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1.
Mol Genet Metab ; 143(1-2): 108572, 2024 Sep 05.
Article de Anglais | MEDLINE | ID: mdl-39265286

RÉSUMÉ

INTRODUCTION: Diseases caused by lysosomal dysfunction often exhibit multisystemic involvement, resulting in substantial morbidity and mortality. Ensuring accurate diagnoses for individuals with lysosomal diseases (LD) is of great importance, especially with the increasing prominence of genetic testing as a primary diagnostic method. As the list of genes associated with LD continues to expand due to the use of more comprehensive tests such as exome and genome sequencing, it is imperative to understand the clinical validity of the genes, as well as identify appropriate genes for inclusion in multi-gene testing and sequencing panels. The Clinical Genome Resource (ClinGen) works to determine the clinical importance of genes and variants to support precision medicine. As part of this work, ClinGen has developed a semi-quantitative framework to assess the strength of evidence for the role of a gene in a disease. Given the diversity in gene composition across LD panels offered by various laboratories and the evolving comprehension of genetic variants affecting secondary lysosomal functions, we developed a scoring system to define LD (Lysosomal Disease Scoring System - LDSS). This system sought to aid in the prioritization of genes for clinical validity curation and assess their suitability for LD-targeted sequencing panels. METHODS: Through literature review encompassing terms associated with both classically designated LD and LFRD, we identified 14 criteria grouped into "Overall Definition," "Phenotype," and "Pathophysiology." These criteria included concepts such as the "accumulation of undigested or partially digested macromolecules within the lysosome" and being "associated with a wide spectrum of clinical manifestations impacting multiple organs and systems." The criteria, along with their respective weighted values, underwent refinement through expert panel evaluation differentiating them between "major" and "minor" criteria. Subsequently, the LDSS underwent validation on 12 widely acknowledged LD and was later tested by applying these criteria to the Lysosomal Disease Network's (LDN) official Gene List. RESULTS: The final LDSS comprised 4 major criteria and 10 minor criteria, with a cutoff of 2 major or 1 major and 3 minor criteria established to define LD. Interestingly, when applied to both the LDN list and a comprehensive gene list encompassing genes included in clinical panels and published as LFRD genes, we identified four genes (GRN, SLC29A3, CLN7 and VPS33A) absent from the LDN list, that were deemed associated with LD. Conversely, a subset of non-classic genes included in the LDN list, such as MTOR, OCRL, and SLC9A6, received lower LDSS scores for their associated disease entities. While these genes may not be suitable for inclusion in clinical LD multi-gene panels, they could be considered for inclusion on other, non-LD gene panels. DISCUSSION: The LDSS offers a systematic approach to prioritize genes for clinical validity assessment. By identifying genes with high scores on the LDSS, this method enhanced the efficiency of gene curation by the ClinGen LD GCEP. CONCLUSION: The LDSS not only serves as a tool for gene prioritization prior to clinical validity curation, but also contributes to the ongoing discussion on the definition of LD. Moreover, the LDSS provides a flexible framework adaptable to future discoveries, ensuring its relevance in the ever-expanding landscape of LD research.

2.
medRxiv ; 2024 Aug 10.
Article de Anglais | MEDLINE | ID: mdl-39211849

RÉSUMÉ

Lysosomal diseases (LDs) are a heterogeneous group of rare genetic disorders that result in impaired lysosomal function, leading to progressive multiorgan system dysfunction. Accurate diagnosis is paramount to initiating targeted therapies early in the disease process in addition to providing prognostic information and appropriate support for families. In recent years, genomic sequencing technologies have become the first-line approach in the diagnosis of LDs. Understanding the clinical validity of the role of a gene in a disease is critical for the development of genomic technologies, such as which genes to include on next generation sequencing panels, and the interpretation of results from exome and genome sequencing. To this aim, the ClinGen Lysosomal Diseases Gene Curation Expert Panel utilized a semi-quantitative framework incorporating genetic and experimental evidence to assess the clinical validity of the 56 LD-associated genes on the Lysosomal Disease Network's list. Here, we describe the results, and the key themes and challenges encountered.

3.
Nutr Clin Pract ; 39 Suppl 1: S57-S77, 2024 Apr.
Article de Anglais | MEDLINE | ID: mdl-38429959

RÉSUMÉ

Cystic fibrosis (CF) is a progressive, genetic, multi-organ disease affecting the respiratory, digestive, endocrine, and reproductive systems. CF can affect any aspect of the gastrointestinal (GI) tract, including the esophagus, stomach, small intestine, colon, pancreas, liver, and gall bladder. GI pathophysiology associated with CF results from CF membrane conductance regulator (CFTR) dysfunction. The majority of people with CF (pwCF) experience exocrine pancreatic insufficiency resulting in malabsorption of nutrients and malnutrition. Additionally, other factors can cause or worsen fat malabsorption, including the potential for short gut syndrome with a history of meconium ileus, hepatobiliary diseases, and disrupted intraluminal factors, such as inadequate bile salts, abnormal pH, intestinal microbiome changes, and small intestinal bacterial overgrowth. Signs and symptoms associated with fat malabsorption, such as abdominal pain, bloating, malodorous flatus, gastroesophageal reflux, nausea, anorexia, steatorrhea, constipation, and distal intestinal obstruction syndrome, are seen in pwCF despite the use of pancreatic enzyme replacement therapy. Given the association of poor nutrition status with lung function decline and increased mortality, aggressive nutrition support is essential in CF care to optimize growth in children and to achieve and maintain a healthy body mass index in adults. The introduction of highly effective CFTR modulator therapy and other advances in CF care have profoundly changed the course of CF management. However, GI symptoms in some pwCF may persist. The use of current knowledge of the pathophysiology of the CF GI tract as well as appropriate, individualized management of GI symptoms continue to be integral components of care for pwCF.


Sujet(s)
Mucoviscidose , Maladies gastro-intestinales , Syndromes de malabsorption , Malnutrition , Enfant , Adulte , Humains , Mucoviscidose/complications , Mucoviscidose/traitement médicamenteux , Protéine CFTR/génétique , Syndromes de malabsorption/complications , Syndromes de malabsorption/traitement médicamenteux , Maladies gastro-intestinales/traitement médicamenteux , Maladies gastro-intestinales/étiologie , Maladies gastro-intestinales/diagnostic , Malnutrition/complications
4.
J Cyst Fibros ; 22(6): 1027-1035, 2023 Nov.
Article de Anglais | MEDLINE | ID: mdl-37453889

RÉSUMÉ

BACKGROUND: Association of a high-fat diet with increased risks of cardiovascular disease (CVD) and type 2 diabetes, has prompted evaluation of lipids in people with CF (pwCF). However, most evidence on dyslipidemia was published before CF transmembrane conductance regulator (CFTR) modulators became a standard of care. The main goal of this study was to investigate the effect of CFTR modulator therapies on lipid and lipoprotein profiles in children and adolescents with CF. METHODS: Blood samples were collected from 153 pwCF (10.1 ± 4.7 years of age) and 60 age-matched controls. Most pwCF were pancreatic insufficient on pancreatic enzyme replacement therapy. By the end of the study, 65% of CF participants were on CFTR modulator therapy for >1 month. The results of traditional and advanced lipid testing in pwCF were correlated with clinical and dietary information. RESULTS: Total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly lower in pwCF compared to non-CF participants. Those not receiving CFTR modulators also had significantly lower high-density lipoprotein (HDL) cholesterol and HDL particle number than controls. Individuals with CF on modulator therapy had significantly higher concentrations of anti-atherogenic HDL cholesterol and HDL particles along with lower levels of atherogenic large very-low density lipoprotein (VLDL) particles, total and small LDL particles, and triglycerides compared to those without CFTR modulator therapy. CONCLUSION: CFTR modulator therapy has a beneficial effect on dyslipidemia in CF. It remains to be seen if these positive changes translate into decreased CVD risk later in life given the increasing life expectancy in CF.


Sujet(s)
Maladies cardiovasculaires , Mucoviscidose , Diabète de type 2 , Dyslipidémies , Humains , Adolescent , Enfant , Adulte d'âge moyen , Mucoviscidose/complications , Protéine CFTR , Diabète de type 2/traitement médicamenteux , Lipoprotéines/usage thérapeutique , Cholestérol , Dyslipidémies/diagnostic , Dyslipidémies/traitement médicamenteux
5.
Mol Genet Metab ; 139(3): 107604, 2023 07.
Article de Anglais | MEDLINE | ID: mdl-37236006

RÉSUMÉ

Peroxisomal disorders are heterogeneous in nature, with phenotypic overlap that is indistinguishable without molecular testing. Newborn screening and gene sequencing for a panel of genes implicated in peroxisomal diseases are critical tools for the early and accurate detection of these disorders. It is therefore essential to evaluate the clinical validity of the genes included in sequencing panels for peroxisomal disorders. The Peroxisomal Gene Curation Expert Panel (GCEP) assessed genes frequently included on clinical peroxisomal testing panels using the Clinical Genome Resource (ClinGen) gene-disease validity curation framework and classified gene-disease relationships as Definitive, Strong, Moderate, Limited, Disputed, Refuted, or No Known Disease Relationship. Subsequent to gene curation, the GCEP made recommendations to update the disease nomenclature and ontology in the Monarch Disease Ontology (Mondo) database. Thirty-six genes were assessed for the strength of evidence supporting their role in peroxisomal disease, leading to 36 gene-disease relationships, after two genes were removed for their lack of a role in peroxisomal disease and two genes were curated for two different disease entities each. Of these, 23 were classified as Definitive (64%), one as Strong (3%), eight as Moderate (23%), two as Limited (5%), and two as No known disease relationship (5%). No contradictory evidence was found to classify any relationships as Disputed or Refuted. The gene-disease relationship curations are publicly available on the ClinGen website (https://clinicalgenome.org/affiliation/40049/). The changes to peroxisomal disease nomenclature are displayed on the Mondo website (http://purl.obolibrary.org/obo/MONDO_0019053). The Peroxisomal GCEP-curated gene-disease relationships will inform clinical and laboratory diagnostics and enhance molecular testing and reporting. As new data will emerge, the gene-disease classifications asserted by the Peroxisomal GCEP will be re-evaluated periodically.


Sujet(s)
Techniques de diagnostic moléculaire , Dépistage néonatal , Nouveau-né , Humains , Bases de données factuelles , Dépistage génétique
6.
Curr Protoc ; 3(4): e758, 2023 Apr.
Article de Anglais | MEDLINE | ID: mdl-37099696

RÉSUMÉ

Quantitative analysis of urine acylglycines has shown to be a highly sensitive and specific method with proven clinical utility for the diagnosis of several inherited metabolic disorders including: medium chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, short chain acyl-CoA dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, 2-methylbutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, propionic academia, and isobutyryl-CoA dehydrogenase deficiency. Here, a method that is currently performed using ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) is described. © 2023 Wiley Periodicals LLC. Basic Protocol: Urinary acylglycine analysis by UPLC-MS/MS Support Protocol 1: Quality control preparation Support Protocol 2: Internal standard (ISTD) preparation Support Protocol 3: Standard (STD)/calibrator preparation.


Sujet(s)
Aminoacidopathies congénitales , Spectrométrie de masse en tandem , Humains , Chromatographie en phase liquide/méthodes , Spectrométrie de masse en tandem/méthodes , Chromatographie en phase liquide à haute performance/méthodes , Aminoacidopathies congénitales/diagnostic , Glycine
7.
Crit Rev Clin Lab Sci ; 60(5): 366-381, 2023 08.
Article de Anglais | MEDLINE | ID: mdl-36876586

RÉSUMÉ

Pediatric patients with exocrine pancreatic insufficiency (EPI) have symptoms that include abdominal pain, weight loss or poor weight gain, malnutrition, and steatorrhea. This condition can be present at birth or develop during childhood for certain genetic disorders. Cystic fibrosis (CF) is the most prevalent disorder in which patients are screened for EPI; other disorders also are associated with pancreatic dysfunction, such as hereditary pancreatitis, Pearson syndrome, and Shwachman-Diamond syndrome. Understanding the clinical presentation and proposed pathophysiology of the pancreatic dysfunction of these disorders aids in diagnosis and treatment. Testing pancreatic function is challenging. Directly testing aspirates produced from the pancreas after stimulation is considered the gold standard, but the procedures are not standardized or widely available. Instead, indirect tests are often used in diagnosis and monitoring. Although indirect tests are more widely available and easier to perform, they have inherent limitations due to a lack of sensitivity and/or specificity for EPI.


Sujet(s)
Mucoviscidose , Insuffisance pancréatique exocrine , Nouveau-né , Humains , Enfant , Fèces , Pancreatic elastase , Insuffisance pancréatique exocrine/diagnostic , Insuffisance pancréatique exocrine/génétique , Pancréas/physiologie , Mucoviscidose/diagnostic , Mucoviscidose/génétique , Mucoviscidose/complications
8.
Clin Chim Acta ; 542: 117295, 2023 Mar 01.
Article de Anglais | MEDLINE | ID: mdl-36914043

RÉSUMÉ

Plasmalogens are glycerophospholipids characterized by a vinyl-ether bond with a fatty alcohol at the sn-1 position, a polyunsaturated fatty acid at the sn-2 position, and a polar head at the sn-3 position, commonly phosphoethanolamine. Plasmalogens play crucial roles in several cellular processes. Reduced levels have been associated with Alzheimer's and Parkinson's disease progression. Markedly reduced plasmalogens are a classic feature of peroxisome biogenesis disorders (PBD) because plasmalogen synthesis requires functional peroxisomes. Particularly, severe plasmalogen deficiency is the biochemical hallmark of rhizomelic chondrodysplasia punctata (RCDP). Traditionally, plasmalogens are evaluated in red blood cells (RBCs) by gas-chromatography/mass-spectrometry (GC-MS), which cannot distinguish individual species. We developed a liquid-chromatography/tandem mass-spectrometry (LC-MS/MS) method to quantify eighteen phosphoethanolamine plasmalogens in RBCs to diagnose PBD patients, especially RCDP. Validation results showed a specific, robust, and precise method with broad analytical range. Age-specific reference intervals were established; control medians were used to assess plasmalogen deficiency in patients' RBCs. Clinical utility was also confirmed in Pex7 deficient mouse models recapitulating severe and milder RCDP clinical phenotypes. To our knowledge, this is the first attempt to replace the GC-MS method in the clinical laboratory. In addition to diagnosing PBDs, structure-specific plasmalogen quantitation could help understand disease pathogenesis and monitor therapy.


Sujet(s)
Chondrodysplasie ponctuée rhizomélique , Acétalphosphatides , Souris , Animaux , Chromatographie en phase liquide , Spectrométrie de masse en tandem , Chondrodysplasie ponctuée rhizomélique/génétique , Chondrodysplasie ponctuée rhizomélique/anatomopathologie , Érythrocytes/anatomopathologie
9.
Methods Mol Biol ; 2546: 149-163, 2022.
Article de Anglais | MEDLINE | ID: mdl-36127586

RÉSUMÉ

Quantitation of long-chain fatty acids in serum/plasma and red blood cells is a useful diagnostic tool in the evaluation of nutritional status and assessment of risk for essential fatty acid deficiency (EFAD). Serum/plasma has been the traditional sample type for this method, yet it requires prolonged fasting which is not compatible with some patient populations. More recently, red blood cells have become an important sample type due to less intraindividual variability and obviating the need for fasting. Here we present a method for the quantitation of 22 fatty acids in serum/plasma or red blood cells. Fatty acids are hydrolyzed and extracted from the biological matrix, followed by derivatization with pentafluorobenzyl bromide and subsequent analysis by gas chromatography-negative chemical ionization-mass spectrometry (GC-NCI-MS).


Sujet(s)
Érythrocytes , Acides gras indispensables , Numération des érythrocytes , Chromatographie gazeuse-spectrométrie de masse/méthodes , Humains
10.
Mol Genet Metab Rep ; 31: 100857, 2022 Jun.
Article de Anglais | MEDLINE | ID: mdl-35782604

RÉSUMÉ

Gyrate atrophy of the choroid and retina (GACR) secondary to deficiency of ornithine aminotransferase (OAT) is a rare autosomal recessive metabolic disorder usually diagnosed in childhood when patients develop myopia and a characteristic retinal degeneration accompanied by hyperornithinemia. Plasma ammonia is normal or sub-normal after the neonatal period. A few GACR patients present in early infancy with hyperammonemia, encephalopathy and a biochemical profile of low plasma ornithine, citrulline and arginine, with increased urinary excretion of homocitrulline and orotic acid, resembling a primary urea cycle disorder. In these patients, ornithine levels do not increase until late infancy or following arginine or citrulline supplementation. We describe a patient with OAT deficiency who presented in the first month of life with episodes of lethargy, vomiting, and hypothermia. He had two episodes of hyperammonemia associated with subnormal levels of plasma ornithine, citrulline and arginine as well as elevated urinary excretion of homocitrulline and orotic acid. Unlike previously reported cases, intermittent hyperornithinemia was observed prior to the first hyperammonemic episode and citrulline supplementation. The latter alleviated the symptoms, normalized ammonia level, and led to increased plasma ornithine concentration. Furthermore, despite a protein restricted diet and ammonia scavenger treatment, continued supplemental citrulline was necessary to prevent hyperammonemia. Molecular analysis confirmed OAT deficiency, differentiating it from proximal urea cycle disorders and deficiency of the mitochondrial ornithine transporter, ORC1, (Hyperammonemia-Hyperornithinemia-Homocitrullinuria syndrome). Synopsis: Hyperornithinemia alternating with hypoornithinemia and hyperammonemia in a neonatal-onset case of gyrate atrophy with ornithine aminotransferase deficiency.

11.
Clin Chim Acta ; 523: 285-289, 2021 Dec.
Article de Anglais | MEDLINE | ID: mdl-34634292

RÉSUMÉ

BACKGROUND: Acylglycine species accumulate in specific disorders of branched-chain amino acid metabolism and fatty acid ß-oxidation. These species are excreted in urine and their analysis can facilitate diagnosis. Previous studies evaluated reference ranges and increases in metabolic patients, but these involved small numbers of individuals. We have conducted an analysis encompassing large numbers of individuals to better characterize the reference ranges of these analytes and additionally describe our findings from patients with confirmed metabolic disorders. METHODS: We conducted a retrospective analysis of approximately 9 y of urine acylglycine data from our clinical laboratory. Acylglycines were extracted from urine, derivatized and analyzed using UPLC-MS/MS. Reference ranges were determined from the non-diseased population. Data from confirmed patients were used to document the range of increases observed in these conditions and to generate multiple of the median graphs. RESULTS: In total, 6162 urine specimens from 5633 patients with and without metabolic disorders were analyzed. Magnitude and pattern of acylglycine elevations in patients with confirmed metabolic disorders were documented. CONCLUSION: This manuscript extends our previously published method by providing the reference ranges and disease specific elevations and patterns of urine acylglycine species using the largest data set published to date.


Sujet(s)
Erreurs innées du métabolisme lipidique , Spectrométrie de masse en tandem , Chromatographie en phase liquide à haute performance , Chromatographie en phase liquide , Acides gras , Humains , Laboratoires cliniques , Valeurs de référence , Études rétrospectives
13.
Clin Biochem ; 97: 25-33, 2021 Nov.
Article de Anglais | MEDLINE | ID: mdl-34329622

RÉSUMÉ

BACKGROUND: The current assessment of nutritional status and diagnosis of essential fatty acids deficiency (EFAD) utilizes the analysis of long-chain fatty acids (LCFAs) in serum or plasma; however, these concentrations do not represent habitual LCFA intake. LCFAs in red blood cells (RBCs) are less prone to intra-individual variability and exclude the need for fasting, which is unrealistic in pediatric populations. Our study objective was to characterize the RBC LCFA profiles in pediatric and adult reference populations and establish age-specific reference intervals (RIs). METHODS: Twenty-one LCFAs in RBCs were measured in 523 pediatric and adult controls by gas chromatography-mass spectrometry. Model-based clustering was used to identify possible age subgroups. After removing outliers by the Tukey method, initial age subgroups were then compared using the Harris-Boyd method in an iterative manner. RIs (95%), with confidence intervals (90%), in the final age groups were established using parametric or non-parametric statistics. RESULTS: Our data showed heterogeneous changes in the concentrations of most LCFAs and the EFAD biomarkers (mead acid, Triene/Tetraene ratio) during infancy. Model-based clustering identified six initial age subgroups per fatty acid, on average. Our application of the iterative Harris-Boyd method decreased the average number of age groups to three per fatty acid, with 13 total unique age cut-offs. Finally, using these age groups, we established age-specific RIs for 21 fatty acids, six group totals, and the Triene/Tetraene ratio. CONCLUSION: Our study revealed significant age-dependent changes in RBC fatty acid profiles warranting separate pediatric and adults RIs. Model-based clustering and the iterative application of the Harris-Boyd method were successfully used to establish RBC fatty acid RIs for an objective assessment of long-term nutritional status in pediatric and adult populations.


Sujet(s)
Analyse chimique du sang/méthodes , Érythrocytes/composition chimique , Acides gras/sang , Adolescent , Adulte , Facteurs âges , Analyse de regroupements , Humains , Nourrisson , Nouveau-né , Valeurs de référence
14.
Clin Chim Acta ; 518: 38-42, 2021 Jul.
Article de Anglais | MEDLINE | ID: mdl-33713689

RÉSUMÉ

BACKGROUND: Analysis of lipoprotein size and composition by nuclear magnetic resonance (NMR) has been advocated as a method for identifying individuals at high CVD risk. We compared risk stratification between NMR-based LDL particle number (LDL-PNUM), LDL-cholesterol (LDL-C), and apolipoprotein B (apoB). METHODS: Retrospective data from patients with simultaneous orders for LDL-PNUM, LDL-C, and apoB were analyzed and included data from an NMR assay (Numares). Quantitative and qualitative analyses were performed. Additional lipid parameters were investigated for patients with discordant risk classifications in LDL-related measurements. The percent change of LDL-PNUM was compared to the percent change of LDL-C or apoB for patients with serial measurements. RESULTS: We observed good quantitative and qualitative correlation when comparing LDL-PNUM to either LDL-C or apoB (Spearman's ρ ≥ 0.83, percent agreements ≥ 85%). Among the patients with discordant risk stratification, most had increased LDL-PNUM and normal LDL-C and apoB. For patients with serial measurements, a strong correlation between the LDL-PNUM percent change and the LDL-C or apoB percent change was observed (Spearman's ρ > 0.93). CONCLUSION: For many patients, risk stratification of LDL-PNUM is similar to apoB or LDL-C using cut-offs proposed by guidelines.


Sujet(s)
Apolipoprotéines B , Lipoprotéines , Cholestérol LDL , Humains , Études rétrospectives
15.
Clin Biochem ; 87: 85-92, 2021 Jan.
Article de Anglais | MEDLINE | ID: mdl-33159964

RÉSUMÉ

INTRODUCTION: Measurement of lipoprotein subclass concentration (-c), particle number (-p), and size (-s) by nuclear magnetic resonance (NMR) has gained traction in the clinical laboratory due to associations between smaller lipid particle sizes and atherogenic risk, especially for LDL-p. The standard protocols for lipoprotein measurements by NMR require fasting blood samples; however, patients may not fast properly before sample collection. The study objective was to evaluate the impact of fasting status on the NMR-based lipid profile and to identify key parameters differentiating between fasting and post-meal specimens. METHODS: Forty-eight self-reported healthy male and female participants were recruited. Blood was collected after a 12 h fast and 4 h after a high fat meal. Samples were analyzed using the AXINON LipoFIT by NMR assay. The measurements included triglyceride, total cholesterol, IDL-c, and LDL, HDL, VLDL concentration, particle number, and size, as well as glucose, and four amino acids (alanine, valine, leucine and isoleucine). RESULTS: As expected, triglycerides increased after the meal (58%, p < 0.0001). Significant changes were also observed for VLDL, LDL, and HDL parameters, and the branched chain amino acids. The ratio of Valine*VLDL-c/LDL-c or Isoleucine*VLDL-c/LDL-c provided equally effective differentiation of fasting and post-meal samples. The ratio cutoffs (79.1 and 23.6 when calculated using valine and isoleucine, respectively) had sensitivities of 86% and specificities of 93-95%. CONCLUSIONS: The clinical impact on NMR results from post-meal samples warrants further evaluation. Algorithms to differentiate fasting and post-meal specimens may be useful in identifying suboptimal specimens.


Sujet(s)
Cholestérol LDL/sang , Cholestérol VLDL/sang , Jeûne/sang , Isoleucine/sang , Spectroscopie par résonance magnétique/méthodes , Valine/sang , Adulte , Algorithmes , Femelle , Humains , Mâle , Période post-prandiale , Études prospectives , Facteurs de risque
16.
Clin Chim Acta ; 509: 126-134, 2020 Oct.
Article de Anglais | MEDLINE | ID: mdl-32533987

RÉSUMÉ

The homocystinurias, caused by defects of remethylation and cystathionine-beta-synthase (CBS) deficiency, are characterized by elevated homocysteine and abnormal methionine levels. Various treatments, including injectable hydroxycobalamin and oral betaine, aim to reduce homocysteine toxicity and normalize methionine, but only limited biochemical data has been reported assessing biochemical response to treatment. We analyzed laboratory results in 812 plasma samples from 56 patients with remethylation disorders and 67 patients with CBS deficiency. Total plasma homocysteine (tHcys) decreased with therapy, but rarely normalized regardless of treatment, with highest levels seen in CBS (116 ±â€¯79 µmol/L) and MTHFR (102 ±â€¯56 µmol/L) deficiencies. In CBS deficiency, tHcys correlated positively with methionine (rs = 0.51, p < 0.0001) and inversely with cystine (rs = -0.57, p < 0.0001) consistent with a metabolic block downstream of homocysteine. In patients with remethylation disorders, methionine was mostly normal on therapy, and inversely correlated with tHcys (rs = -0.57, p < 0.0001) demonstrating effectiveness of hydroxycobalamin and/or betaine in stimulating tHcys remethylation. Betaine also significantly increased sarcosine from its pre-treatment level on average 19-fold in remethylation disorders and 3-fold in CBS deficiency, with sarcosine > 5 µmol/L being 97% sensitive and 95% specific for betaine therapy. These results show that existing therapies improve sulfur amino acid metabolism without completely normalizing it and that sarcosine can determine compliance to betaine supplementation.


Sujet(s)
Homocystéine , Homocystinurie , Bétaïne , Cystathionine beta-synthase , Études de suivi , Homocystéine/métabolisme , Homocystinurie/traitement médicamenteux , Humains , Laboratoires , Méthionine , Méthylation
17.
Front Pediatr ; 7: 337, 2019.
Article de Anglais | MEDLINE | ID: mdl-31508398

RÉSUMÉ

Purpose: To evaluate the effects of a single oral dose of pyridoxine on lysine metabolites including α-aminoadipic semialdehyde (a-AASA), piperideine-6-carboxylate (P6C), the sum of AASA and P6C (AASA-P6C), pipecolic acid (PA), and α-aminoadipic acid (α-AAA) in PDE patients. Methods: The lysine metabolites of 15 patients with molecularly confirmed PDE were detected before and 4 h after taking a single oral dose of pyridoxine, respectively, using liquid chromatography-mass spectrometry (LC-MS/MS) method. Five types of samples were freshly prepared, including plasma, serum, dried blood spots (DBS), urine, and dried urine spots (DUS). Results: All the patients had been treated with long-term oral pyridoxine for several months to years, with doses of 30-360 mg/d. The concentrations of a-AASA, P6C, AASA-P6C, PA, and a-AAA before and after taking a single oral dose of pyridoxine for the same analyte detected in the same type of sample varied among patients. The mean concentrations increased in almost all the metabolites after taking an oral dose of pyridoxine, with or without statistical significance. Whereas, the metabolites concentrations might increase or decrease among different patients, or in different samples of the same patient, without a regular tendency. There was no statistical correlation between the concentrations before and after taking pyridoxine in the same type of sample for most metabolites. Conclusions: No obvious relationship between the metabolite levels or concentration differences and the age, pyridoxine dose (a single oral dose and long-term maintenance dose), duration of treatment, or neurodevelopmental phenotype was found at present study. The large individual differences among patients, probably affected by various genotypes, leading to quite different effects of pyridoxine on the change degree of metabolites concentrations. Our study suggested that long-term pyridoxine treatment could control seizures rather than getting toxic lysine metabolites such as a-AASA and P6C back to normal. In the future, more therapies should be focused to alleviate the metabolites accumulation and further improve the prognosis of PDE.

18.
Sci Rep ; 9(1): 11371, 2019 08 06.
Article de Anglais | MEDLINE | ID: mdl-31388081

RÉSUMÉ

The measurements of lysine metabolites provide valuable information for the rapid diagnosis of pyridoxine-dependent epilepsy (PDE). Here, we aimed to develop a sensitive method to simultaneously quantify multiple lysine metabolites in PDE, including α-aminoadipic semialdehyde (a-AASA), piperideine-6-carboxylate (P6C), pipecolic acid (PA) and α-aminoadipic acid (α-AAA) in plasma, serum, dried blood spots (DBS), urine and dried urine spots (DUS). Fifteen patients with molecularly confirmed PDE were detected using liquid chromatography-mass spectrometry (LC-MS/MS) method. Compared to the control groups, the concentrations of a-AASA, P6C and the sum of a-AASA and P6C (AASA-P6C) in all types of samples from PDE patients were markedly elevated. The PA and a-AAA concentrations ranges overlapped partially between PDE patients and control groups. The concentrations of all the analytes in plasma and serum, as well as in urine and DUS were highly correlated. Our study provided more options for the diverse sample collection in the biochemical tests according to practical requirements. With treatment modality of newly triple therapy investigated, biomarker study might play important role not only on diagnosis but also on treatment monitoring and fine tuning the diet. The persistently elevated analytes with good correlation between plasma and DBS, as well as urine and DUS made neonatal screening using DBS and DUS possible.


Sujet(s)
Acide 2-amino-adipique/analogues et dérivés , Acide 2-amino-adipique/sang , Épilepsie/sang , Acides picoliniques/sang , Acides pipécoliques/sang , Spectrométrie de masse en tandem/méthodes , Acide 2-amino-adipique/métabolisme , Acide 2-amino-adipique/urine , Marqueurs biologiques/sang , Marqueurs biologiques/urine , Enfant , Enfant d'âge préscolaire , Chromatographie en phase liquide/méthodes , Épilepsie/diagnostic , Épilepsie/urine , Femelle , Humains , Nourrisson , Lysine/métabolisme , Mâle , Dépistage de masse , Acides picoliniques/métabolisme , Acides picoliniques/urine , Acides pipécoliques/métabolisme , Acides pipécoliques/urine
20.
Mol Genet Metab ; 125(3): 258-265, 2018 11.
Article de Anglais | MEDLINE | ID: mdl-30172461

RÉSUMÉ

Impaired activity of galactose-1-phosphate uridyltransferase (GALT) causes classic galactosemia (OMIM 230400), characterized by the accumulation of galactose-1-phosphate (GAL1P) in patients' red blood cells (RBCs). Our recent study demonstrated a correlation between RBC GAL1P and long-term outcomes in galactosemia patients. Here, we analyze biochemical and molecular results in 77 classic galactosemia patients to evaluate the association between GALT genotypes and GAL1P concentration in RBCs. Experimental data from model organisms were also included to assess the correlation between GAL1P and predicted residual activity of each genotype. Although all individuals in this study showed markedly reduced RBC GALT activity, we observed significant differences in RBC GAL1P concentrations among galactosemia genotypes. While levels of GAL1P on treatment did not correlate with RBC GALT activities (p = 0.166), there was a negative nonlinear correlation between mean GAL1P concentrations and predicted residual enzyme activity of genotype (p = 0.004). These studies suggest that GAL1P levels in RBCs on treatment likely reflect the overall functional impairment of GALT in patients with galactosemia.


Sujet(s)
Érythrocytes/métabolisme , Galactosémies/génétique , Galactose phosphate/sang , UTP hexose 1-phosphate uridylyltransferase/génétique , Adolescent , Adulte , Enfant , Enfant d'âge préscolaire , Érythrocytes/anatomopathologie , Femelle , Galactosémies/sang , Galactosémies/anatomopathologie , Génotype , Humains , Nourrisson , Nouveau-né , Mâle , Jeune adulte
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