BackgroundHepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.MethodsVia questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 μM) and NTBC-levels in the therapeutic range (20–40 μM). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).ConclusionBased on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

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The French-Canadian variant of COX-deficient Leigh syndrome (LSFC) is unique to Québec and caused by a founder mutation in the LRPPRC gene. Using whole exome sequencing, Oláhová et al. identify mutations in this gene associated with multisystem mitochondrial disease and early-onset neurodevelopmental problems in ten patients from different ethnic backgrounds.

In persistent hyperinsulinemic hypoglycemia of infancy, ketone body concentrations are abnormally low at times of hypoglycemia, depriving the brain of its most important alternative fuel. The neuroprotective effect of endogenous ketone bodies is evidenced by animal and human studies, but knowledge about exogenous supply is limited. Assuming that exogenous ketone body compounds as a dietetic food might replace this alternative energy source for the brain, we have monitored the fate of orally supplemented DL sodium ␤-hydroxybutyrate (␤-OHB) in two 6-mo-old infants with persistent hyperinsulinemic hypoglycemia for 5 and 7 mo, while on frequent tube-feedings and treatment with octreotide. Near total (95%) pancreatectomy had been ineffective in one patient and was refused in the other. In blood, concentrations of ␤-OHB increased to levels comparable to a 16-to 24-h fast while on DL sodium ␤-OHB 880 to 1000 mg/kg per day. In cerebrospinal fluid, concentrations of ␤-OHB increased to levels comparable to a 24-to 40-h fast, after single dosages of 4 and 8 g, respectively. High ratios of ␤-OHB to acetoacetate indicated exogenous origin of ␤-OHB. An increase of intracerebral concentrations of ␤-OHB could be demonstrated by repetitive single-voxel proton magnetic resonance spectroscopy by a clear doublet at 1.25 ppm. Oral DL sodium ␤-OHB was tolerated without side effects. This first report on oral supplementation of DL sodium ␤-OHB in two patients with persistent hyperinsulinemic hypoglycemia demonstrates effective uptake across the blood-brain barrier and could provide the basis for further evaluation of the neuroprotective effect of ␤-OHB in conditions with hypoketotic hypoglycemia. PHHI is the most common cause of recurrent hypoglycemia in infancy (1). PHHI is characterized by inappropriately high blood insulin levels in the presence of symptomatic hypoglycemia (2) and by a prompt responsiveness to glucagon (3).Pathogenetically, PHHI may result from different molecular defects in the regulation of ␤-cell-mediated insulin release with diffuse or focal ␤-cell hyperplasia (4, 5).Treatment with diazoxide, a potassium-channel opener at the pancreatic ␤-cell and inhibitor of insulin secretion, and octreotide, a long-acting somatostatin analog, is often hampered by poor effect or severe side effects (3, 6 -9), and pancreatectomy, at least in cases with diffuse hyperplasia, bears the risk of postoperative diabetes (10).In most hypoglycemic states, ketone bodies (␤-OHB and AA) are released from counterregulatory lipolysis, serving as an alternative, neuroprotective, energetic fuel for the brain (3,

The bacterially expressed enzymes proved that the mutations found in patients and studied here indeed are detrimental. However, as in the case of red cell ASL activity assays, some mutations found in genetically homozygous patients with mild presentations resulted in virtual loss of enzyme activity in the bacterial system, suggesting a more protective environment for the mutant enzyme in the liver than in the heterologous expression system and/or in the highly dilute assays utilized here.