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1.
J Inherit Metab Dis ; 47(2): 220-229, 2024 03.
Artículo en Inglés | MEDLINE | ID: mdl-38375550

RESUMEN

Carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies are rare urea cycle disorders, which can lead to life-threatening hyperammonemia. Liver transplantation (LT) provides a cure and offers an alternative to medical treatment and life-long dietary restrictions with permanent impending risk of hyperammonemia. Nevertheless, in most patients, metabolic aberrations persist after LT, especially low plasma citrulline levels, with questionable clinical impact. So far, little is known about these alterations and there is no consensus, whether l-citrulline substitution after LT improves patients' symptoms and outcomes. In this multicentre, retrospective, observational study of 24 patients who underwent LT for CPS1 (n = 11) or OTC (n = 13) deficiency, 25% did not receive l-citrulline or arginine substitution. Correlation analysis revealed no correlation between substitution dosage and citrulline levels (CPS1, p = 0.8 and OTC, p = 1). Arginine levels after liver transplantation were normal after LT independent of citrulline substitution. Native liver survival had no impact on mental impairment (p = 0.67). Regression analysis showed no correlation between l-citrulline substitution and failure to thrive (p = 0.611) or neurological outcome (p = 0.701). Peak ammonia had a significant effect on mental impairment (p = 0.017). Peak plasma ammonia levels correlate with mental impairment after LT in CPS1 and OTC deficiency. Growth and intellectual impairment after LT are not significantly associated with l-citrulline substitution.


Asunto(s)
Hiperamonemia , Trasplante de Hígado , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa , Humanos , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/cirugía , Hiperamonemia/tratamiento farmacológico , Citrulina , Carbamoil Fosfato/metabolismo , Carbamoil Fosfato/uso terapéutico , Amoníaco/metabolismo , Estudios Retrospectivos , Carbamoil-Fosfato Sintasa (Amoniaco)/metabolismo , Arginina/uso terapéutico , Ornitina Carbamoiltransferasa
2.
Int J Mol Sci ; 25(10)2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38791454

RESUMEN

Previous omics research in patients with complex congenital heart disease and single-ventricle circulation (irrespective of the stage of palliative repair) revealed alterations in cardiac and systemic metabolism, inter alia abnormalities in energy metabolism, and inflammation, oxidative stress or endothelial dysfunction. We employed an affinity-proteomics approach focused on cell surface markers, cytokines, and chemokines in the serum of 20 adult Fontan patients with a good functioning systemic left ventricle, and we 20 matched controls to reveal any specific processes on a cellular level. Analysis of 349 proteins revealed 4 altered protein levels related to chronic inflammation, with elevated levels of syndecan-1 and glycophorin-A, as well as decreased levels of leukemia inhibitory factor and nerve growth factor-ß in Fontan patients compared to controls. All in all, this means that Fontan circulation carries specific physiological and metabolic instabilities, including chronic inflammation, oxidative stress imbalance, and consequently, possible damage to cell structure and alterations in translational pathways. A combination of proteomics-based biomarkers and the traditional biomarkers (uric acid, γGT, and cholesterol) performed best in classification (patient vs. control). A metabolism- and signaling-based approach may be helpful for a better understanding of Fontan (patho-)physiology. Syndecan-1, glycophorin-A, leukemia inhibitory factor, and nerve growth factor-ß, especially in combination with uric acid, γGT, and cholesterol, might be interesting candidate parameters to complement traditional diagnostic imaging tools and the determination of traditional biomarkers, yielding a better understanding of the development of comorbidities in Fontan patients, and they may play a future role in the identification of targets to mitigate inflammation and comorbidities in Fontan patients.


Asunto(s)
Biomarcadores , Proteínas Sanguíneas , Procedimiento de Fontan , Inflamación , Proteómica , Humanos , Adulto , Masculino , Inflamación/metabolismo , Femenino , Proteínas Sanguíneas/metabolismo , Procedimiento de Fontan/efectos adversos , Biomarcadores/sangre , Proteómica/métodos , Cardiopatías Congénitas/cirugía , Cardiopatías Congénitas/metabolismo , Cardiopatías Congénitas/sangre , Cardiopatías Congénitas/patología , Fibrosis , Adulto Joven , Neovascularización Patológica/metabolismo , Estrés Oxidativo , Angiogénesis
3.
Am J Hum Genet ; 107(2): 234-250, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32668217

RESUMEN

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.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Fenilcetonurias/epidemiología , Fenilcetonurias/genética , Alelos , Biopterinas/análogos & derivados , Biopterinas/genética , Europa (Continente) , Frecuencia de los Genes/genética , Estudios de Asociación Genética/métodos , Genotipo , Homocigoto , Humanos , Mutación/genética , Fenotipo , Fenilalanina/sangre , Fenilalanina Hidroxilasa/genética , Fenilcetonurias/sangre
4.
J Inherit Metab Dis ; 46(3): 482-519, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36221165

RESUMEN

Glutaric aciduria type 1 is a rare inherited neurometabolic disorder of lysine metabolism caused by pathogenic gene variations in GCDH (cytogenic location: 19p13.13), resulting in deficiency of mitochondrial glutaryl-CoA dehydrogenase (GCDH) and, consequently, accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid and glutarylcarnitine detectable by gas chromatography/mass spectrometry (organic acids) and tandem mass spectrometry (acylcarnitines). Depending on residual GCDH activity, biochemical high and low excreting phenotypes have been defined. Most untreated individuals present with acute onset of striatal damage before age 3 (to 6) years, precipitated by infectious diseases, fever or surgery, resulting in irreversible, mostly dystonic movement disorder with limited life expectancy. In some patients, striatal damage develops insidiously. In recent years, the clinical phenotype has been extended by the finding of extrastriatal abnormalities and cognitive dysfunction, preferably in the high excreter group, as well as chronic kidney failure. Newborn screening is the prerequisite for pre-symptomatic start of metabolic treatment with low lysine diet, carnitine supplementation and intensified emergency treatment during catabolic episodes, which, in combination, have substantially improved neurologic outcome. In contrast, start of treatment after onset of symptoms cannot reverse existing motor dysfunction caused by striatal damage. Dietary treatment can be relaxed after the vulnerable period for striatal damage, that is, age 6 years. However, impact of dietary relaxation on long-term outcomes is still unclear. This third revision of evidence-based recommendations aims to re-evaluate previous recommendations (Boy et al., J Inherit Metab Dis, 2017;40(1):75-101; Kolker et al., J Inherit Metab Dis 2011;34(3):677-694; Kolker et al., J Inherit Metab Dis, 2007;30(1):5-22) and to implement new research findings on the evolving phenotypic diversity as well as the impact of non-interventional variables and treatment quality on clinical outcomes.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Encefalopatías Metabólicas , Humanos , Glutaril-CoA Deshidrogenasa , Lisina/metabolismo , Encefalopatías Metabólicas/diagnóstico , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/terapia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Glutaratos/metabolismo
5.
Cell Mol Life Sci ; 79(11): 562, 2022 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-36271951

RESUMEN

Multifunctional proteins are challenging as it can be difficult to confirm pathomechanisms associated with disease-causing genetic variants. The human 17ß-hydroxysteroid dehydrogenase 10 (HSD10) is a moonlighting enzyme with at least two structurally and catalytically unrelated functions. HSD10 disease was originally described as a disorder of isoleucine metabolism, but the clinical manifestations were subsequently shown to be linked to impaired mtDNA transcript processing due to deficient function of HSD10 in the mtRNase P complex. A surprisingly large number of other, mostly enzymatic and potentially clinically relevant functions have been attributed to HSD10. Recently, HSD10 was reported to exhibit phospholipase C-like activity towards cardiolipins (CL), important mitochondrial phospholipids. To assess the physiological role of the proposed CL-cleaving function, we studied CL architectures in living cells and patient fibroblasts in different genetic backgrounds and lipid environments using our well-established LC-MS/MS cardiolipidomic pipeline. These experiments revealed no measurable effect on CLs, indicating that HSD10 does not have a physiologically relevant function towards CL metabolism. Evolutionary constraints could explain the broad range of reported substrates for HSD10 in vitro. The combination of an essential structural with a non-essential enzymatic function in the same protein could direct the evolutionary trajectory towards improvement of the former, thereby increasing the flexibility of the binding pocket, which is consistent with the results presented here.


Asunto(s)
3-Hidroxiacil-CoA Deshidrogenasas , Hidroxiesteroide Deshidrogenasas , Humanos , 3-Hidroxiacil-CoA Deshidrogenasas/genética , 3-Hidroxiacil-CoA Deshidrogenasas/metabolismo , Cardiolipinas , Cromatografía Liquida , Espectrometría de Masas en Tándem , ADN Mitocondrial , Fosfolipasas de Tipo C
6.
Mol Genet Metab ; 137(3): 308-322, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36274442

RESUMEN

Propionic acidemia (PA) is an inherited metabolic disorder of propionate metabolism, where the gut microbiota may play a role in pathophysiology and therefore, represent a relevant therapeutic target. Little is known about the gut microbiota composition and activity in patients with PA. Although clinical practice varies between metabolic treatment centers, management of PA requires combined dietary and pharmaceutical treatments, both known to affect the gut microbiota. This study aimed to characterize the gut microbiota and its metabolites in fecal samples of patients with PA compared with healthy controls from the same household. Eight patients (aged 3-14y) and 8 controls (4-31y) were recruited from Center 1 (UK) and 7 patients (11-33y) and 6 controls (15-54y) from Center 2 (Austria). Stool samples were collected 4 times over 3 months, alongside data on dietary intakes and medication usage. Several microbial taxa differed between patients with PA and controls, particularly for Center 1, e.g., Proteobacteria levels were increased, whereas butyrate-producing genera, such as Roseburia and Faecalibacterium, were decreased. Most measured microbial metabolites were lower in patients with PA, and butyrate was particularly depleted in patients from Center 1. Furthermore, microbiota profile of these patients showed the lowest compositional and functional diversity, and lowest stability over 3 months. As the first study to map the gut microbiota of patients with PA, this work represents an important step forward for developing new therapeutic strategies to further improve PA clinical status. New dietary strategies should consider microbial propionate production as well as butyrate production and microbiota stability.


Asunto(s)
Microbioma Gastrointestinal , Acidemia Propiónica , Humanos , Propionatos , Heces/microbiología , Butiratos
7.
J Inherit Metab Dis ; 45(2): 144-156, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34595757

RESUMEN

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare disorders characterized by disruption of metabolic pathways. To date, data on incidence and prevalence of IMDs are limited. Taking advantage of a functioning network within the Austrian metabolic group, our registry research aimed to update the data of the "Registry for Inherited Metabolic Disorders" started between 1985 and 1995 with retrospectively retrieved data on patients with IMDs according to the Society for the Study of Inborn Errors of Metabolism International Classification of Diseases 11 (SSIEM ICD11) catalogue. Included in this retrospective register were 2631 patients with an IMD according to the SSIEM ICD11 Classification, who were treated in Austria. Thus, a prevalence of 1.8/10 000 for 2020 and a median minimal birth prevalence of 16.9/100 000 (range 0.7/100 000-113/100 000) were calculated for the period 1921 to February 2021. We detected a male predominance (m:f = 1.2:1) and a mean age of currently alive patients of 17.6 years (range 5.16 months-100 years). Most common diagnoses were phenylketonuria (17.7%), classical galactosaemia (6.6%), and biotinidase deficiency (4.2%). The most common diagnosis categories were disorders of amino acid and peptide metabolism (819/2631; 31.1%), disorders of energy metabolism (396/2631; 15.1%), and lysosomal disorders (395/2631; 15.0%). In addition to its epidemiological relevance, the "Registry for Inherited Metabolic Disorders" is an important tool for enhancing an exchange between care providers. Moreover, by pooling expertise it prospectively improves patient treatment, similar to pediatric oncology protocols. A substantial requirement for ful filling this goal is to regularly update the registry and provide nationwide coverage with inclusion of all medical specialties.


Asunto(s)
Enfermedades Metabólicas , Errores Innatos del Metabolismo , Austria/epidemiología , Niño , Femenino , Humanos , Lactante , Masculino , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/epidemiología , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/epidemiología , Prevalencia , Sistema de Registros , Estudios Retrospectivos
8.
Pediatr Emerg Care ; 38(2): e639-e643, 2022 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-34267157

RESUMEN

OBJECTIVES: The Manchester Triage System (MTS) has entered widespread international use in emergency departments (EDs). This retrospective study analyzes urgency of patient visits (PV) at the ED of the Clinic for Pediatrics at the Medical University of Innsbruck. METHODS: We collected demographic and outcome information, including PV urgency levels (UL) according to the MTS, for 3 years (2015-2018), separating PV during regular office hours (ROH; 8:00 am to 5:00 pm) from PV during afternoon and night hours (5:00 pm to 8:00 am), and PV on weekdays from PV on weekends and bank holidays (WE). RESULTS: A total of 56,088 PV were registered with a UL. Most (68.4%) PV were classified as nonurgent. During ROH, more PV per hour (PV/h) were recorded than during afternoon and night hours (3.0 PV/h vs 1.6 PV/h), with a higher proportion of less urgent cases during ROH. On WE, the amount of PV/h was higher than on weekdays (3.6 PV/h vs 2.8 PV/h), with a higher proportion of nonurgent cases (74.6% vs 68.6%). Likelihoods of inpatient admission and hospital stay lengths increased in step with UL. CONCLUSIONS: The MTS proved useful for delineating UL distributions. The MTS analyses may be of value in managing EDs. Prompted by the results of our study, a general practice pediatric care unit was established to support the ED during WE.


Asunto(s)
Servicio de Urgencia en Hospital , Triaje , Austria , Niño , Hospitales Universitarios , Humanos , Estudios Retrospectivos
9.
Genet Med ; 23(1): 202-210, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32807972

RESUMEN

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.


Asunto(s)
Catarata , Galactoquinasa/deficiencia , Galactosemias , Galactoquinasa/genética , Galactosemias/epidemiología , Galactosemias/genética , Homocigoto , Humanos , Recién Nacido , Sistema de Registros
10.
Mol Genet Metab ; 133(3): 257-260, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34083143

RESUMEN

BACKGROUND: High rates of lost to follow-up (LTFU) adult patients are a major concern in the long-term management of phenylketonuria (PKU). To address this issue, we designed the project "Backtoclinic" with the purpose of identifying LTFU adult PKU patients in Austria as a first step to reestablish appropriate treatment. SUBJECTS AND METHODS: Individuals born between 1966 and 1999 and diagnosed with PKU through the National Austrian Newborn Screening Program (NANSP) were identified using the NANSP's database. Follow-up data were collected in the Austrian metabolic centers (Medical University of Vienna, Graz, Innsbruck and Salzburg). Patients with no contact to any of these centers within the previous two years were classified as LTFU. Epidemiological characteristics of the whole study population as well as of LTFU- and currently in follow-up patients were analyzed. RESULTS: Between 1966 and 1999, 281 individuals were diagnosed with PKU through the NANSP. Two patients died in their first year of life and were excluded from the analysis. Of the remaining 279 patients (mean age ± SD: 36.7 ± 9.1 y, 42.7% females), 177 (63.4%) are currently LTFU. The rate of LTFU patients is higher in men than in women (68.1% vs 57.5%), and markedly increases with age in both sexes. The gender gap is greatest in young adults (52.6% vs. 25.0% in the age range 20.0-24.9 y) and declines with age (94.4% vs. 80.0% in the age range > 45.0 y). CONCLUSIONS: We found an alarming rate of 63.4% of LTFU adult PKU patients in Austria, and observed a gender gap in the PKU state of care. Our findings illustrate the urgent need for the metabolic community to identify LTFU adult PKU patients and to develop strategies to reestablish appropriate treatment for men and women with PKU.


Asunto(s)
Perdida de Seguimiento , Fenilcetonurias/diagnóstico , Fenilcetonurias/tratamiento farmacológico , Adulto , Factores de Edad , Instituciones de Atención Ambulatoria , Austria , Manejo de la Enfermedad , Femenino , Humanos , Recién Nacido , Masculino , Persona de Mediana Edad , Tamizaje Neonatal , Fenilcetonurias/epidemiología , Factores Sexuales
11.
J Inherit Metab Dis ; 44(3): 566-592, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33595124

RESUMEN

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.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Acidemia Propiónica/diagnóstico , Acidemia Propiónica/terapia , Manejo de la Enfermedad , Humanos
12.
Neuropediatrics ; 52(6): 423-430, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34233372

RESUMEN

Based on a patient encounter in which genetically confirmed Marfan's syndrome (MFS) underlay a spontaneously resolving subdural hygroma (SDHy) diagnosed in infancy, we review the literature of MFS clinically manifest in early life (early-onset MFS [EOMFS]) and of differential diagnoses of SDHy and subdural hemorrhage (SDHe) at this age. We found that rare instances of SDHy in the infant are associated with EOMFS. The most likely triggers are minimal trauma in daily life or spontaneous intracranial hypotension. The differential diagnosis of etiologies of SDHy include abusive and nonabusive head trauma, followed by perinatal events and infections. Incidental SDHy and benign enlargement of the subarachnoid spaces must further be kept in mind. SDHy exceptionally also may accompany orphan diseases. Thus, in the infant, EOMFS should be considered as a cause of SDHe and/or SDHy. Even in the absence of congestive heart failure, the combination of respiratory distress syndrome, muscular hypotonia, and joint hyperflexibility signals EOMFS. If EOMFS is suspected, monitoring is indicated for development of SDHe and SDHy with or without macrocephaly. Close follow-up is mandatory.


Asunto(s)
Traumatismos Craneocerebrales , Síndrome de Marfan , Efusión Subdural , Hematoma Subdural/complicaciones , Hematoma Subdural/diagnóstico , Humanos , Lactante , Síndrome de Marfan/complicaciones , Síndrome de Marfan/diagnóstico , Espacio Subaracnoideo , Efusión Subdural/complicaciones
13.
Genet Med ; 22(5): 908-916, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31904027

RESUMEN

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.


Asunto(s)
Cardiomiopatías , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa , Ácido 3-Hidroxibutírico , Acil-CoA Deshidrogenasa/genética , Humanos , Lactante , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/tratamiento farmacológico , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/genética , Estudios Retrospectivos
14.
Metabolomics ; 16(12): 128, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-33319318

RESUMEN

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).


Asunto(s)
Aminoácidos/sangre , Cromatografía Líquida de Alta Presión , Cardiopatías Congénitas/sangre , Cardiopatías Congénitas/diagnóstico , Ninhidrina , Espectrometría de Masas en Tándem , Biomarcadores , Estudios de Casos y Controles , Cromatografía Líquida de Alta Presión/métodos , Humanos , Metabolómica/métodos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem/métodos
15.
Mod Pathol ; 32(6): 755-763, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30723298

RESUMEN

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).


Asunto(s)
Enfermedades por Almacenamiento Lisosomal/diagnóstico , Enfermedades por Almacenamiento Lisosomal/patología , Piel/ultraestructura , Adolescente , Adulto , Biopsia , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Estudios Retrospectivos , Piel/patología , Adulto Joven
17.
Acta Paediatr ; 108(10): 1861-1866, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30968969

RESUMEN

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.


Asunto(s)
Anquiloglosia/cirugía , Frenillo Lingual/cirugía , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Estudios Retrospectivos
18.
Am J Hum Genet ; 96(2): 309-17, 2015 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-25658047

RESUMEN

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.


Asunto(s)
Ataxia/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Debilidad Muscular/genética , Fenotipo , Ubiquinona/deficiencia , Secuencia de Aminoácidos , Ataxia/patología , Secuencia de Bases , Exoma/genética , Resultado Fatal , Femenino , Componentes del Gen , Humanos , Masculino , Enfermedades Mitocondriales/patología , Datos de Secuencia Molecular , Debilidad Muscular/patología , Mutación/genética , Linaje , Saccharomyces cerevisiae , Análisis de Secuencia de ADN , Ubiquinona/genética
19.
Pediatr Res ; 81(5): 787-794, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28141791

RESUMEN

BACKGROUND: Amino acid analysis is a valuable tool for cardiovascular risk assessment. Preterm infants display plasma amino acid changes in the newborn period. Whether these changes persist is unknown to date. The aim of this study was to assess whether former very preterm infants (VPI) show alterations in amino acid patterns indicative of an unfavorable cardiovascular risk profile at a preschool age. METHODS: From 5-7 y-old children born at term or <32 wk gestation (VPI) were included in the study. Plasma amino acid concentrations were determined after an overnight fast. RESULTS: 29 former term infants and 79 former VPI were included in the study. Former VPI showed changes in various plasma amino acids including glutamine, arginine, citrulline, tryptophan, glutamate, ornithine, and taurine. Branched-chain amino acids were lower, alanine/lysine ratios significantly higher in the preterm population. CONCLUSION: Former VPI show altered plasma amino acid profiles indicative of a dualistic cardiovascular risk profile (e.g., potentially beneficial elevations in citrulline, arginine, glutamine, and tryptophan, but also raised alanine/lysine ratios, low ornithine and taurine levels) at a preschool age. Whether this is associated with an adverse cardiovascular outcome has to be addressed by future studies. Long-term cardiometabolic follow-up of VPI might be warranted.


Asunto(s)
Aminoácidos/sangre , Enfermedades Cardiovasculares/etiología , Desarrollo Infantil , Recien Nacido Prematuro/crecimiento & desarrollo , Factores de Edad , Austria , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/fisiopatología , Niño , Preescolar , Femenino , Edad Gestacional , Humanos , Recién Nacido , Masculino , Pronóstico , Factores de Riesgo
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