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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.

In recent years, an increasing number of national guidelines on the treatment of phenylketonuria (PKU) have emerged. Most of these guidelines are dedicated to the care of children, while less attention is paid to the care of adults, although all guidelines underline the importance of diet for life. This review aims to summarize issues that need to be addressed within a guideline on the treatment of PKU, especially when care for patients beyond childhood is concerned. In this respect, it is of importance that adult patients, both willing and unwilling to be treated, need a guideline for care and follow-up. In PKU there is certainly a need for an improved unified guideline, especially after childhood, although many of the considerations in this article also apply to recommendations for treatment of children. Such a guideline will be a tool to improve treatment in PKU patients but should also include recommendations for collecting data for clinical and research purposes. Guideline development should also focus on nutritional, neuropsychological and psychosocial issues and not only on target plasma phenylalanine concentrations. In addition, guidelines must address not only what has to be done but also how it can be done, thereby improving concordance with the recommendations for treatment and management.

Contains fulltext : 69088.pdf (Publisher’s version ) (Closed access) Brain magnetic resonance spectroscopy in two patients with Leigh syndrome revealed the presence of lactate in gray and white matter brain tissue and relatively high choline levels in the white matter. The latter observation, most probably related to an ongoing demyelination process, underlines specific involvement of white matter metabolism in Leigh syndrome even in cases without involvement of the white matter as visualized on MRI. Magnetic resonance spectroscopy might thus be of help in differentiating Leigh syndrome from a range of other mitochondrial diseases, such as ophthalmoplegia and Kearns-Sayre syndrome, showing lack of lactate in brain tissues appearing normal on MRI.

Histopathological findings of muscle biopsies from five patients with two different muscular glycogen storage diseases (mGSD) were presented. From these investigations it emerged that the yield of histopathology in mGSD is low. In only one of five patients histopathological findings gave a clue towards diagnosis. It can be concluded that non-specific findings or even normal appearance of a muscle biopsy does not exclude mGSD. (c) 2007 Elsevier Inc. All rights reserved.

MR spectroscopy in two patients with glutaric aciduria type I revealed reductions in the white matter N-acetylaspartate signal, in the more severe case accompanied by a loss of glutamate and the appearance of lactate signals. (c) 2006 Elsevier Inc. 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.

The prerequisite for liver transplantation as a therapeutic option for inherited metabolic diseases should be that the enzyme defect, being responsible for the major clinical (hepatic and/or extra-hepatic) abnormalities, is localised in the liver. Furthermore, no adequate dietary or pharmacological treatment should be available or such treatment should have an unacceptable influence on the quality of life. We report an infant, who developed end-stage liver disease with persistent lactic acidaemia in his first months of life. Analysis of the mitochondrial respiratory chain in liver tissue revealed a combined partial complex I and IV deficiency. No extra-hepatic involvement could be demonstrated by careful screening for multiple organ involvement, including analysis of the mitochondrial respiratory chain in muscle tissue and cultured skin fibroblasts. The boy received a reduced size liver graft at the age of 8 months. He recovered successfully. Almost 5 years after transplantation he is in good clinical condition. No clinical or biochemical signs of any organ dysfunction have been demonstrated. The considerations on which basis it was decided that there was no contra-indication to perform liver transplantation in this patient are discussed.The possibility of a mitochondrial respiratory chain deficiency should be considered in liver disease of unknown origin prior to liver transplantation. Liver transplantation is a therapeutic option in mitochondrial respiratory chain deficiency-based end-stage liver disease provided that extra-hepatic involvement is carefully excluded.

WB Geven,a KE Niezen-Koning,b A Timmer,c AJ van Loon,d RJA Wanders,e FJ van Spronsenf a Department of Pediatrics, Martini Hospital, Groningen, the Netherlands b Laboratory for Metabolic Diseases and cDepartment of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands, d Department of Obstetrics, Martini Hospital, Groningen, the Netherlands e Department of Clinical Chemistry and Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands f Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands Correspondence: Dr WB Geven, Department of Pediatrics, Martini Hospital, PO Box 30033,9700 RM Groningen, the Netherlands. Email w.b.geven@MZH.nl

Partial hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency, also known as the Kelley-Seegmiller syndrome, can give rise to a wide range of neurological symptoms, and renal insufficiency. Biochemically, it is characterized by high uric acid concentrations in blood, high uric acid and hypoxanthine excretion in urine, and decreased activity of hypoxanthine-guanine phosphoribosyl transferase activity (HGPRT). However, normal uric acid concentrations in blood and uric acid excretions in urine have been reported. Here, a boy is presented with normal development and suffering from recurrent attacks of acute renal failure with slightly to clearly increased urinary uric acid excretion. Between these attacks, episodes of elevated urinary excretion of uric acid were observed with normal blood concentrations of uric acid and normal urinary excretion of hypoxanthine. HGPRT activity in erythrocytes, leukocytes, and fibroblasts was found to be strongly decreased. This case shows that not only normal blood uric acid but also normal urinary hypoxanthine concentrations do not exclude the diagnosis of partial HGPRT deficiency. (c) 2006 Elsevier Inc. 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.

Dysmorphic features, multisystem disease, and central nervous system involvement are common symptoms in congenital disorders of glycosylation, including several recently discovered Golgi-related glycosylation defects. In search for discriminative features, we assessed eleven children suspected with a Golgi-related inborn error of glycosylation. We evaluated all genetically unsolved patients, diagnosed with a type 2 transferrin isofocusing pattern in the period of 1999-2009. By combining biochemical results with characteristic clinical symptoms, we used a diagnostic flow chart to approach the underlying defect in patients with congenital disorders of glycosylation-IIx. According to specific symptoms and laboratory results, we initiated additional, targeted biochemical and genetic studies. We found a distinctive spectrum of congenital disorders of glycosylation type 2-associated anomalies including sudden hearing loss, brain malformations, wrinkled skin, and epilepsy in combination with skeletal dysplasia, dilated cardiomyopathy, sudden cardiac arrest, abnormal copper and iron metabolism, and endocrine abnormalities in our patients. One patient with severe cortical malformations and mild skin abnormalities was diagnosed with a known genetic syndrome, due to an ATP6V0A2 defect Here, we present unique congenital disorders of glycosylation type 2-associated anomalies, including both ATPase-related and unrelated cutis laxa and sensorineural hearing loss, a recently recognized symptom of congenital disorders of glycosylation. Based on our findings, we recommend clinicians to consider congenital disorders of glycosylation in patients with cardiac rhythm disorders, spondylodysplasia and biochemical abnormalities of the copper and iron metabolism even in absence of intellectual disability. (C) 2011 Elsevier B.V. All rights reserved.

In untreated phenylketonuria (PKU), deficiency of phenylalanine hydroxylase (PAH) results in elevated blood phenylalanine (Phe) concentrations and severe mental retardation. Current dietary treatment prevents mental retardation, but cognitive outcome remains suboptimal. The mechanisms by which elevated blood Phe concentrations disturb cerebral metabolism and cognitive function have not been fully elucidated. In this review, we discuss different hypotheses on the pathogenesis of PKU, focusing on the effects of disturbed large neutral amino acid (LNAA) transport from blood to brain on cerebral neurotransmitter and protein synthesis. Although the definitive roles of these processes in PKU pathogenesis are not fully understood yet, both substantially influence clinical outcome. (C) 2009 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 …