Gisela Haege

Use of guidelines improves the neurological outcome in glutaric aciduria type I

To evaluate the effect of treatment according to current evidence‐based recommendations on the neurological outcome of patients with glutaric aciduria type I (GA‐I).

Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany *

BackgroundNational newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome.MethodsIn a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated.ResultsOptimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two.ConclusionsPhysical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.

Complementary dietary treatment using lysine-free, arginine-fortified amino acid supplements in glutaric aciduria type I — A decade of experience

The cerebral formation and entrapment of neurotoxic dicarboxylic metabolites (glutaryl-CoA, glutaric and 3-hydroxyglutaric acid) are considered to be important pathomechanisms of striatal injury in glutaric aciduria type I (GA-I). The quantitatively most important precursor of these metabolites is lysine. Recommended therapeutic interventions aim to reduce lysine oxidation (low lysine diet, emergency treatment to minimize catabolism) and to enhance physiologic detoxification of glutaryl-CoA via formation of glutarylcarnitine (carnitine supplementation). It has been recently shown in Gcdh(-/-) mice that cerebral lysine influx and oxidation can be modulated by arginine which competes with lysine for transport at the blood-brain barrier and the inner mitochondrial membrane [Sauer et al., Brain 134 (2011) 157-170]. Furthermore, short-term outcome of 12 children receiving arginine-fortified diet showed very promising results [Strauss et al., Mol. Genet. Metab. 104 (2011) 93-106]. Since lysine-free, arginine-fortified amino acid supplements (AAS) are commercially available and used in Germany for more than a decade, we evaluated the effect of arginine supplementation in a cohort of 34 neonatally diagnosed GA-I patients (median age, 7.43 years; cumulative follow-up period, 221.6 patient years) who received metabolic treatment according to a published guideline [Kölker et al., J. Inherit. Metab. Dis. 30 (2007) 5-22]. Patients used one of two AAS product lines during the first year of life, resulting in differences in arginine consumption [group 1 (Milupa Metabolics): mean=111 mg arginine/kg; group 2 (Nutricia): mean=145 mg arginine/kg; p<0.001]. However, in both groups the daily arginine intake was increased (mean, 137 mg/kg body weight) and the dietary lysine-to-arginine ratio was decreased (mean, 0.7) compared to infants receiving human milk and other natural foods only. All other dietary parameters were in the same range. Despite significantly different arginine intake, the plasma lysine-to-arginine ratio did not differ in both groups. Frequency of dystonia was low (group 1: 12.5%; group 2: 8%) compared with patients not being treated according to the guideline, and gross motor development was similar in both groups. In conclusion, the development of complementary dietary strategies exploiting transport competition between lysine and arginine for treatment of GA-I seems promising. More work is required to understand neuroprotective mechanisms of arginine, to develop dietary recommendations for arginine and to evaluate the usefulness of plasma monitoring for lysine and arginine levels as predictors of cerebral lysine influx.

Medium-Chain Acyl-CoA Dehydrogenase Deficiency: Evaluation of Genotype-Phenotype Correlation in Patients Detected by Newborn Screening

BACKGROUND Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is included in many newborn screening programmes worldwide. In addition to the prevalent mutation c.985A>G in the ACADM gene, potentially mild mutations like c.199T>C are frequently found in screening cohorts. There is ongoing discussion whether this mutation is associated with a clinical phenotype. METHODS In 37 MCADD patients detected by newborn screening, biochemical phenotype (octanoylcarnitine (C8), ratios of C8 to acetylcarnitine (C2), decanoylcarnitine (C10) and dodecanoylcarnitine (C12) at screening and confirmation) and clinical phenotype (inpatient emergency treatment, metabolic decompensations, clinical assessments, psychometric tests) were assessed in relation to genotype. RESULTS 16 patients were homozygous for c.985A>G (group 1), 11 compound heterozygous for c.199T>C and c.985A>G/another mutation (group 2) and 7 compound heterozygous for c.985A>G and mutations other than c.199T>C (group 3) and 3 carried neither c.985A>G nor c.199T>C but other known homozygous mutations (group 4). At screening C8/C2 and C8/C10, at confirmation C8/C2, C8/C10 and C8/C12 differed significantly between patients compound heterozygous for c.199T>C (group 2) and other genotypes. C8, C10 and C8/C2 at screening were strongly associated with time of sampling in groups 1 + 3 + 4, but not in group 2. Clinical phenotype did not differ between genotypes. Two patients compound heterozygous for c.199T>C and a severe mutation showed neonatal decompensation with hypoglycaemia. CONCLUSION Biochemical phenotype differs between MCADD patients compound heterozygous for c.199T>C with a severe mutation and other genotypes. In patients detected by newborn screening, clinical phenotype does not differ between genotypes following uniform treatment recommendations. Neonatal decompensation can also occur in patients with the presumably mild mutation c.199T>C prior to diagnosis.

A cross-sectional controlled developmental study of neuropsychological functions in patients with glutaric aciduria type I

BackgroundGlutaric aciduria type I (GA-I) is an inherited metabolic disease due to deficiency of glutaryl-CoA dehydrogenase (GCDH). Cognitive functions are generally thought to be spared, but have not yet been studied in detail.MethodsThirty patients detected by newborn screening (n = 13), high-risk screening (n = 3) or targeted metabolic testing (n = 14) were studied for simple reaction time (SRT), continuous performance (CP), visual working memory (VWM), visual-motor coordination (Tracking) and visual search (VS). Dystonia (n = 13 patients) was categorized using the Barry-Albright-Dystonia Scale (BADS). Patients were compared with 196 healthy controls. Developmental functions of cognitive performances were analysed using a negative exponential function model.ResultsBADS scores correlated with speed tests but not with tests measuring stability or higher cognitive functions without time constraints. Developmental functions of GA-I patients significantly differed from controls for SRT and VS but not for VWM and showed obvious trends for CP and Tracking. Dystonic patients were slower in SRT and CP but reached their asymptote of performance similar to asymptomatic patients and controls in all tests. Asymptomatic patients did not differ from controls, except showing significantly better results in Tracking and a trend for slower reactions in visual search. Data across all age groups of patients and controls fitted well to a model of negative exponential development.ConclusionsDystonic patients predominantly showed motor speed impairment, whereas performance improved with higher cognitive load. Patients without motor symptoms did not differ from controls. Developmental functions of cognitive performances were similar in patients and controls. Performance in tests with higher cognitive demand might be preserved in GA-I, even in patients with striatal degeneration.

Visual functions in phenylketonuria-evaluating the dopamine and long-chain polyunsaturated fatty acids depletion hypotheses.

BACKGROUND In phenylketonuria presymptomatic treatment following newborn screening prevents severe mental and physical impairment. The reasons for subtle impairments of cerebral functions despite early treatment remain unclear. We assessed a broad spectrum of visual functions in early-treated patients with phenylketonuria and evaluated two hypotheses-the dopamine and the long-chain polyunsaturated fatty acids (LCPUFAs) depletion hypotheses. METHODS Contrast sensitivity, colour vision, electroretinography, frequency doubling technology campimetry (FDT), and their relation with blood phenylalanine and docosahexaenoic acid levels were assessed in 36 patients with phenylketonuria and 18 age-matched healthy controls. RESULTS Contrast sensitivity was significantly lower and total error scores in colour vision significantly higher in patients than controls. Electroretinography results differed significantly between patients and controls. We found a trend for the effect of phenylalanine-levels on contrast sensitivity and a significant effect on colour vision/FDT results. Docosahexaenoic acid levels in erythrocytes were not associated with visual functions. CONCLUSION This is the first evaluation of visual functions in phenylketonuria using a comprehensive ophthalmological test battery. We found no evidence supporting the long-chain polyunsaturated fatty acids depletion hypothesis. However, the effect of phenylalanine-levels on visual functions suggests that imbalance between phenylalanine and tyrosine may affect retinal dopamine levels in phenylketonuria. This is supported by the similar patterns of visual functions in patients with phenylketonuria observed in our study and patients with Parkinsons disease.

Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation (J Inherit Metab Dis, 10.1007/s10545-015-9839-3)

Stefan Kölker & Angeles Garcia Cazorla & Vassili Valayannopoulos & Allan M. Lund & Alberto B. Burlina & Jolanta Sykut-Cegielska & Frits A. Wijburg & Elisa Leão Teles & Jiri Zeman & Carlo Dionisi-Vici & Ivo Barić & Daniela Karall & Persephone Augoustides-Savvopoulou & Lise Aksglaede & Jean-Baptiste Arnoux & Paula Avram & Matthias R. Baumgartner & Javier Blasco-Alonso & Brigitte Chabrol & Anupam Chakrapani & Kimberly Chapman & Elisenda Cortès i Saladelafont & Maria L. Couce & Linda de Meirleir & Dries Dobbelaere & Veronika Dvorakova & Francesca Furlan & Florian Gleich & Wanda Gradowska & Stephanie Grünewald & Anil Jalan & Johannes Häberle & Gisela Haege & Robin Lachmann & Alexander Laemmle & Eveline Langereis & Pascale de Lonlay & Diego Martinelli & Shirou Matsumoto & Chris Mühlhausen & Hélène Ogier de Baulny & Carlos Ortez & Luis Peña-Quintana & Danijela Petković Ramadža & Esmeralda Rodrigues & Sabine Scholl-Bürgi & Etienne Sokal & Christian Staufner & Marshall L. Summar & Nicholas Thompson & Roshni Vara & Inmaculada Vives Pinera & John H. Walter & Monique Williams & Peter Burgard

Erratum to: The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype (J Inherit Metab Dis, 10.1007/s10545-015-9840-x)

Stefan Kölker & Vassili Valayannopoulos & Alberto B. Burlina & Jolanta Sykut-Cegielska & Frits A. Wijburg & Elisa Leão Teles & Jiri Zeman & Carlo Dionisi-Vici & Ivo Barić & Daniela Karall & Jean-Baptiste Arnoux & Paula Avram & Matthias R. Baumgartner & Javier Blasco-Alonso & S. P. Nikolas Boy & Marlene Bøgehus Rasmussen & Peter Burgard & Brigitte Chabrol & AnupamChakrapani &Kimberly Chapman & Elisenda Cortès i Saladelafont & Maria L. Couce & Linda de Meirleir & Dries Dobbelaere & Francesca Furlan & Florian Gleich & Maria Julieta González & Wanda Gradowska & Stephanie Grünewald & Tomas Honzik & Friederike Hörster & Hariklea Ioannou & Anil Jalan & Johannes Häberle & Gisela Haege & Eveline Langereis & Pascale de Lonlay &DiegoMartinelli & ShirouMatsumoto &ChrisMühlhausen &ElaineMurphy &HélèneOgier de Baulny & Carlos Ortez & Consuelo C. Pedrón & Guillem Pintos-Morell & Luis Pena-Quintana & Danijela Petković Ramadža & Esmeralda Rodrigues & Sabine Scholl-Bürgi & Etienne Sokal & Marshall L. Summar & Nicholas Thompson & Roshni Vara & Inmaculada Vives Pinera & John H. Walter & Monique Williams & Allan M. Lund & Angeles Garcia Cazorla