in the development and progression of the disease to nonalcoholic steatohepatitis (NASH). Recently, the rs738409 C>G adiponutrin/patatin‐like phospholipase domain‐containing 3 (PNPLA3) polymorphism, which encodes the I148M protein variant in the catalytic domain, has been associated with severe steatosis, NASH, and liver fibrosis in adults. In this study, we investigated the association between the rs738409 PNPLA3 gene polymorphism and NAFLD in 149 consecutive children and adolescents (age = 6‐13 years) with biopsy‐proven NAFLD. We analyzed the rs738409 polymorphism by a 5′‐nuclease TaqMan assay and assessed its association with NASH: 41% of the subjects with NAFLD showed heterozygosity and 15% showed homozygosity for the at‐risk G allele. The rs738409 genotype did not influence the body mass, adiposity, lipid levels, or insulin resistance and was not associated with alanine aminotransferase levels. Interestingly, the rs738409 G allele was strongly associated with the severity of steatosis (P < 0.0001), the presence of NASH (P < 0.0001), hepatocellular ballooning (P < 0.0001), lobular inflammation (P < 0.0001), and the presence of fibrosis (P = 0.01) independently of confounders. Individuals carrying two minor G alleles almost always had severe steatosis and NASH, heterozygotes were at intermediate risk, and patients negative for G alleles had milder and often uncomplicated steatosis. Conclusion: The PNPLA3 rs738409 polymorphism is associated with steatosis severity, hepatocellular ballooning, lobular inflammation, and perivenular fibrosis in pediatric NAFLD. (HEPATOLOGY 2010)

Extracorporeal dialysis in neonatal hyperammonemia: modalities and prognostic indicators.

Abstract. We investigated the prognostic indicators in ten hyperammonemic neonates: four treated by continuous arteriovenous hemodialysis (CAVHD), four with continuous venovenous hemodialysis (CVVHD), and two with hemodialysis (HD). Plasma ammonium levels decreased significantly within the first 24 h irrespective of dialysis modality (from 1419 to 114 µmol/l, median values; P<0.0001). CVVHD achieved the highest ammonium clearance. HD provided highest ammonium extraction but clearance was hampered by severe hemodynamic instability. Five patients had a good outcome (normal at follow-up of 9–59 months), five had poor outcome (four died and one has severe neurological damage). Total coma duration was shorter in patients who had a good outcome (47±11 vs 78±13 h; P=0.02). Remarkably, only coma duration before dialysis determined this difference (22.2±10.1 vs 48.8±11.2 h; P=0.02). In cases with good outcome, coma duration was <33 h, whereas the others exceeded this limit. The prognosis was not related to dialysis modality, rapidity in reducing ammonium levels or to the underlying metabolic defect. In conclusion, results showed CVVHD to be the optimal modality for extracorporeal ammonium detoxification. However, the most relevant indicator for prognosis was coma duration before the start of dialysis. Therefore, major efforts should be made to refer patients quickly to highly specialized centers.

Fatal infantile liver failure associated with mitochondrial DNA depletion

A 3-month-old girl was admitted to the hospital because of hypotonia and frequent vomiting. She had severe metabolic acidosis and her liver function was abnormal. Hepatomegaly and rapidly progressive liver failure developed, and she died at 4 months of age. Two half-siblings from a different mother had died in infancy of an undiagnosed myopathy. The liver was fatty and hepatocytes were filled with large and small lipid droplets. Other tissues were morphologically normal. The respiratory chain enzymes containing subunits encoded by mitochondrial DNA were markedly decreased in liver, partially decreased in muscle, but normal in other tissues. Southern blot analysis showed 90% depletion of mitochondrial DNA in liver, 53% depletion in muscle, and normal amounts in other tissues. This is the second case of fatal infantile liver failure associated with mitochondrial DNA depletion. This pathogenetic mechanism should be considered in infants with multiple respiratory chain defects and variable tissue expression.

Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency

An 11-month-old girl presented acute episodes of hypoglycaemia and hepatic encephalopathy reminiscent of Reye syndrome and 3-hydroxydicarboxylic aciduria. The patient showed peculiar clinical manifestations of severe sensory-motor neuropathy, pigmentary retinopathy, and cardiomyopathy. She died of cardiac failure. Pathological studies of peripheral nerve showed signs of axonal neuropathy and demyelination. Enzymatic studies in cultured fibroblasts showed a deficiency of mitochondrial long-chain 3-hydroxyacyl-CoA-dehydrogenase. Peripheral nerve involvement and retinal pigmentary degeneration have as yet not been described in patients with proven defects of mitochondrial β-oxidation.

Severity of Liver Injury and Atherogenic Lipid Profile in Children With Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. The aim of this study was to assess the relationship between severity of liver injury and atherogenic lipid profile in a large group of children with NAFLD. A total of 118 consecutive children with biopsy-proven NAFLD were included. Patients underwent extensive metabolic profiling. The NAFLD activity and fibrosis scores showed a significant positive correlation with triglyceride/HDL, total cholesterol/HDL, and LDL/HDL ratios (p <0.05) but not with apolipoprotein B/apolipoprotein A-1 ratio (p = 0.58). After adjusting for BMI, homeostatic model assessment, impaired glucose tolerance, and presence of metabolic syndrome, both the NAFLD activity score and stage of fibrosis remained independent predictors of proatherogenic lipid profile. All lipid ratios, except for apolipoprotein B/apolipoprotein A-1, were found to be markedly higher in children with nonalcoholic steatohepatitis compared with those with simple steatosis or borderline disease (p <0.05). This study shows for the first time that in children with NAFLD, the severity of liver injury is strongly associated with the presence of a more atherogenic lipid profile, having potential significant diagnostic and therapeutic implications.

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

Beckwith–Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype–phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n=190), IC1 gain of methylation (IC1-GoM, n=31), chromosome 11p15 paternal uniparental disomy (UPD, n=87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n=10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (P<0.001). Exomphalos was more common in IC2/CDKN1C patients (P<0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (P<0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (P<0.001). Macroglossia was less common among UPD patients (P<0.001). Wilms’ tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (P<0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P=0.009). In conclusion, (epi)genotype–phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.

Preemptive liver transplantation in a child with familial hypercholesterolemia

Maiorana A, Nobili V, Calandra S, Francalanci P, Bernabei S, El Hachem M, Monti L, Gennari F, Torre G, de Ville de Goyet J, Bartuli A. Preemptive liver transplantation in a child with familial hypercholesterolemia.
Pediatr Transplantation 2011: 15:E25–E29.

Homozygous familial hypercholesterolaemia

A 5-year-old boy aff ected with homozygous familial hypercholesterolaemia, diagnosed aged 1 year, was referred to us after having an acute ischaemic cardiac event. He presented with an LDL-cholesterol concentration of 26 mmol/L, and tendon xanthomas at the wrists, knees, and achilles (fi gure A–C). He had been treated with colestyramine. Coronary angio graphy showed a complete obstruction of the left coronary artery (fi gure D; see also webvideo) and a partial obstruction of the right coronary artery, which required stent placement. After the

Medical Management and Dialysis Therapy for the Infant With an Inborn Error of Metabolism

Optimal care of the neonate with hyperammonemia requires expertise in the evaluation, medical management, and decision to initiate dialytic therapy, and therefore compels expeditious collaboration between neonatal intensive care physicians, medical geneticists, and pediatric nephrologists. Neonatal and dialysis nursing expertise also is paramount for the successful provision of dialysis therapy in this setting. The current article addresses the underlying causes, medical management strategies, and dialytic therapy considerations in caring for the neonate with hyperammonemia.

Inborn errors of metabolism: An update on epidemiology and on neonatal-onset hyperammonemia

Inborn errors of metabolism (IEM) are a highly heterogeneous group of genetic conditions and represent a relevant cause of morbidity and mortality in the pediatric population. IEM, which are individually rare but collectively numerous, are well‐recognized entities of the generic class of “rare” diseases. Since the first descriptions by Garrod at the beginning of the 20th century, several hundred new disorders have been defined, as new biochemical and molecular diagnostic tools became available. The clinical pictures of single diseases are extremely diverse, ranging from acute life‐threatening manifestations to chronic late‐onset forms, with single or multiorgan involvement. Mental retardation and progressive neurological impairment often characterize the clinical course. One of the principles to prevent high morbidity and mortality rates is early recognition followed by prompt therapeutic intervention. Therefore, a small number of treatable IEM is subject to neonatal mass screening. More recently, an innovative technique, based on tandem mass spectrometry, has expanded the range of neonatal screening to several additional disorders. Owing to the extreme heterogeneity, as well as to the increasing number of new disorders, exhaustive and updated epidemiological data on the overall occurrence of IEM are lacking. A national retrospective study was conducted to define the epidemiological profile of IEM in Italy and to estimate the costs related to the disease burden. Other relevant issues of our investigations focused on creating protocols of treatment for neonatal IEM, and on the development of new methods for the biochemical diagnosis.