Diagnosis and management of glutaric aciduria type I – revised recommendations

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline

Hörstörungen bei alpha-Mannosidose im Langzeitverlauf

Hintergrund: Eine frühe Diagnostik und Behandlung der autosomal-rezessiven lysosomalen Speicherkrankheit alpha-Mannosidose (Prävalenz: 1: 1.000.000, Mutationen im Gen MAN2B1 auf Chromosom 19) ist für den chronisch-progredienten Krankheitsverlauf maßgeblich. Eine Enzymersatztherapie (ERT) mit Velmanase alfa ist möglich.Material und Methoden: Im Rahmen einer prospektiven Krankheitsverlaufsstudie wurden 25 Patienten mit alpha-Mannosidose (1-42 Jahre; 9 weiblich - 16 männlich) im Zeitraum von 2007-2009 u.a. audiologisch untersucht und ausgewertet. Nach 10 Jahren konnten nun aus dieser Studie noch 7 Patienten (3 Frauen, 4 Männer im Alter von 24 bis 39 Jahren) nachuntersucht und der Langzeitverlauf der Hörstörung dokumentiert werden. 6 neue Patienten (4-41 Jahre) unter Enzymersatztherapie konnten hinzugewonnen werden.Ergebnisse: 6 der 7 Patienten der 10-Jahres-Follow-Up-Gruppe trugen weiterhin Hörgeräte. Ein Ohr wies eine leichte Verbesserung, 5 Ohren ein stabiles Hörvermögen auf. 8 Ohren waren um 5% bis max. 17% progredient (nach Röser 1973). Bei 10 Ohren könnte - mit einem Hörverlust von über 90 % - eine CI-Versorgung in Frage kommen. Unter den neuen Patienten waren 3 Mädchen unter 6 Jahre, von denen zwei bisher nicht mit Hörgeräten versorgt waren. Eines wies lediglich temporäre Schallleitungsschwerhörigkeiten auf, die nur durch T-Tube-Einlagen behandelt werden mussten. Ein 10-jähriger Junge hatte eine mittel- bis hochgradige und hochgradige Schallempfindungsschwerhörigkeit, die mit Hörgeräten bds. sehr gut versorgt war. Eine 41-Jährige blieb im Verlauf der letzten 4 Jahre unter ERT stabil bei einer hochgradig bis an Taubheit grenzenden Schwerhörigkeit bds., erhielt eine CI-Diagnostik im Alter von 37 Jahren, blieb jedoch Hörgeräte-versorgt. Eine 25-Jährige war bei einer hochgradig bis an Taubheit grenzenden Schwerhörigkeit bds. ausreichend mit Hörgeräten versorgtDiskussion: Aufgrund des komplexen Krankheitsbildes mit mentaler Retardierung, Sehstörungen, Hepato-/Splenomegalie, Hüftdysplasie, Ataxie, Dysarthrie und meist einer Vielzahl operativer Eingriffe, rezid. entzündlichen Erkrankungen wie Otitiden, Zahnabszessen besteht kaum eine Bereitschaft für eine Versorgung mit einem Cochlea-Implantat und der anschließenden Rehabilitation. Dennoch sollte eine adäquate Hörgeräteversorgung sichergestellt werden. Bei noch jungen Patienten mit progredientem Verlauf der Hörstörung, aber nur leichter neurologischer Symptomatik unter ERT, sollte eine CI-Versorgung bei unzureichendem Gewinn mit einem Hörgerät angestrebt werden

Retinale Neurodegeneration bei Phenylketonurie

Proceedings of the 2007 Winter Simulation Conference S. G. Henderson, B. Biller, M.-H. Hsieh, J. Shortle, J. D. Tew, and R. R. Barton, eds.This work presents a framework and a Graphical User Interface, Viskit, for the creation and analysis of component- based Discrete Event Simulation models. Two primary elements of the tool are discussed. In component design mode, a new component is created by drawing the Event Graph and filling in parameters, so that the simulation modeler need not be a sophisticated programmer. In component construction (assembly) mode, components are hooked together to create a model. In analysis mode, the models are exercised and run according to the desired experimental design.We start with basic terminology and concepts of modeling, and decompose the art of modeling as a process. This overview of the process helps clarify when we should or should not use simulation models. We discuss some common missteps made by many inexperienced modelers, and propose a concrete approach for avoiding those mistakes. After a quick review random number and random variate generation, we view the simulation model as a black-box which transforms inputs to outputs. This helps frame the need for designed experiments to help us gain better understanding of the system being modeled

Sapropterin dihydrochloride for the treatment of hyperphenylalaninemias

INTRODUCTION: Phenylketonuria (PKU) is caused by mutation of the enzyme, phenylalanine (Phe) hydroxylase (PAH). The hyperphenylalaninemia characteristic of PKU causes devastating neurological damage if not identified and treated at birth with a Phe-restricted diet. Sapropterin dihydrochloride, a pharmaceutical formulation of the natural cofactor for PAH (6R-tetrahydrobiopterin; BH4), is now available for the management of hyperphenylalaninemia in some PKU patients, including BH4 deficiencies. Sapropterin dihydrochloride improves dietary Phe tolerance in about 20% of patients with PKU. AREAS COVERED: This evaluation describes the identification of patients suitable for treatment of sapropterin dihydrochloride, together with its indications, therapeutic properties and efficacy. Furthermore, the article reviews its safety and tolerability in patients with PKU or BH4 deficiency. EXPERT OPINION: A reduction in blood Phe of at least 30% occurred in ∼ 20 - 30% of sapropterin-treated PKU patients (mostly with milder forms of PKU). Treatment with sapropterin resulted in clinically significant and sustained reductions in blood Phe concentrations and increased dietary Phe tolerance in well-designed clinical studies in PKU patients who responded to BH4. Successful treatment with sapropterin may lead to a relaxation of the Phe-restricted diet, although continued monitoring of blood Phe is required. Sapropterin was well tolerated

Galactokinase deficiency in a patient with congenital hyperinsulinism

Background: Galactokinase catalyses the first committed step in galactose metabolism, the conversion of galactose to galactose-1-phosphate. Galactokinase deficiency is an extremely rare form of galactosaemia, and the most frequent complication reported is cataracts. Congenital hyperinsulinism (CHI) is a cause of severe hypoglycaemia in the newborn period. Galactosaemia has not previously been reported in a neonate with concomitant CHI. Aims: To report the first case of a patient with CHI and galactokinase deficiency, and to describe the diagnostic pitfalls with bedside blood glucose testing in a neonate with combined galactokinase deficiency and CHI. Patients/methods: A 3-day-old baby girl from consanguineous parents presented with poor feeding, irritability and seizures. Capillary blood glucose testing using bedside test strips and glucometer showed a glucose level of 18 mmol/L, but the actual laboratory blood glucose level was only 1.8 mmol/L. After discontinuation of oral feeding (stopping provision of dietary galactose), the bedside capillary blood glucose correlated with laboratory glucose concentrations. Results: Biochemically the patient had CHI (blood glucose level 2.3 mmol/L with simultaneous serum insulin level of 30 mU/L) and galactokinase deficiency (elevated serum galactose level 0.62 μmol/L). Homozygous loss of function mutations in ABCC8 and GALK1 were found, which explained the patient’s CHI and galactokinase deficiency, respectively. Conclusion: This is the first reported case of CHI and galactokinase deficiency occurring in the same patient. Severe hypoglycaemia in neonates with CHI may go undetected with bedside blood glucose meters in patients with galactokinase deficiency