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Common inborn errors of metabolism treated by low natural protein diets [amino acid (AA) disorders, organic acidemias and urea cycle disorders] are responsible for a collection of diverse clinical symptoms, each condition presenting at different ages with variable severity. Precursor-free or essential l-AAs are important in all these conditions. Optimal long-term outcome depends on early diagnosis and good metabolic control, but because of the rarity and severity of conditions, randomized controlled trials are scarce. In all of these disorders, it is commonly described that dietary adherence deteriorates from the age of 10 years onwards, at least in part representing the transition of responsibility from the principal caregivers to the patients. However, patients may have particular difficulties in managing the complexity of their treatment because of the impact of the condition on their neuropsychological profile. There are little data about their ability to self-manage their own diet or the success of any formal educational programs that may have been implemented. Trials conducted in non-phenylketonuria (PKU) patients are rare, and the development of specialist l-AAs for non-PKU AA disorders has usually shadowed that of PKU. There remains much work to be done in refining dietary treatments for all conditions and gaining acceptable dietary adherence and concordance, which is crucial for an optimal outcome.

Diffusion tensor imaging (DTI) is reported for the first time in a patient with Sjogren-Larsson syndrome, an autosomal recessive neurocutaneous disorder. Magnetic resonance spectroscopy (MRS) revealed normal levels of choline, creatine and N-acetyl aspartate (NAA) and the characteristic lipid signals in the white matter brain tissue. Conventional MRI showed increased signal intensity around the lateral ventricles indicating abnormal myelination. DTI revealed normal apparent diffusion coefficient (ADC) values, but reduced fractional anisotropy (FA) in the white matter. After co-registration of the parameters obtained with DTI with the results of MRS (36 voxels), significant correlations were obtained of lipid content with FA (r = 0.81), ADC (r = -0.62), choline (r = 0.51), and NAA (r = 0.44) (P

Background: Predicting later outcome in neonates presenting with severe inborn errors of metabolism (IEM) is difficult. The assessment of the early motor repertoire is a reliable method of evaluating the integrity of the central nervous system in young infants. This method is based on an age-specific qualitative assessment of general movements (GMs, 0-8 weeks of age), fidgety movements (FMs) and the concurrent motor repertoire (9-20 weeks of age).Aim: To determine the quality of the early motor repertoire (at 0-20 weeks post term age) in relation to later neurological outcome in infants with severe IEM.Study design: Prospective cohort study. The quality of the motor repertoire was assessed from serial videotape recordings.Subjects: Five infants with IEM. Four presented with a severe IEM in the neonatal period: an undefined gluconeogenesis defect, propionic acidemia, arginosuccinate synthetase and arginosuccinate lyase deficiency. One neonate was antenatally diagnosed with arginosuccinate synthetase deficiency.Outcome measures: Outcome at the age of at least 18 m was determined by neurological examination and developmental tests.Results: All infants initially had abnormal GMs: hypokinesia, followed by GMs of a poor repertoire. The quality of the early motor repertoire normalised in 3 infants, and remained abnormal in 2. The more severe and persistent abnormalities of the motor repertoire were considered with the more abnormal neurological and developmental scores, later on.Conclusions: The quality of the early motor repertoire might be related to later neurological outcome in infants with inborn errors of metabolism. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

Objective: Fetal thrombotic vasculopathy (FTV) has been related to pregnancy complications and neonatal thrombosis separately. We assessed whether a relationship existed in our population of women with neonates who were admitted to our Neonatal Intensive Care Unit (NICU). In addition, the presence of thrombophilic factors in children and parents was investigated.Methods: Two groups were detected by a search of the departmental databases. Group A was a cohort of 5000 neonates admitted to our NICU (1992-2002). Infants who developed thrombotic complications were selected. Group B was a cohort of placentae from our institution (2000, n=141). Those with a diagnosis of FTV were selected. Case-notes and laboratory results were obtained through the hospital information system.Results: Of Group A, thrombosis was reported in 55 children. Of these, 20 matching placentae were available. Eight placentae showed FTV (40 per cent). Of the eight corresponding pregnancies, seven were complicated by pre-eclampsia and/or intra uterine growth restriction (IUGR). Of the 12 placentae without FTV, five of the pregnancies had pre-eclampsia and/or IUGR (odds ratio for relation FTV-Complications: 9.8, 95 per cent CI=0.9-107). In Group B, nine placentae showed FTV (6.4 per cent). Of these nine, six of the pregnancies were complicated by pre-eclampsia and/or IUGR. None of the neonates developed thrombosis.Conclusion: Pre-eclampsia and/or IUGR as well as neonatal thrombosis are both associated with fetal thrombotic vasculopathy in the placenta. However, in our selected-tertiary centre-population, FTV did not predict neonatal thrombosis. The thrombophilic investigations of parents and children were incomplete. A standard approach for evaluating parents at risk for FTV and evaluating neonates at risk for thrombosis should be developed. (C) 2004 IFPA and Elsevier Ltd. All rights reserved.

MR spectroscopy in a patient with argininosuccinate lyase deficiency revealed elevated cerebral guanidinoacetate signals, indicating that the phenomenon of increased levels of this compound in brain tissue is not limited to creatine deficiencies. (c) 2005 Elsevier Inc. All rights reserved.

A total of 33 patients with early and continuously-treated phenylketonuria (PKU) between 7 and 16 years of age and 33 matched controls participated in a study examining perceptual, central, and response-related mechanisms of information processing. The specific mechanisms studied were: perceptual filtering, memory search, response selection, response execution, and motor presetting. In addition, groups were compared on mean intelligence level and task oriented behaviour. The performance of the PKU patients practically matched that of the controls on all three tasks, suggesting that PKU patients who are continuously maintained on a well-controlled phenylalanine-restricted diet are not impaired in the elementary mechanisms of information processing. Furthermore, groups did not differ in mean IQ or task-oriented behaviour.Conclusion These results under-line the importance of continued, well- controlled dietary treatment. Further studies are recommended to obtain a more complete evaluation the potential of PKU patients under these stricter dietary treatment conditions.

The rapid development of new modes of treatment including organ transplantation, enzyme inhibition, enzyme replacement, liver cell transplantation and gene therapy necessitates knowledge about the results of all modes of treatment to allow decisions on treatment strategies. In hereditary tyrosinaemia type I, apart from the dietary treatment, both orthotopic liver transplantation (OLT) and treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) have become available (Lindstedt et al 1992). However, this disease seems clinically very heterogeneous. Therefore, we should first attempt to categorize different clinical forms since treatment strategies may be quite different. Based on clinical heterogeneity, Halvorsen (1990) divided patients with tyrosinaemia into three forms - acute, subacute and chronic - but could not report the exact outcome on dietary treatment with possible consequences for treatment strategies. We have therefore investigated the clinical course on dietary treatment of our own patients and conducted an international survey on the clinical course of patients managed by dietary treatment and/or OLT, of which the results in part are described elsewhere (van Spronsen et al 1994). The results may enable us to compare the outcome on NTBC and to decide on treatment strategy in tyrosinaemia type I patients.

The aim of this paper is to provide a concise summary of findings from outcome studies in early-treated phenylketonuria (PKU). The paper should not be considered as an extensive review of the many different outcome measures that have been used in PKU-research, but as an attempt to integrate such findings so that they will be of additional value for day to day monitoring of PKU-patients and may direct future research to fill the present gaps of knowledge. Neurological, neuropsychological, neurophysiological, neuroimaging, quality of life, and psychosocial findings will be discussed in the context of their potential contributions to lifelong follow-up and treatment of PKU-patients being summarized in statements. (C) 2011 Elsevier Inc. All rights reserved.

Hereditary tyrosinaemia type I is an autosomal recessive inborn error of tyrosine catabolism caused by a deficiency of the enzyme fumarylacetoacetase that results in liver failure, hepatocellular carcinoma, renal tubular dysfunction and acute intermittent porphyria. When treated with liver transplantation, tyrosinaemia type I was considered to be cured. Some years after the first liver transplantations in these patients, some reports focused on the renal function after transplantation. These reports showed that urinary succinylacetone excretion remained but that tubular function normalized. In this report we discuss the long-term renal follow-up (mean follow-up time 11 years, range 7-14 years) after liver transplantation in 9 patients with tyrosinaemia type I treated by liver transplantation in our centre. An evaluation was made of renal function and succinylacetone excretion in urine. In all patients we found a persistent excretion of succinylacetone in the urine. With respect to the glomerular function, we can conclude that there is no clear change in GFR. At the same time, tubulopathy persisted in some patients. We consider that excretion of metabolites such as succinylacetone will be an important contributing factor to tubular dysfunction after liver transplantation in patients with tyrosinaemia type I. Therefore, notwithstanding the major effect of liver transplantation on tyrosine metabolism, renal tubular dysfunction remains at risk and needs careful monitoring. Progressive tubular dysfunction can cause glomerular damage. The use of low-dose NTBC might be considered after liver transplantation in case of tubulopathy to prevent progression of tubular and glomerular dysfunction.

Mitochondrial respiratory chain disease may lead to neonatal or late onset liver failure, requiring liver transplantation. In rare cases, the disease is restricted to the liver and the patient is cured after surgery. More frequently, other organs are simultaneously involved and neuromuscular or other extra-hepatic symptoms may pre-exist, or appear in the post-transplant follow up. Pre-transplant evaluation should aim to rule out neurological disease, which may be difficult to differentiate from signs accompanying liver insufficiency. Cerebrospinal fluid lactic acid levels, compared to blood lactate, may be suggestive of central nervous system involvement. Of 11 cases with respiratory chain disorders who had liver transplantation in various centres, 4 are alive and well on follow up, and 6 died, three of them having developed neurological disease post orthotopic liver transplantation. All three patients with initial liver and gastro-intestinal disease died early after transplantation, indicating that these may be poor candidates for this procedure. Conclusion Liver transplantation is feasible in hepatic respiratory chain disorders, but extra-hepatic disease should be ruled out before transplantation. Extra-hepatic manifestations may, however, appear and cause patient death despite successful transplantation.

In phenylketonuria (PKU), the enzyme phenylalanine hydroxylase is deficient, resulting in a decreased conversion of phenylalanine (Phe) into tyrosine (Tyr). The severity of the disease is expressed as the tolerance for Phe at 5 yr of age. In PKU patients it is assumed that the decreased conversion of Phe into Tyr is directly correlated with the tolerance for Phe. We investigated this correlation by an in vivo stable isotope study. The in vivo residual hydroxylation was quantitated using a primed continuous infusion of L-[ring-H-2(5)]Phe and L-[1-C-13]Tyr and the determination of the isotopic enrichments of L-[ring-H-2(5)]Phe, L-[ring-H-2(4)]Tyr, and L-[1-C-13]Tyr in plasma. Previous reports by Thompson and coworkers (Thompson, G.N., and D. Halliday. 1990. J. Clin. Invest. 86:317-322; Thompson, G.N., J.H. Waiter, J.V. Leonard, and D. Halliday. 1990, Metabolism. 39:799-807; Treacy, E., J.J. Pitt, K. Seller, G.N. Thompson, S. Ramus, and R.G.H. Cotton. 1996. J. Inherited Metab. Dis. 19:595-602), applying the same technique, showed normal in vivo hydroxylation rates of Phe in almost all PKU patients. Therefore, our study was divided up in two parts, First, the method was re-evaluated. Second, the correlation between the in vivo hydroxylation of Phe and the tolerance for Phe was tested in seven classical PKU patients. Very low (0.13-0.95 mu mol/kg per hour) and normal (4.11 and 6.33 mu mol/kg per hour) conversion rates were found in patients and controls, respectively. Performing the infusion study twice in the same patient and wash-out studies of the labels at the end of the experiment in a patient and control showed that the method is applicable in PKU patients and gives consistent data. No significant correlation was observed between the in vivo hydroxylation rates and the tolerances. The results of this study, therefore, showed that within the group of patients with classical PKU, the tolerance does not depend on the in vivo hydroxylation.

Dietary adherence in phenylketonuria (PKU)—measured by plasma phenylalanine (Phe) concentrations—is a major issue.1,2 In the so-called professionally steered situation, it was our practice to take all blood samples for measurement of Phe during patients’ hospital visits. Phe concentrations were interpreted by the paediatrician, and the dietician phoned patients/parents with dietary advice. Self-management has been suggested to improve dietary adherence.1 We report Phe concentrations during our first six months experiences with self-management in 48 PKU patients above 1 year of age. During this period, patients decided frequency of blood sampling and sent samples (filter paper) to the laboratory by post. A nurse without knowledge of PKU phoned the results to patients/parents without interpretation/advice. Patients/parents decided independently regarding …