Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A](2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.

A 24-h fasting test was performed in 48 control children, in 9 hypoketotic patients with inherited defects of fatty acid oxidation and in 2 hyperketotic patients with inherited defects of ketolysis. The control group was then divided into three age groups on the basis of different adaptation to fasting. Concentrations of blood glucose, lactate, free fatty acids (FFA), 3-hydroxybutyrate, acetoacetate and carnitine were measured after 15 h, 20 h and 24 h of fasting. Significant negative correlations were found in the control group between plasma total ketone bodies (KB) and plasma glucose (P less than 0.001), plasma carnitine (P less than 0.005) and the amplitude of glycaemic response to glucagon at the end of the fast (P less than 0.01). FFA/KB ratio and the product of final fasting values of glucose and ketones were useful to differentiate between hypoketotic or hyperketotic patients and normal subjects. In children with a suspected or definite hyperketotic or hypoketotic disorder, a fasting test must only be performed in healthy patients, in good nutritional condition with non-diagnostic basal biochemical investigations. Carefully supervised fasting should be continued sufficiently to allow ketogenesis and ketolysis to become activated.

have received fees for teaching activities from the pharmaceutical company that markets the drug for the disease subject of this update.

We report the cases of 5 patients from 2 sibships with the "adult" or chronic form of GM2 gangliosidosis and 2 patients from another sibship with the juvenile form. We demonstrated hexosaminidase A deficiency in all cases but in 1 sibship the enzymatic profile was identical to that in Tay-Sachs disease, whereas in the remaining 2 families it was that of the B1 variant. There was no correlation between the clinical features and the enzymatic profile. Hexosaminidase A deficiency should be considered in unexplained progressive neurologic disorders of childhood and adolescence, including isolated dementia. EMG evidence of anterior horn cell involvement in association with neurologic or cognitive deterioration may be a diagnostic clue in the juvenile forms.

From the description of 2 unrelated patients with succinyl-CoA transferase (3- OAT) deficiency and 1 patient with acetoacetyl-CoA thiolase (AAT) deficiency, we have attempted to draw the clinical and metabolic consequences of such defects. The association of recurrent attacks of severe ketoacidosis with blood glucose levels generally high or normal, low lactacidemia and low ammonemia is the most common presentation of these disorders. In 3-OAT deficiency, a potentially fatal disorder, there is a permanent ketosis with the only excretion of 3-hydroxybutyrate, acetoacetate and 3-hydroxyisovalerate. AAT patients usually excrete, in addition to the usual ketone bodies, 2-methyl-3-hydroxybutyrate and tiglylglycine; 2-methyl-acetoacetate may also be present. Both conditions can be identified by enzymatic analysis in cultured fibroblast. These disorders can mimic diabetic ketoacidosis or salicylism and can easily be missed. The knowledge of these ketolytic defects must severely question the complacent diagnosis of ‘fasting ketoacidosis’ or ‘idiopathic ketotic hypoglycemia’, mainly when severe metabolic acidosis is present.