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1.
J Inherit Metab Dis ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373028

RESUMO

INTRODUCTION: Primary Carnitine Deficiency (PCD) affects fatty acid oxidation and is associated with cardiomyopathy and cardiac arrhythmia, but the risk of sudden death in PCD is unknown. The Faroe Islands have a high prevalence of PCD, 1:300. This study systematically investigated a possible association between untreated PCD and sudden death in young Faroese subjects. METHODS: We investigated all medico-legal cases of sudden death between 1979-2012 among subjects below the age of 45. Stored biomaterial was examined with molecular genetic analysis to reveal PCD. We compared the prevalence of PCD among sudden death cases with that of the background population (0.23%) to calculate the odds ratio for sudden death with PCD. RESULTS: Biomaterial was available and genetically analyzed from 53 of 65 sudden death cases (82%) in the Faroe Islands. Six (one male and five females) of the 53 cases were homozygous for the PCD related c.95A>G mutation - a prevalence of 11.3% (95%CI 5-23%) and an odds ratio of 54.3 (95% CI 21-138, p<0.0001) for the association between sudden death and untreated PCD. Only 11 of the 53 sudden death cases were women - of whom five were homozygous for the c.95A>G mutation (45.5%) yielding an odds ratio of 348.8 (95% CI 94-1,287, p<0.0001) for the association between sudden death and untreated PCD in females. CONCLUSION: This study showed a strong association between sudden death and untreated PCD, especially in females. This article is protected by copyright. All rights reserved.

2.
Adv Ther ; 36(7): 1786-1811, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31102204

RESUMO

INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) is a rare, autosomal disease affecting the clearance of low-density lipoprotein cholesterol (LDL-C) from circulation, and leading to early-onset atherosclerotic cardiovascular disease (ASCVD). Treatment consists mainly of statins, lipoprotein apheresis (LA) and, more recently, the microsomal triglyceride transfer protein inhibitor lomitapide. Lomitapide is not licensed for use in children, but has been made available through an expanded access programme or on a named patient basis. METHODS: This case series includes 11 HoFH patients in 10 different centres in eight countries, less than 18 years of age (mean 11.6 ± 1.1 years, 64% male), with signs of ASCVD, and who have received treatment with lomitapide (mean dose 24.5 ± 4.3 mg/day; mean exposure 20.0 ± 2.9 months). Background lipid-lowering therapy was given according to local protocols. Lomitapide was commenced with a stepwise dose escalation from 2.5 mg or 5 mg/day; dietary advice and vitamin supplements were provided as per the product label for adults. Laboratory analysis was conducted as part of regular clinical care. RESULTS: In the 11 cases, mean baseline LDL-C was 419 ± 74.6 mg/dL and was markedly reduced by lomitapide to a nadir of 176.7 ± 46.3 mg/dL (58.4 ± 6.8% decrease). Six patients achieved recommended target levels for children below 135 mg/dL, five of whom had LA frequency reduced. In one case, LDL-C levels were close to target when lomitapide was started but remained stable despite 75% reduction in LA frequency (from twice weekly to biweekly). Adverse events were mainly gastrointestinal in nature, occurred early in the treatment course and were well managed. Three patients with excursions in liver function tests were managed chiefly without intervention; two patients had decreases in lomitapide dose. CONCLUSIONS: Lomitapide demonstrated promising effectiveness in paediatric HoFH patients. Adverse events were manageable, and the clinical profile of the drug is apparently similar to that in adult patients. FUNDING: Amryt Pharma.

3.
Mol Genet Metab ; 126(4): 397-405, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30827756

RESUMO

BACKGROUND AND AIM: Patients with methylmalonic acidemia (MMA) and propionic acidemia (PA) and urea cycle disorders (UCD), treated with a protein restricted diet, are prone to growth failure. To obtain optimal growth and thereby efficacious protein incorporation, a diet containing the essential and functional amino acids for growth is necessary. Optimal growth will result in improved protein tolerance and possibly a decrease in the number of decompensations. It thus needs to be determined if amino acid deficiencies are associated with the growth retardation in these patient groups. We studied the correlations between plasma L-arginine levels, plasma branched chain amino acids (BCAA: L-isoleucine, L-leucine and L-valine) levels (amino acids known to influence growth), and height in MMA/PA and UCD patients. METHODS: We analyzed data from longitudinal visits made in stable metabolic periods by patients registered at the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD, Chafea no. 2010 12 01). RESULTS: In total, 263 MMA/PA and 311 UCD patients were included, all aged below 18 years of age. In patients with MMA and PA, height z-score was positively associated with patients' natural-protein-to-energy prescription ratio and their plasma L-valine and L-arginine levels, while negatively associated with the amount of synthetic protein prescription and their age at visit. In all UCDs combined, height z-score was positively associated with the natural-protein-to-energy prescription ratio. In those with carbamylphosphate synthetase 1 deficiency (CPS1-D), those with male ornithine transcarbamylase deficiency (OTC-D), and those in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome subgroup, height z-score was positively associated with patients' plasma L-leucine levels. In those with argininosuccinate synthetase deficiency (ASS-D) and argininosuccinate lyase deficiency (ASL-D), height was positively associated with patients' plasma L-valine levels. CONCLUSION: Plasma L-arginine and L-valine levels in MMA/PA patients and plasma L-leucine and L-valine levels in UCD patients, as well as the protein-to-energy prescription ratio in both groups were positively associated with height. Optimization of these plasma amino acid levels is essential to support normal growth and increase protein tolerance in these disorders. Consequently this could improve the protein-to-energy intake ratio.

4.
Mol Vis ; 25: 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30820140

RESUMO

Purpose: To identify the mutation for Volkmann cataract (CTRCT8) at 1p36.33. Methods: The genes in the candidate region 1p36.33 were Sanger and parallel deep sequenced, and informative single nucleotide polymorphisms (SNPs) were identified for linkage analysis. Expression analysis with reverse transcription polymerase chain reaction (RT-PCR) of the candidate gene was performed using RNA from different human tissues. Quantitative transcription polymerase chain reaction (qRT-PCR) analysis of the GNB1 gene was performed in affected and healthy individuals. Bioinformatic analysis of the linkage regions including the candidate gene was performed. Results: Linkage analysis of the 1p36.33 CCV locus applying new marker systems obtained with Sanger and deep sequencing reduced the candidate locus from 2.1 Mb to 0.389 Mb flanked by the markers STS-22AC and rs549772338 and resulted in an logarithm of the odds (LOD) score of Z = 21.67. The identified mutation, rs763295804, affects the donor splice site in the long non-coding RNA gene RP1-140A9.1 (ENSG00000231050). The gene including splice-site junctions is conserved in primates but not in other mammalian genomes, and two alternative transcripts were shown with RT-PCR. One of these transcripts represented a lens cell-specific transcript. Meta-analysis of the Cross-Linking-Immuno-Precipitation sequencing (CLIP-Seq) data suggested the RNA binding protein (RBP) eIF4AIII is an active counterpart for RP1-140A9.1, and several miRNA and transcription factors binding sites were predicted in the proximity of the mutation. ENCODE DNase I hypersensitivity and histone methylation and acetylation data suggest the genomic region may have regulatory functions. Conclusions: The mutation in RP1-140A9.1 suggests the long non-coding RNA as the candidate cataract gene associated with the autosomal dominant inherited congenital cataract from CCV. The mutation has the potential to destroy exon/intron splicing of both transcripts of RP1-140A9.1. Sanger and massive deep resequencing of the linkage region failed to identify alternative candidates suggesting the mutation in RP1-140A9.1 is causative for the CCV phenotype.


Assuntos
Catarata/congênito , Cromossomos Humanos Par 1/química , Mutação , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Acetilação , Adulto , Sequência de Bases , Sítios de Ligação , Catarata/diagnóstico , Catarata/genética , Catarata/patologia , Fator de Iniciação 4A em Eucariotos/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Éxons , Família , Feminino , Genes Dominantes , Loci Gênicos , Marcadores Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Histonas/genética , Histonas/metabolismo , Humanos , Íntrons , Masculino , Metilação , Pessoa de Meia-Idade , Linhagem , Sítios de Splice de RNA , Processamento de RNA , RNA Longo não Codificante/metabolismo , RNA Mensageiro/metabolismo
5.
J Inherit Metab Dis ; 42(1): 128-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30740731

RESUMO

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

6.
J Inherit Metab Dis ; 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30734935

RESUMO

Organic acidurias (OAD) and urea-cycle disorders (UCD) are rare inherited disorders affecting amino acid and protein metabolism. As dietary practice varies widely, we assessed their long-term prescribed dietary treatment against published guideline and studied plasma amino acids levels. We analyzed data from the first visit recorded in the European registry and network for intoxication type metabolic diseases (E-IMD, Chafea no. 2010 12 01). In total, 271 methylmalonic aciduria (MMA) and propionic aciduria (PA) and 361 UCD patients were included. Median natural protein prescription was consistent with the recommended daily allowance (RDA), plasma L-valine (57%), and L-isoleucine (55%) levels in MMA and PA lay below reference ranges. Plasma levels were particularly low in patients who received amino acid mixtures (AAMs-OAD) and L-isoleucine:L-leucine:L-valine (BCAA) ratio was 1.0:3.0:3.2. In UCD patients, plasma L-valine, L-isoleucine, and L-leucine levels lay below reference ranges in 18%, 30%, and 31%, respectively. In symptomatic UCD patients who received AAM-UCD, the median natural protein prescription lay below RDA, while their L-valine and L-isoleucine levels and plasma BCAA ratios were comparable to those in patients who did not receive AAM-UCD. Notably, in patients with ornithine transcarbamylase syndrome (OTC-D), carbamylphosphate synthetase 1 syndrome (CPS1-D) and hyperammonemia-hyperornithinemia-homocitrullinemia (HHH) syndrome selective L-citrulline supplementation resulted in higher plasma L-arginine levels than selective L-arginine supplementation. In conclusion, while MMA and PA patients who received AAMs-OAD had very low BCAA levels and disturbed plasma BCAA ratios, AAMs-UCD seemed to help UCD patients obtain normal BCAA levels. In patients with OTC-D, CPS1-D, and HHH syndrome, selective L-citrulline seemed preferable to selective L-arginine supplementation.

7.
J Inherit Metab Dis ; 42(2): 333-352, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30773687

RESUMO

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.

8.
Nephrol Dial Transplant ; 34(9): 1525-1533, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535327

RESUMO

BACKGROUND: Nephropathy is common in Fabry disease (FD). Prior studies of renal function during enzyme replacement therapy (ERT) have primarily used estimated glomerular filtration rate (eGFR). We studied the attrition of renal function in FD by measured GFR (mGFR) and urine protein excretion, and explored the influence of age. METHODS: This was a long-term observational study of a nationwide, family-screened cohort of FD patients. All Danish genetically verified FD patients on ERT, without end-stage renal disease at baseline and with three or more mGFR values were included. RESULTS: In all, 52 patients with consecutive mGFR values (n = 841) over median 7 years (range 1-13) were evaluated. Blood pressure remained normal and urine protein excretion was unchanged. Plasma globotriaosylceramide (Gb-3) levels normalized while plasma lyso-Gb-3 remained abnormal in 34% of patients. Baseline mGFR was 90 ± 3 mL/min/1.73 m2 and rate of renal function loss 0.9 ± 0.2 mL/min/1.73 m2/year. Baseline eGFR was 97 ± 5 mL/min/1.73 m2 and rate of renal function loss 0.8 ± 0.3 mL/min/1.73 m2/year. mGFR was age- adjusted to renal healthy non-FD subjects, giving a standard deviation score of -0.8 ± 0.2 with an annual slope of -0.03 ± 0.01 (P = 0.099), without differences between genders. Age grouping of age-adjusted data showed exaggerated renal function loss with age. Urine albumin-creatinine ratio (UACR) >300 mg/g was associated with faster renal function loss, independent of baseline mGFR, age and gender. CONCLUSIONS: ERT-treated FD patients did not have a faster attrition of renal function than renal healthy non-FD subjects (background population). The rate of renal function loss with age was independent of gender and predicted by high UACR. We suggest cautious interpretation of non-age-adjusted FD renal data.

9.
Acta Paediatr ; 107(12): 2059-2065, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30242902

RESUMO

AIM: Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening. METHODS: An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I. It consisted of 13 experts in paediatrics, rare diseases and inherited metabolic diseases from Europe and the Middle East. RESULTS: It is becoming increasingly clearer that the delay between symptom onset and clinical diagnosis is considerable for mucopolysaccharidosis type I and other rare lysosomal storage disorders, despite numerous awareness campaigns since therapies became available. Diagnosis currently depends on recognising the signs and symptoms of the disease. The practice of newborn screening, which is being explored by pilot programmes around the world, enables early diagnosis and consequently early treatment. However, these studies have highlighted numerous new problems and pitfalls that must be faced before newborn screening becomes generally available. CONCLUSION: Newborn screening for mucopolysaccharidosis type I offers the potential for early diagnosis and early pre-symptomatic treatment, but existing hurdles need to be overcome.

10.
Pediatr Res ; 84(2): 228-232, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29892033

RESUMO

BACKGROUND: Galactosemia has not been recognized as a cause of extreme neonatal hyperbilirubinemia, although growing evidence supports this association. METHODS: In a retrospective cohort study, we identified children with galactosemia due to GALT deficiency using the Danish Metabolic Laboratory Database. Among these, we identified children with extreme neonatal hyperbilirubinemia or symptoms of ABE. Extreme neonatal hyperbilirubinemia was defined as maximum total serum bilirubin (TSBmax)) level ≥450 µmol/L and a ratio of conjugated serum bilirubin/TSB <0.30. RESULTS: We identified 21 children with galactosemia (incidence:1:48,000). Seven children developed extreme neonatal hyperbilirubinemia (median [range] TSBmax level: 491 [456-756] µmol/L), accounting for 1.7% of all extreme neonatal hyperbilirubinemia cases. During the first 10 days of life, hyperbilirubinemia was predominantly of unconjugated type. Four children developed symptoms of intermediate/advanced ABE. One additional child had symptoms of intermediate/advanced ABE without having extreme neonatal hyperbilirubinemia. On follow-up, one child had KSD. CONCLUSIONS: Galactosemia is a potential cause of extreme neonatal hyperbilirubinemia, ABE, and KSD. It is crucial that putative galactosemic children are treated aggressively with phototherapy to prevent ABE and KSD. Thus it is important that galactosemia is part of the work up for unconjugated hyperbilirubinemia.

11.
J Inherit Metab Dis ; 2018 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-29846843

RESUMO

INTRODUCTION: This phase III, double-blind, randomised, placebo-controlled trial (and extension phase) was designed to assess the efficacy and safety of velmanase alfa (VA) in alpha-mannosidosis (AM) patients. METHODS: Twenty-five patients were randomised to weekly 1 mg/kg VA or placebo for 52 weeks. At study conclusion, placebo patients switched to VA; 23 patients continued receiving VA in compassionate-use/follow-on studies and were evaluated in the extension phase [last observation (LO)]. Co-primary endpoints were changes in serum oligosaccharide (S-oligo) and in the 3-min stair-climb test (3MSCT). RESULTS: Mean relative change in S-oligo in the VA arm was -77.6% [95% confidence interval (CI) -81.6 to -72.8] at week 52 and -62.9% (95% CI -85.8 to -40.0) at LO; mean relative change in the placebo arm was -24.1% (95% CI -40.3 to -3.6) at week 52 and -55.7% (95% CI -76.4 to -34.9) at LO after switch to active treatment. Mean relative change in 3MSCT at week 52 was -1.1% (95% CI -9.0 to 7.6) and - % (95% CI -13.4 to 6.5) for VA and placebo, respectively. At LO, the mean relative change was 3.9% (95% CI -5.5 to 13.2) in the VA arm and 9.0% (95% CI -10.3 to 28.3) in placebo patients after switch to active treatment. Similar improvement pattern was observed in secondary parameters. A post hoc analysis investigated whether some factors at baseline could account for treatment outcome; none of those factors were predictive of the response to VA, besides age. CONCLUSIONS: These findings support the utility of VA for the treatment of AM, with more evident benefit over time and when treatment is started in the paediatric age.

12.
Acta Paediatr ; 107(8): 1402-1408, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29797470

RESUMO

AIM: The aim of this study was to develop an algorithm to prompt early clinical suspicion of mucopolysaccharidosis type I (MPS I). METHODS: An international working group was established in 2016 that comprised 11 experts in paediatrics, rare diseases and inherited metabolic diseases. They reviewed real-world clinical cases, selected key signs or symptoms based on their prevalence and specificity and reached consensus about the algorithm. The algorithm was retrospectively tested. RESULTS: An algorithm was developed. In patients under two years of age, kyphosis or gibbus deformity were the key symptoms that raised clinical suspicion of MPS I and in those over two years they were kyphosis or gibbus deformity, or joint stiffness or contractures without inflammation. The algorithm was tested on 35 cases, comprising 16 Hurler, 10 Hurler-Scheie, and nine Scheie patients. Of these 35 cases, 32 (91%) - 16 Hurler, nine Hurler-Scheie and seven Scheie patients - would have been referred earlier if the algorithm had been used. CONCLUSION: The expert panel developed and tested an algorithm that helps raise clinical suspicion of MPS I and would lead to a more prompt final diagnosis and allow earlier treatment.

13.
J Inherit Metab Dis ; 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29725868

RESUMO

INTRODUCTION: Long-term outcome data provide important insights into the clinical utility of enzyme replacement therapies. Such data are presented for velmanase alfa in the treatment of alpha-mannosidosis (AM). METHODS: Patient data (n = 33; 14 adults, 19 paediatric) from the clinical development programme for velmanase alfa were integrated in this prospectively-designed analysis of long-term efficacy and safety. Patients who participated in the phase I/II or phase III trials and were continuing to receive treatment after completion of the trials were invited to participate in a comprehensive evaluation visit to assess long-term outcomes. Primary endpoints were changes in serum oligosaccharide and the 3-minute stair climb test (3MSCT). RESULTS: Mean (SD) treatment exposure was 29.3 (15.2) months. Serum oligosaccharide levels were significantly reduced in the overall population at 12 months (mean change: -72.7%, P < 0.001) and remained statistically significant at last observation (-62.8%, P < 0.001). A mean improvement of +9.3% in 3MSCT was observed at 12 months (P = 0.013), which also remained statistically significant at last observation (+13.8%, P = 0.004), with a more pronounced improvement detected in the paediatric subgroup. No treatment-emergent adverse events were reported leading to permanent treatment discontinuation. CONCLUSIONS: Patients treated with velmanase alfa experienced improvements in biochemical and functional measures that were maintained for up to 4 years. Long term follow-up is important and further supports the use of velmanase alfa as an effective and well-tolerated treatment for AM. Based on the currently available data set, no baseline characteristic can be predictive of treatment outcome. Early treatment during paediatric age showed better outcome in functional endpoints.

14.
J Nutr Metab ; 2018: 6352919, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29511574

RESUMO

Introduction: Management of phenylketonuria (PKU) is achieved through low-phenylalanine (Phe) diet, supplemented with low-protein food and mixture of free-synthetic (FS) amino acid (AA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese-making and does not contain Phe. Lacprodan® CGMP-20 used in this study contained a small amount of Phe due to minor presence of other proteins/peptides. Objective: The purpose of this study was to compare absorption of CGMP-20 to FSAA with the aim of evaluating short-term effects on plasma AAs as well as biomarkers related to food intake. Methods: This study included 8 patients, who had four visits and tested four drink mixtures (DM1-4), consisting of CGMP, FSAA, or a combination. Plasma blood samples were collected at baseline, 15, 30, 60, 120, and 240 minutes (min) after the meal. AA profiles and ghrelin were determined 6 times, while surrogate biomarkers were determined at baseline and 240 min. A visual analogue scale (VAS) was used for evaluation of taste and satiety. Results: The surrogate biomarker concentrations and VAS scores for satiety and taste were nonsignificant between the four DMs, and there were only few significant results for AA profiles (not Phe). Conclusion: CGMP and FSAA had the overall same nonsignificant short-term effect on biomarkers, including Phe. This combination of FSAA and CGMP is a suitable supplement for PKU patients.

17.
Am J Physiol Gastrointest Liver Physiol ; 314(1): G91-G96, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28971838

RESUMO

Patients with type 2 diabetes (T2D) and patients with nonalcoholic fatty liver disease (NAFLD) frequently exhibit elevated plasma concentrations of glucagon (hyperglucagonemia). Hyperglucagonemia and α-cell hyperplasia may result from elevated levels of plasma amino acids when glucagon's action on hepatic amino acid metabolism is disrupted. We therefore measured plasma levels of glucagon and individual amino acids in patients with and without biopsy-verified NAFLD and with and without type T2D. Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease. Elevated levels of total amino acids were observed in participants with NAFLD and NGT compared with NGT controls (1,310 ± 235 µM vs. 937 ± 281 µM, P = 0.03) and in T2D and NAFLD compared with T2D without liver disease (1,354 ± 329 µM vs. 511 ± 235 µM, P < 0.0001). Particularly amino acids with known glucagonotropic effects (e.g., glutamine) were increased. Plasma levels of total amino acids correlated to plasma levels of glucagon also when adjusting for body mass index (BMI), glycated hemoglobin (HbA1c), and cholesterol levels (ß = 0.013 ± 0.007, P = 0.024). Elevated plasma levels of total amino acids associate with hyperglucagonemia in NAFLD patients independently of glycemic control, BMI or cholesterol - supporting the potential importance of a "liver-α-cell axis" in which glucagon regulates hepatic amino acid metabolism. Fasting hyperglucagonemia as seen in T2D may therefore represent impaired hepatic glucagon action with increasing amino acids levels. NEW & NOTEWORTHY Hypersecretion of glucagon (hyperglucagonemia) has been suggested to be linked to type 2 diabetes. Here, we show that levels of amino acids correlate with levels of glucagon. Hyperglucagonemia may depend on hepatic steatosis rather than type 2 diabetes.

18.
Scand J Clin Lab Invest ; 77(8): 617-621, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29037082

RESUMO

Fabry disease is an X- linked inherited lysosomal storage disease caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A). The possible pathological significance of the D313Y variant in the GLA gene has not been verified and it may be a Fabry variant. Our aim was to elucidate whether the presence of the D313Y variant influenced the α-Gal A activity or resulted in Fabry symptoms or Fabry organ involvement. In two Danish families the presence of the D313Y variant did not result in reduced α-Gal A activity or clinical Fabry manifestations in males, and the presence in Fabry females did not significantly enhance the phenotype of a known causative mutation in the GLA gene (G271S). Our findings indicate that the D313Y variant is not causative to nor enhancing Fabry disease phenotype. The D313Y variant in the GLA gene was not disease causative in 2 Danish families. Investigating male family members were crucial in excluding the Fabry phenotype, and thus very important for proper genetic counceling of all family members, as well as overdiagnosing a devastating genetic disease.


Assuntos
Doença de Fabry/genética , Mutação de Sentido Incorreto , alfa-Galactosidase/genética , Adulto , Idoso , Células Cultivadas , Criança , Análise Mutacional de DNA , Doença de Fabry/enzimologia , Feminino , Fibroblastos/enzimologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Leucócitos/enzimologia , Masculino , Pessoa de Meia-Idade , Linhagem , Inativação do Cromossomo X , alfa-Galactosidase/metabolismo
19.
JIMD Rep ; 36: 35-40, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28105570

RESUMO

Primary carnitine deficiency (PCD) causes low levels of carnitine in patients potentially leading to metabolic and cardiac symptoms. Newborn screening for PCD is now routine in many countries by measuring carnitine levels in infants. In this study we report Apgar scores, length and weight in newborns with PCD and newborns born to mothers with PCD compared to controls. Furthermore we report how effective different screening algorithms have been to detect newborns with PCD in the Faroe Islands. RESULTS: Newborns with PCD and newborns born to mothers with PCD did not differ with regard to Apgar scores, length and weight compared to controls. Newborns with PCD and newborns born to mothers with PCD had significantly lower levels of free carnitine (fC0) than controls. Screening algorithms focusing only on fC0 had a high rate of detection of newborns with PCD. Sample collection 4-9 days after birth seems to result in a higher detection rate than the current 2-3 days. CONCLUSION: The clinical status at birth in infants with PCD and infants born to mothers with PCD does not differ compared to control infants. Screening algorithms for PCD should focus on fC0, and blood samples should be taken when the maternal influence on fC0 has diminished.

20.
J Inherit Metab Dis ; 39(5): 661-672, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27106216

RESUMO

BACKGROUND: Patients with urea cycle disorders (UCDs) have an increased risk of neurological disease manifestation. AIMS: Determining the effect of diagnostic and therapeutic interventions on the neurological outcome. METHODS: Evaluation of baseline, regular follow-up and emergency visits of 456 UCD patients prospectively followed between 2011 and 2015 by the E-IMD patient registry. RESULTS: About two-thirds of UCD patients remained asymptomatic until age 12 days [i.e. the median age at diagnosis of patients identified by newborn screening (NBS)] suggesting a potential benefit of NBS. In fact, NBS lowered the age at diagnosis in patients with late onset of symptoms (>28 days), and a trend towards improved long-term neurological outcome was found for patients with argininosuccinate synthetase and lyase deficiency as well as argininemia identified by NBS. Three to 17 different drug combinations were used for maintenance therapy, but superiority of any single drug or specific drug combination above other combinations was not demonstrated. Importantly, non-interventional variables of disease severity, such as age at disease onset and peak ammonium level of the initial hyperammonemic crisis (cut-off level: 500 µmol/L) best predicted the neurological outcome. CONCLUSIONS: Promising results of NBS for late onset UCD patients are reported and should be re-evaluated in a larger and more advanced age group. However, non-interventional variables affect the neurological outcome of UCD patients. Available evidence-based guideline recommendations are currently heterogeneously implemented into practice, leading to a high variability of drug combinations that hamper our understanding of optimised long-term and emergency treatment.


Assuntos
Compostos de Amônio/metabolismo , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Argininossuccinato Sintase/metabolismo , Criança , Citrulinemia/diagnóstico , Citrulinemia/metabolismo , Feminino , Humanos , Hiperamonemia/diagnóstico , Hiperamonemia/metabolismo , Recém-Nascido , Transtornos de Início Tardio/diagnóstico , Transtornos de Início Tardio/metabolismo , Masculino , Triagem Neonatal/métodos , Estudos Prospectivos , Ureia/metabolismo
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