Publications by authors named "Sabine Scholl-Bürgi"

85 Publications

Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: First revision.

J Inherit Metab Dis 2021 Feb 17. Epub 2021 Feb 17.

Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.

Isolated methylmalonic acidaemia (MMA) and propionic acidaemia (PA) are rare inherited metabolic diseases. Six years ago, a detailed evaluation of the available evidence on diagnosis and management of these disorders has been published for the first time. The article received considerable attention, illustrating the importance of an expert panel to evaluate and compile recommendations to guide rare disease patient care. Since that time, a growing body of evidence on transplant outcomes in MMA and PA patients and use of precursor free amino acid mixtures allows for updates of the guidelines. In this article, we aim to incorporate this newly published knowledge and provide a revised version of the guidelines. The analysis was performed by a panel of multidisciplinary health care experts, who followed an updated guideline development methodology (GRADE). Hence, the full body of evidence up until autumn 2019 was re-evaluated, analysed and graded. As a result, 21 updated recommendations were compiled in a more concise paper with a focus on the existing evidence to enable well-informed decisions in the context of MMA and PA patient care.
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http://dx.doi.org/10.1002/jimd.12370DOI Listing
February 2021

Ketogenic diet in a patient with refractory status epilepticus due to mutation.

JIMD Rep 2021 Jan 1;57(1):3-8. Epub 2020 Oct 1.

Department of Pediatrics I Inherited Metabolic Disorders, Medical University of Innsbruck Innsbruck Austria.

We present a 16-year-old female patient with syndrome, treated with ketogenic diet after she presented with refractory status epilepticus. Initially, benefit of the ketogenic diet could be seen, but the outcome was fatal, with death 3 months after presenting symptoms. Additionally, we give a literature review of the utility of ketogenic diet in patients with disease.
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http://dx.doi.org/10.1002/jmd2.12169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802623PMC
January 2021

Long-term experience with triheptanoin in 12 Austrian patients with long-chain fatty acid oxidation disorders.

Orphanet J Rare Dis 2021 Jan 14;16(1):28. Epub 2021 Jan 14.

Department of Pediatrics I (Inherited Metabolic Disorders), Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

Background: Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of rare inborn errors of metabolism with autosomal recessive inheritance that may cause life-threatening events. Treatment with triheptanoin, a synthetic seven-carbon fatty acid triglyceride compound with an anaplerotic effect, seems beneficial, but clinical experience is limited. We report our long-term experience in an Austrian cohort of LC-FAOD patients.

Methods: We retrospectively assessed clinical outcome and total hospitalization days per year before and after start with triheptanoin by reviewing medical records of 12 Austrian LC-FAOD patients RESULTS: For 12 Austrian LC-FAOD patients at three metabolic centers, triheptanoin was started shortly after birth in 3/12, and between 7.34 and 353.3 (median 44.5; mean 81.1) months of age in 9/12 patients. For 11 pediatric patients, mean duration of triheptanoin intake was 5.3 (median 3.9, range 1.2-15.7) years, 10/11 pediatric patients have an ongoing intake of triheptanoin. One patient quit therapy due to reported side effects. Total hospitalization days per year compared to before triheptanoin treatment decreased by 82.3% from 27.1 (range 11-65) days per year to 4.8 (range 0-13) days per year, and hospitalization days in the one year pre- compared to the one year post-triheptanoin decreased by 69.8% from 27.1 (range 4-75) days to 8.2 (range 0-25) days. All patients are in good clinical condition, show normal psychomotor development and no impairment in daily life activities.

Conclusion: In this retrospective observational study in an Austrian LC-FAOD cohort, triheptanoin data show improvement in disease course. Triheptanoin appears to be a safe and beneficial treatment option in LC-FAOD. For further clarification, additional prospective randomized controlled trials are needed.
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http://dx.doi.org/10.1186/s13023-020-01635-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807521PMC
January 2021

Increased Fecal Neopterin Parallels Gastrointestinal Symptoms in COVID-19.

Clin Transl Gastroenterol 2021 01 12;12(1):e00293. Epub 2021 Jan 12.

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria.

Introduction: Coronavirus disease (COVID-19) has spread from Wuhan, China, and become a worldwide pandemic. Most patients display respiratory symptoms but up to 50% report gastrointestinal symptoms. Neopterin is a surrogate marker for viral inflammation, and its production by macrophages is driven by interferon-γ.

Methods: We measured fecal neopterin in 37 hospitalized COVID-19 patients not requiring intensive care measures and 22 healthy controls.

Results: Fecal neopterin was elevated in stool samples from COVID-19 patients compared with that in samples from healthy controls. Especially, patients reporting gastrointestinal symptoms exhibited increased fecal neopterin values.

Discussion: COVID-19 is associated with an inflammatory immune response in the gastrointestinal tract.
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http://dx.doi.org/10.14309/ctg.0000000000000293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806232PMC
January 2021

Method comparison of HPLC-ninhydrin-photometry and UHPLC-PITC-tandem mass spectrometry for serum amino acid analyses in patients with complex congenital heart disease and controls.

Metabolomics 2020 12 15;16(12):128. Epub 2020 Dec 15.

Department of Pediatrics I, Division of Pediatric Cardiology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.

Introduction: Metabolomics studies are not routine when quantifying amino acids (AA) in congenital heart disease (CHD).

Objectives: Comparative analysis of 24 AA in serum by traditional high-performance liquid chromatography (HPLC) based on ion exchange and ninhydrin derivatisation followed by photometry (PM) with ultra-high-performance liquid chromatography and phenylisothiocyanate derivatisation followed by tandem mass spectrometry (TMS); interpretation of findings in CHD patients and controls.

Methods: PM: Sample analysis as above (total run time, ~ 119 min). TMS: Sample analysis by AbsoluteIDQ® p180 kit assay (BIOCRATES Life Sciences AG, Innsbruck, Austria), which employs PITC derivatisation; separation of analytes on a Waters Acquity UHPLC BEH18 C18 reversed-phase column, using water and acetonitrile with 0.1% formic acid as the mobile phases; and quantification on a Triple-Stage Quadrupole tandem mass spectrometer (Thermo Fisher Scientific, Waltham, MA) with electrospray ionisation in the presence of internal standards (total run time, ~ 8 min). Calculation of coefficients of variation (CV) (for precision), intra- and interday accuracies, limits of detection (LOD), limits of quantification (LOQ), and mean concentrations.

Results: Both methods yielded acceptable results with regard to precision (CV < 10% PM, < 20% TMS), accuracies (< 10% PM, < 34% TMS), LOD, and LOQ. For both Fontan patients and controls AA concentrations differed significantly between methods, but patterns yielded overall were parallel.

Conclusion: Serum AA concentrations differ with analytical methods but both methods are suitable for AA pattern recognition. TMS is a time-saving alternative to traditional PM under physiological conditions as well as in patients with CHD.

Trial Registration Number: ClinicalTrials.gov Identifier NCT03886935, date of registration March 27th, 2019 (retrospectively registered).
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http://dx.doi.org/10.1007/s11306-020-01741-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736021PMC
December 2020

Comparative Serum Analyses Identify Cytokines and Hormones Commonly Dysregulated as Well as Implicated in Promoting Osteolysis in MMP-2-Deficient Mice and Children.

Front Physiol 2020 25;11:568718. Epub 2020 Sep 25.

Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Deficiency of matrix metalloproteinase 2 (MMP-2) causes a complex syndrome characterized by multicentric osteolysis, nodulosis, and arthropathy (MONA) as well as cardiac valve defects, dwarfism and hirsutism. MMP-2 deficient () mice are a model for this rare multisystem pediatric syndrome but their phenotype remains incompletely characterized. Here, we extend the phenotypic characterization of MMP-2 deficiency by comparing the levels of cytokines and chemokines, soluble cytokine receptors, angiogenesis factors, bone development factors, apolipoproteins and hormones in mice and humans. Initial screening was performed on an 8-year-old male presenting a previously unreported deletion mutation c1294delC (Arg432fs) in the gene and diagnosed with MONA. Of eighty-one serum biomolecules analyzed, eleven were upregulated (>4-fold), two were downregulated (>4-fold) and sixty-eight remained unchanged, compared to unaffected controls. Specifically, Eotaxin, GM-CSF, M-CSF, GRO-α, MDC, IL-1β, IL-7, IL-12p40, MIP-1α, MIP-1β, and MIG were upregulated and epidermal growth factor (EGF) and ACTH were downregulated in this patient. Subsequent analysis of five additional MMP-2 deficient patients confirmed the upregulation in Eotaxin, IL-7, IL-12p40, and MIP-1α, and the downregulation in EGF. To establish whether these alterations are phenotypic traits of MMP-2 deficiency, we further studied mice. Among 32 cytokines measured in plasma of mice, the cytokines Eotaxin, IL-1β, MIP-1α, and MIG were commonly upregulated in mice as well as patients with MMP-2 deficiency. Moreover, bioactive cortisol (a factor that exacerbates osteoporosis) was also elevated in MMP-2 deficient mice and patients. Among the factors we have identified to be dysregulated in MMP-2 deficiency many are osteoclastogenic and could potentially contribute to bone disorder in MONA. These new molecular phenotypic traits merit being targeted in future research aimed at understanding the pathological mechanisms elicited by MMP-2 deficiency in children.
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http://dx.doi.org/10.3389/fphys.2020.568718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546215PMC
September 2020

[Taking Stock: Figures, Data, Facts].

Padiatr Padol 2020 15;55(4):160-161. Epub 2020 Sep 15.

Department für Kinder- und Jugendheilkunde, Universitätsklinik für Pädiatrie I, Bereich Angeborene Stoffwechselstörungen, Medizinische Universität Innsbruck, Anichstraße 35, 6020 Innsbruck, Österreich.

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http://dx.doi.org/10.1007/s00608-020-00826-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490319PMC
September 2020

Paroxysmal and non-paroxysmal dystonia in 3 patients with biallelic ECHS1 variants: Expanding the neurological spectrum and therapeutic approaches.

Eur J Med Genet 2020 Nov 26;63(11):104046. Epub 2020 Aug 26.

Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; Institute of Human Genetics, Technische Universität München, Munich, Germany; Centre for Rare Diseases, University of Tuebingen, Tübingen, Germany.

Background: ECHS1 encodes the mitochondrial short chain enoyl CoA hydratase 1 (SCEH). Biallelic ECHS1 variants have been associated with Leigh-like presentations and milder phenotypes with paroxysmal exercise-induced dystonia.

Patients/methods: We used exome sequencing to investigate molecular bases of paroxysmal and non-paroxysmal dystonia in three patients and performed functional studies in fibroblasts. Disease presentation and response upon dietary interventions were documented.

Results: We identified compound heterozygous ECHS1 missense variants in all individuals; all of them harbouring an c.518C > T (p.Ala173Val) variant. SCEH activity was impaired in patients' fibroblasts, respiratory chain-, and pyruvate-dehydrogenase-complex activities were normal in one individual. Patient 1 presented from the age of 2.5 years on with paroxysmal opisthotonic posturing. Patient 2 had a first metabolic crisis at the age 20 months developing recurrent exercise-induced dystonic episodes. Disease history of patient 3 was unremarkable for neurological findings until he first presented at the age of 20 years with persistent dystonia. Ketogenic diet had beneficial effects in patient 1. Neither ketogenic nor low protein diets led to milder symptoms in patient 2. Patient 3 benefits from low protein diet with improvement of his torticollis.

Conclusions: In line with literature, our findings corroborate that the pathogenic ECHS1 variant c.518C > T (p.Ala173Val) is associated with milder phenotypes characterized by paroxysmal and non-paroxysmal dystonia. Because of the potentially treatable defect, especially in milder affected patients, it is important to consider SCEH deficiency not only in patients with Leigh-like syndrome but also in patients with paroxysmal dystonia and normal neurological findings between episodes.
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http://dx.doi.org/10.1016/j.ejmg.2020.104046DOI Listing
November 2020

Elevated Homocysteine after Elevated Propionylcarnitine or Low Methionine in Newborn Screening Is Highly Predictive for Low Vitamin B12 and Holo-Transcobalamin Levels in Newborns.

Diagnostics (Basel) 2020 Aug 24;10(9). Epub 2020 Aug 24.

Austrian Newborn Screening, Division of Pediatric Pulmonology, Allergology and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria.

Early diagnostics and treatment of vitamin B12 deficiency (B12D) in infants, mainly maternally conditioned, is crucial in preventing possible developmental delay and neurological deficits. Currently, B12D is rarely listed in regular newborn screening panels and mostly regarded as an incidental finding. The aim of this study was to evaluate a targeted newborn screening strategy for detection of suspected B12D. A decision strategy based on the primary parameters propionylcarnitine and methionine for selection of samples to be analyzed for total homocysteine by mass spectrometry was established. Therefore, 93,116 newborns were initially screened. Concentrations of vitamin B12 and holotranscobalamin in serum were obtained from clinical follow-up analyses of recalled newborns. Moreover, an extremely sensitive mass spectrometric method to quantify methylmalonic acid from the dried blood spots was developed. Overall, 0.15% of newborns were screened positive for suspected B12D, of which 64% had vitamin B12 concentrations below 148 pM. We also determined a cutoff value for methylmalonic acid in dried blood spots indicative for B12D in infants. Overall, we calculated a prevalence of 92/100,000 for suspected B12D in the Austrian newborns. In conclusion, we present a screening algorithm including second-tier measurement of total homocysteine that allows detection of low B12 serum concentrations with a high detection rate and low false-positive rate.
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http://dx.doi.org/10.3390/diagnostics10090626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555675PMC
August 2020

Galactokinase deficiency: lessons from the GalNet registry.

Genet Med 2021 Jan 18;23(1):202-210. Epub 2020 Aug 18.

Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Purpose: Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype.

Methods: Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020.

Results: Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17-5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM_000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial.

Conclusion: The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed.
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http://dx.doi.org/10.1038/s41436-020-00942-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790741PMC
January 2021

The Genetic Landscape and Epidemiology of Phenylketonuria.

Am J Hum Genet 2020 08 14;107(2):234-250. Epub 2020 Jul 14.

Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, Clinic I, University Hospital Heidelberg, 69120 Heidelberg, Germany; Division of Metabolism, University Children's Hospital, 8032 Zürich, Switzerland. Electronic address:

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413859PMC
August 2020

Targeted metabolomic analysis of serum amino acids in the adult Fontan patient with a dominant left ventricle.

Sci Rep 2020 06 2;10(1):8930. Epub 2020 Jun 2.

Department of Pediatrics I, Division of Inherited Metabolic Disorders, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.

Growing interest lies in the assessment of the metabolic status of patients with a univentricular circulation after Fontan operation, especially in changes of amino acid metabolism. Using targeted metabolomic examinations, we investigated amino acid metabolism in a homogeneous adult Fontan-patient group with a dominant left ventricle, seeking biomarker patterns that might permit better understanding of Fontan pathophysiology and early detection of subtle ventricular or circulatory dysfunction. We compared serum amino acid levels (42 analytes; AbsoluteIDQ p180 kit, Biocrates Life Sciences, Innsbruck, Austria) in 20 adult Fontan patients with a dominant left ventricle and those in age- and sex-matched biventricular controls. Serum concentrations of asymmetric dimethylarginine, methionine sulfoxide, glutamic acid, and trans-4-hydroxyproline and the methionine sulfoxide/methionine ratio (Met-SO/Met) were significantly higher and serum concentrations of asparagine, histidine, taurine, and threonine were significantly lower in patients than in controls. Met-SO/Met values exhibited a significant negative correlation with oxygen uptake during exercise. The alterations in amino acid metabolome that we found in Fontan patients suggest links between Fontan pathophysiology, altered cell energy metabolism, oxidative stress, and endothelial dysfunction like those found in biventricular patients with congestive heart failure. Studies of extended amino acid metabolism may allow better understanding of Fontan pathophysiology that will permit early detection of subtle ventricular or circulatory dysfunction in Fontan patients.
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http://dx.doi.org/10.1038/s41598-020-65852-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265548PMC
June 2020

Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH) deficiencies.

Orphanet J Rare Dis 2020 05 26;15(1):126. Epub 2020 May 26.

Division of Child Neurology and Metabolic Disorders, University Children's Hospital, Heidelberg, Germany.

Background: Tetrahydrobiopterin (BH) deficiencies comprise a group of six rare neurometabolic disorders characterized by insufficient synthesis of the monoamine neurotransmitters dopamine and serotonin due to a disturbance of BH biosynthesis or recycling. Hyperphenylalaninemia (HPA) is the first diagnostic hallmark for most BH deficiencies, apart from autosomal dominant guanosine triphosphate cyclohydrolase I deficiency and sepiapterin reductase deficiency. Early supplementation of neurotransmitter precursors and where appropriate, treatment of HPA results in significant improvement of motor and cognitive function. Management approaches differ across the world and therefore these guidelines have been developed aiming to harmonize and optimize patient care. Representatives of the International Working Group on Neurotransmitter related Disorders (iNTD) developed the guidelines according to the SIGN (Scottish Intercollegiate Guidelines Network) methodology by evaluating all available evidence for the diagnosis and treatment of BH deficiencies.

Conclusion: Although the total body of evidence in the literature was mainly rated as low or very low, these consensus guidelines will help to harmonize clinical practice and to standardize and improve care for BH deficient patients.
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http://dx.doi.org/10.1186/s13023-020-01379-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251883PMC
May 2020

Targeted metabolomic analysis of serum phospholipid and acylcarnitine in the adult Fontan patient with a dominant left ventricle.

Ther Adv Chronic Dis 2020 27;11:2040622320916031. Epub 2020 Apr 27.

Center of Pediatric Cardiology and Congenital Heart Disease, Heart and Diabetes Center North Rhine-Westphalia, Ruhr-University of Bochum, Georgstraße, Bad Oeynhausen, Germany.

Background: Patients with a Fontan circulation have altered cholesterol and lipoprotein values. We analysed small organic molecules in extended phopsholipid and acylcarnitine metabolic pathways ('metabolomes') in adult Fontan patients with a dominant left ventricle, seeking differences between profiles in baseline and Fontan circulations.

Methods: In an observational matched cross-sectional study, we compared phosphatidylcholine (PC), sphingomyelin (SM), and acylcarnitine metabolomes (105 analytes; AbsoluteIDQ p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) in 20 adult Fontan patients having a dominant left ventricle with those in 20 age- and sex-matched healthy controls.

Results: Serum levels of total PC (-value 0.01), total SM (-value 0.0002) were significantly lower, and total acylcarnitines (-value 0.02) were significantly higher in patients than in controls. After normalisation of data, serum levels of 12 PC and 1 SM Fontan patients were significantly lower (-values <0.05), and concentrations of 3 acylcarnitines were significantly higher than those in controls (-values <0.05).

Conclusion: Metabolomic profiling can use small specimens to identify biomarker patterns that track derangement in multiple metabolic pathways. The striking alterations in the phospholipid and acylcarnitine metabolome that we found in Fontan patients may reflect altered cell signalling and metabolism as found in heart failure in biventricular patients, chronic low-level inflammation, and alteration of functional or structural properties of lymphatic or blood vessels.

Trial Registration Number: ClinicalTrials.gov Identifier NCT03886935.
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http://dx.doi.org/10.1177/2040622320916031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222265PMC
April 2020

Clinical aspects of Hyaline Fibromatosis Syndrome and identification of a novel mutation.

Mol Genet Genomic Med 2020 06 20;8(6):e1203. Epub 2020 Mar 20.

Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.

Background: Hyaline fibromatosis syndrome is an autosomal recessive disease caused by mutations in ANTXR2 which leads to loss of function of the transmembrane protein anthrax toxin receptor 2. It is distinguished by characteristic skin lesions, gingival hyperplasia, joint and bone disease, and systemic involvement.

Methods: Based on the case of an 11-year-old female patient with typical features of hyaline fibromatosis syndrome and the underlying pathogenic compound heterozygote variants in ANTXR2 we discuss the genetic and clinical aspects of hyaline fibromatosis syndrome.

Results: The novel mutation in ANTXR2 (c.1223T>C, p.Leu408Pro variant) seems to allow for a protracted course of the disease.

Conclusion: Our findings add to the phenotypic, genetic, and biochemical spectrum of hyaline fibromatosis syndrome.
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http://dx.doi.org/10.1002/mgg3.1203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284039PMC
June 2020

Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.

Genet Med 2020 05 6;22(5):908-916. Epub 2020 Jan 6.

Section of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.

Purpose: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking.

Methods: A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients.

Results: Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%).

Conclusion: The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients.
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http://dx.doi.org/10.1038/s41436-019-0739-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200590PMC
May 2020

Reducing complexity: explaining inborn errors of metabolism and their treatment to children and adolescents.

Orphanet J Rare Dis 2019 11 8;14(1):248. Epub 2019 Nov 8.

Division of Metabolism, University Children's Hospital Zurich, Zurich, Switzerland.

Background: Inborn errors of metabolism (IEM) are a group of rare, heterogeneous and complex genetic conditions. Clinically, IEM often affect the central nervous system and other organs. Some carry the risk of progression and / or potentially life-threatening crises. Many patients have to adhere to lifelong dietary or drug treatment. The complexity of IEM makes it difficult for patients and caregivers to understand their pathophysiology, inheritance and therapy rationale. Especially patients reaching adolescence may have only limited knowledge of their condition since medical care has often entirely been handled by their parents. Knowledge about disease and treatment, however, constitute pillars of self-responsible disease management. Not many standardized patient education materials on IEM are available and their comprehensibility has not been systematically investigated.

Methods: We developed and tested patient education materials for school-aged children and adolescents with IEM. Informative texts and illustrations in paper form and as videos were developed by an international network of metabolic care professionals together with a graphic artist and experts for easy-to-read language. The materials were presented in standardized single or group training sessions to 111 individuals; first, to 74 healthy children and adolescents (recruited via public schools) and consecutively to 37 paediatric patients with IEM (phenylketonuria, galactosemia, urea cycle defects, lysosomal storage disorders) from six metabolic centres. Knowledge-gain was assessed by pre- and post-testing.

Results: Knowledge-gain was significant in healthy children and adolescents as well as in patients (p < .001, r =. -77 /. -70). Effect sizes were large in both groups (r = -.77 / -.70). This result was independent from family language and teacher-rated concentration or cognitive capacity in healthy children.

Conclusion: The newly developed patient education materials are a powerful tool to improve disease- and treatment-related knowledge. They facilitate communication between the medical team and children and adolescents with IEM and their caregivers.
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http://dx.doi.org/10.1186/s13023-019-1236-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842257PMC
November 2019

Frenotomy for tongue-tie (frenulum linguae breve) showed improved symptoms in the short- and long-term follow-up.

Acta Paediatr 2019 10 29;108(10):1861-1866. Epub 2019 Apr 29.

Clinic for Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.

Aim: To evaluate clinical manifestations of tongue-tie as well as short-term and long-term outcomes following frenotomy.

Methods: In this retrospective study, for 329 patients (295 infants and 34 children) who underwent frenotomy between 2011 and 2017, symptoms, short-term and long-term outcomes were evaluated.

Results: Of the 295 infants (median age six weeks), 199 (=60%) showed inadequate breastfeeding. Symptoms were painful or sore maternal nipples, poor weight gain, dribbling milk from the corner of the mouth, reduced milk supply, inadequate latch during bottle-feeding and maternal mastitis. In the 34 children, predominant symptoms were articulation disorders, misaligned teeth and problems with swallowing solid food. Of the 141 patients with short-term feedback, 86% reported improvement, 13% an unchanged situation. In a former premature, the reported worsening of symptoms ('breath spells') are likely related to prematurity. Of the 164 patients where the questionnaire for long-term outcome was provided, 82% reported improvement, 16% an unchanged situation. For two infants worsening was reported, referring to refusal to drink from breast or bottle for two hours after the procedure and fever for one day, respectively.

Conclusion: Frenulum breve is a potential cause of breastfeeding difficulties and can be treated safely and efficiently by frenotomy.
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http://dx.doi.org/10.1111/apa.14811DOI Listing
October 2019

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

J Inherit Metab Dis 2019 03 17;42(2):333-352. Epub 2019 Feb 17.

Inherited Metabolic Diseases Clinic, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado.

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry.

Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities.

Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.
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http://dx.doi.org/10.1002/jimd.12041DOI Listing
March 2019

Impact of the Fontan Operation on Organ Systems.

Cardiovasc Hematol Disord Drug Targets 2019 ;19(3):205-214

Department for Pediatric Cardiology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan.

In patients having undergone the Fontan operation, besides the well discussed changes in the cardiac, pulmonary and gastrointestinal system, alterations of further organ systems including the hematologic, immunologic, endocrinological and metabolic are reported. As a medical adjunct to Fontan surgery, the systematic study of the central role of the liver as a metabolizing and synthesizing organ should allow for a better understanding of the pathomechanism underlying the typical problems in Fontan patients, and in this context, the profiling of endocrinological and metabolic patterns might offer a tool for the optimization of Fontan follow-up, targeted monitoring and specific adjunct treatment.
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http://dx.doi.org/10.2174/1871529X19666190211165124DOI Listing
August 2020

The value of axillary skin electron microscopic analysis in the diagnosis of lysosomal storage disorders.

Mod Pathol 2019 06 5;32(6):755-763. Epub 2019 Feb 5.

Department of Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.

Both lysosomal storage diseases and mitochondrial diseases are a group of genetic-inherited metabolic disorders. In an era, where "old fashioned methods" are apparently being replaced by evolving molecular techniques (i.e. exome and whole genome sequencing), the "old fashioned methods" might help to characterise and thus narrow down the potential differential diagnosis. Therefore, we retrospectively evaluated the relevance of electron microscopy of axillary skin for the diagnosis of lysosomal storage or mitochondrial diseases (=inherited metabolic disorders of energy metabolism). Methods and patients: We included 74 patients with developmental delay with regression or neurodegeneration who underwent an axillary skin biopsy for both fibroblast culture and electron microscopy. Because of insufficient skin biopsy quality, for 8 patients no electron microscopy result was obtained. The electron microscopy biopsies revealed abnormalities in 37/66 (56.1%) patients. 29/66 electron microscopy biopsies showed normal results. A definite diagnosis was established in 21/66 (31.8%) patients with a pathological results of axillary skin electron microscopy analysis. In total, in 25/66 (37.8%) of the patients who underwent an axillary skin electron microscopy analysis, a definite diagnosis was finally established. Taking an axillary skin biopsy during anaesthesia or with use of local intradermal lidocaine application is an inexpensive alternative and useful to establish a diagnosis in patients suspected to have a lysosomal storage disease (or inherited metabolic disorder of energy metabolism).
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http://dx.doi.org/10.1038/s41379-019-0201-4DOI Listing
June 2019

Abdominal Pain and Constipation.

Gastroenterology 2019 02 18;156(3):e12-e13. Epub 2018 Sep 18.

Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.

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http://dx.doi.org/10.1053/j.gastro.2018.09.033DOI Listing
February 2019

Mitochondrial DNA mutation "m.3243A>G"-Heterogeneous clinical picture for cardiologists ("m.3243A>G": A phenotypic chameleon).

Congenit Heart Dis 2018 Sep 21;13(5):671-677. Epub 2018 Aug 21.

Department of Child and Adolescent Health, Pediatrics I/III, Medical University of Innsbruck, Innsbruck, Austria.

Objective: In general, a mitochondrial disorder is diagnosed on the basis of symptom combinations and confirmed by genetic findings. However, patients carrying the m.3243A>G mutation in the mitochondrial tRNA leucine 1 (MT-TL1) do not always meet all the proposed criteria for the most frequently encountered mitochondrial syndrome "MELAS," an acronym for Mitochondrial Encephalomyopathy, Lactic Acidosis, and at least one Stroke-like episode. We here present various phenotypic characteristics of the mitochondrial mutation m.3243A>G with particular focus on cardiac manifestations.

Methods And Results: We followed nine patients (1 month to 68 years old; median 42 years; four female and five male) from nine different families with this m.3243A>G mutation in the MT-TL1. The classical "MELAS" criteria are met by only three of these patients. Electrocardiography (ECG) shows preexcitation pattern with short PR intervals and delta waves (Wolff-Parkinson-White) in three patients and sick sinus syndrome plus atrioventricular block I in one patient. Hypertrophic cardiomyopathy was found in eight patients with moderate to severe regurgitation of various valves.

Conclusion: Cardiac manifestation can encompass hypertrophic or dilated cardiomyopathy, as well as preexcitation syndromes or conduction delay. In general, the clinical presentation to meet the "MELAS" criteria varies due to heteroplasmy. Thus, cardiologists should screen patients with unexplained cardiac features in the context of deafness, short stature and learning disabilities for mtDNA mutations, especially the m.3243A>G mutation. A clear diagnosis is essential as a basis for prognostic advice concerning the disease course and clinical impact on family testing.
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http://dx.doi.org/10.1111/chd.12634DOI Listing
September 2018

Tolerability of inhaled N-chlorotaurine in humans: a double-blind randomized phase I clinical study.

Ther Adv Respir Dis 2018 Jan-Dec;12:1753466618778955

Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Schöpfstr. 41, Innsbruck A-6020, Austria.

Background: N-chlorotaurine (NCT), a long-lived oxidant produced by human leukocytes, can be synthesized chemically and used topically as a well-tolerated antiseptic to different body regions including sensitive ones. The aim of this study was to test the tolerability of inhaled 1% NCT in aqueous solution upon repeated application.

Methods: The study was performed double-blind and randomized with a parallel test group (1% NCT) and control group (0.9% NaCl as placebo). There were two Austrian centres involved, the hospitals, Natters and Vöcklabruck. Healthy, full age volunteers were included, 12 in each centre. A total of 12 patients were treated with NCT, and 12 with placebo, exactly half of each group from each centre. The single dose was 1.2 ml inhaled over a period of 10 min using an AKITA JET nebulizer. One inhalation was done every day for five consecutive days. The primary criterion of evaluation was the forced expiratory volume in 1 second (FEV). Secondary criteria were subjective sensations, further lung function parameters such as airway resistance, physical examination, and blood analyses (gases, electrolytes, organ function values, pharmacokinetic parameters taurine and methionine, immune parameters).

Results: All included 15 females and 9 males completed the treatment and the control examinations according to the study protocol. FEV (100.83% ± 8.04% for NCT and 92.92% ± 11.35% for controls) remained unchanged and constant during the treatment and in control examinations 1 week and 3 months after the treatment (98.75% ± 7.37% for NCT and 91.17% ± 9.46% for controls, p > 0.082 between time points within each group). The same was true for all other objective parameters. Subjective mild sensations with a higher frequency in the test group were chlorine taste ( p < 0.01) and occasional tickle in the throat ( p = 0.057). Taurine and methionine plasma concentrations did not change within 60 min after inhalation or later on.

Conclusions: Inhaled NCT is well tolerated as in other applications of different body regions. Side effects are mild, topical and transitory. The study was registered prospectively in the European Clinical Trials Database of the European Medicines Agency. The EudraCT number is 2012-003700-12.
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http://dx.doi.org/10.1177/1753466618778955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985600PMC
January 2019

Breath profiles of children on ketogenic therapy.

J Breath Res 2018 06 8;12(3):036021. Epub 2018 Jun 8.

Breath Research Institute, University of Innsbruck, Innrain 66, 6020 Innsbruck, Austria. Department of Anesthesia and Intensive Care, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria.

Ketogenic diets (KDs) were initially introduced to clinical practices as alimentary approaches with the aim to control drug-resistant epilepsies. Over the decades, a large and growing body of research has addressed the antiseizure effect of various KDs, and worked out KD-based dietary regimens, including their acting factors and modes of action. KDs have also appeared in weight loss therapies. Therapy control, particularly at initiation, happens through regular blood analysis and control of urine ketone levels. However, there is a lack of fast, reliable, and preferably non-invasive methods to accomplish this. The detection of exhaled breath constituents may offer a solution. The exhaled breath contains hundreds of volatile organic compounds (VOCs), which can be modified by diet. VOC detection technology has resulted in low-cost sensors that can facilitate the self-monitoring of patients in the future if reliable breath markers are available. Therefore, it is of interest to investigate the composition of exhaled breath in children on KDs. Twenty-two pediatric patients between 4 and 18 years of age were recruited in this study. Eleven of them received a KD and suffered from epilepsy, with the exception of one child, who was admitted to a weight-reduction therapy. The control group involved 11 patients with neurological disorders but not on KD. Breath volatiles were analyzed using gas chromatography mass spectrometry (GC-MS) after preconcentration of the analytes on needle traps (NTs). We found that the breath concentrations of a number of VOCs, namely acetaldehyde, acetone, 2-methylfuran, methyl-vinyl-ketone, and 2-pentanone were significantly elevated in the breath of children on a KD in comparison to their control counterparts. Interestingly, breath ethanol was lower in patients on a KD than in non-KD patients. Association studies revealed an interrelationship among (i) lipid parameters and ketone bodies, (ii) methacrolein, methyl-vinyl-ketone, and high-density lipoprotein, as well as (iii) methyl-vinyl-ketone, acetone, and 2-pentanone, thus raising the possibility of a common metabolic source. The duration of diet was positively and negatively associated with breath acetone and breath ethanol, respectively. Some of the changes were linked to β-oxidation, but there are uncertainties in regard to metabolic sources of other metabolites. Lipid peroxidation and alteration of intestinal microbial composition may also be involved in the changes of VOC profiles during KD. Since lipids used for metabolism during KD originate from external sources, the processes occurring cannot simply be compared to and deduced from changes appearing in starvation; however, lipid mobilization is also evident in starvation. To find reliable and sensitive VOC markers that are linked to the respective ketogenic regimen, further investigations are needed to reveal the metabolic background.
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http://dx.doi.org/10.1088/1752-7163/aac4abDOI Listing
June 2018

Isolated choanal and gut atresias: pathogenetic role of serine protease inhibitor type 2 (SPINT2) gene mutations unlikely.

Eur J Med Res 2018 Mar 2;23(1):13. Epub 2018 Mar 2.

Department of Pediatrics I, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.

Background: Choanal (CA) and gastrointestinal atresias (GA) are an important feature of syndromic congenital sodium diarrhea (sCSD), a disorder recently associated with mutations in the gene for serine protease inhibitor type 2 (SPINT2). It is, however, not known whether isolated non-syndromic CA and GA themselves might result from SPINT2 mutations.

Methods: We performed a prospective cohort study to investigate 19 CA and/or GA patients without diarrhea ("non-sCSD") for potential sCSD characteristic clinical features and SPINT2 mutations.

Results: We found a heterozygous SPINT2 splice mutation (c.593-1G>A), previously demonstrated in sCSD in homozygous form, in only 1 of the 19 patients of the "non-sCSD" cohort. This patient presented with isolated anal atresia and borderline low laboratory parameters of sodium balance. In the remaining 18 non-sCSD CA/GA patients investigated, SPINT2 sequence analysis and clinical markers of sodium homeostasis were normal. None of the 188 healthy controls tested in a regional Tyrolean population harbored the c.593-1G>A mutation, which is also not listed in the ExAc and gnomAD databases.

Conclusions: The finding of only one heterozygous SPINT2 mutation in 19 patients with isolated CA/GA was not statistically significant. Therefore, SPINT2 mutations are an unlikely cause of non-sCSD atresia. Trial registration ISRCTN73824458. Retrospectively registered 28 September 2014.
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http://dx.doi.org/10.1186/s40001-018-0312-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834866PMC
March 2018

CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome.

Nat Commun 2017 06 12;8:15861. Epub 2017 Jun 12.

Global Health Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland.

Loss-of-function mutations in capillary morphogenesis gene 2 (CMG2/ANTXR2), a transmembrane surface protein, cause hyaline fibromatosis syndrome (HFS), a severe genetic disorder that is characterized by large subcutaneous nodules, gingival hypertrophy and severe painful joint contracture. Here we show that CMG2 is an important regulator of collagen VI homoeostasis. CMG2 loss of function promotes accumulation of collagen VI in patients, leading in particular to nodule formation. Similarly, collagen VI accumulates massively in uteri of Antxr2 mice, which do not display changes in collagen gene expression, and leads to progressive fibrosis and sterility. Crossing Antxr2 with Col6a1 mice leads to restoration of uterine structure and reversion of female infertility. We also demonstrate that CMG2 may act as a signalling receptor for collagen VI and mediates its intracellular degradation.
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http://dx.doi.org/10.1038/ncomms15861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472780PMC
June 2017