scholarly journals Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

2020 ◽  
Vol 21 (4) ◽  
pp. 1195 ◽  
Author(s):  
Dylan Mordaunt ◽  
David Cox ◽  
Maria Fuller
Keyword(s):  
Mass Spectrometry ◽  
Inborn Errors Of Metabolism ◽  
Early Recognition ◽  
Laboratory Diagnosis ◽  
Screening Tests ◽  
Diagnostic Efficiency ◽  
Inborn Errors ◽  
Screening Programs ◽  
Initiation Of Therapy ◽  
Delays In Diagnosis

Early diagnosis of inborn errors of metabolism (IEM)—a large group of congenital disorders—is critical, given that many respond well to targeted therapy. Newborn screening programs successfully capture a proportion of patients enabling early recognition and prompt initiation of therapy. For others, the heterogeneity in clinical presentation often confuses diagnosis with more common conditions. In the absence of family history and following clinical suspicion, the laboratory diagnosis typically begins with broad screening tests to circumscribe specialised metabolite and/or enzyme assays to identify the specific IEM. Confirmation of the biochemical diagnosis is usually achieved by identifying pathogenic genetic variants that will also enable cascade testing for family members. Unsurprisingly, this diagnostic trajectory is too often a protracted and lengthy process resulting in delays in diagnosis and, importantly, therapeutic intervention for these rare conditions is also postponed. Implementation of mass spectrometry technologies coupled with the expanding field of metabolomics is changing the landscape of diagnosing IEM as numerous metabolites, as well as enzymes, can now be measured collectively on a single mass spectrometry-based platform. As the biochemical consequences of impaired metabolism continue to be elucidated, the measurement of secondary metabolites common across groups of IEM will facilitate algorithms to further increase the efficiency of diagnosis.

Inborn errors of metabolism detectable by tandem mass spectrometry in Beijing

2020 ◽  
Vol 33 (5) ◽  
pp. 639-645
Author(s):  
Nan Yang ◽  
Li-fei Gong ◽  
Jin-qi Zhao ◽  
Hai-he Yang ◽  
Zhi-jun Ma ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Genetic Analysis ◽  
Tandem Mass Spectrometry ◽  
Newborn Screening ◽  
Inborn Errors Of Metabolism ◽  
Propionic Acidemia ◽  
Methylmalonic Acidemia ◽  
Tandem Mass ◽  
Inborn Errors ◽  
Screening Programs

AbstractBackgroundIndividual inborn errors of metabolism (IEMs) are rare disorders. Expanded newborn screening for IEMs by tandem mass spectrometry (TMS) is an efficient approach for early diagnosis. Here we provide the newborn screening program for the application of this approach (between July 2014 and March 2019) to the identification of newborns in Beijing at risk of developing a potentially fatal disease.MethodsThe amino acids and acylcarnitines in dried blood spots were analyzed by TMS. Diagnoses of newborns with elevated metabolites were confirmed by gas chromatography-mass spectrometry, biochemical studies, and genetic analysis.ResultsAmong the healthy newborns, 16 metabolic disorder cases were confirmed, giving a total birth prevalence of 1:3666 live births. Organic acidemia (OA) was the most common (9/16 patients; 56%), and methylmalonic acidemia was the most frequently observed OA (7/9 patients; 89%). Five infants were diagnosed with methylmalonic acidemia with homocystinuria type CblC, two with isolated methylmalonic acidemia, one with propionic acidemia, and one with isovaleric acidemia. Four patients (4/16, 25%) were diagnosed with hyperphenylalaninemia. One suffered with medium-chain acyl CoA dehydrogenase deficiency, one with carnitine uptake deficiency, and one with citrin deficiency. Eleven cases underwent genetic analysis. Seventeen mutations in eight IEM-associated genes were identified in 11 confirmed cases. Symptoms were already present within 2 days after birth in 44% (7/16) cases. The infant with propionic acidemia died at 7 days after birth. The other cases received timely diagnosis and treatment, and most of them grew well.ConclusionsThe results illustrate challenges encountered in disease management highlighting the importance of newborn screening for inherited metabolic disorders, which is not yet nationally available in our country. Regional newborn screening programs will provide a better estimation of the incidence of IEM.

scholarly journals Diagnostic Advancement in Evaluating Inborn Errors of Metabolism: Past, Present and Future: A systematic review

2019 ◽  
Vol 3 (2) ◽  
pp. 58
Author(s):  
Nazmin Fatima ◽  
Shalini Tripathi ◽  
Roshan Alam ◽  
Mohammed Haris Siddiqui ◽  
Abbas Ali Mahdi ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
High Performance ◽  
Inborn Errors Of Metabolism ◽  
Genetic Disorders ◽  
Population Based ◽  
Gas Chromatography Mass Spectrometry ◽  
Molecular Testing ◽  
Inborn Errors ◽  
Biochemical Basis ◽  
Screening Programs

Metabolism is a delicately coordinated entity of chemical reactions. Inborn Errors of Metabolism (IEM) are rare congenital disorders that are mainly due to gene defect of enzymes or cofactors participating in a metabolic pathway or the transport of metabolites within a cell or between cells. The development of knowledge in basic sciences together with technology development in medical field has helped to better understand the molecular and biochemical basis of IEM. Environmental factors, ethnicity, race, consanguinity and genetic factors contribute to the increased prevalence of genetic disorders. The analytical methods have evolved over the years from thin layer chromatography (TLC), high performance liquid chromatography (HPLC) to tandem mass spectrometry (TMS) including gas chromatography mass spectrometry (GC/MS). Their applications for È¡7_Ø‹5_g of IEM has opened the door for screening of conditions that previously required molecular testing or another methodology that was not practical for population-based screening. Future technologies such as Matrix-assisted laser desorption/ ionization timeof- flight mass spectrometry (MALDI-TOF MS), has the potential for rapid and reliable identification of small metabolites and disease biomarkers in daily clinical laboratories, whereas DNA based screening by DNA microarrays or gene chips will allow much more improved diagnosis.These can be the boon to screening programs which will require excellent detection and follow-up servicesInternational Journal of Human and Health Sciences Vol. 03 No. 02 April’19. Page: 58-63

Proteomic analysis of cytochromes P450: a mass spectrometry approach

2006 ◽  
Vol 34 (6) ◽  
pp. 1246-1251 ◽  
Author(s):  
Y. Wang ◽  
A. Al-Gazzar ◽  
C. Seibert ◽  
A. Sharif ◽  
C. Lane ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Fatty Acids ◽  
Inborn Errors Of Metabolism ◽  
Cytochromes P450 ◽  
Acid Biosynthesis ◽  
Inborn Errors ◽  
Steroid Synthesis ◽  
Current State ◽  
Increased Risk ◽  
Risk Of Cancer

In human, the CYP (cytochrome P450) superfamily comprises 57 genes arranged in 18 families and 42 subfamiles. These genes encode for enzymes involved in the metabolism of drugs, foreign chemicals, fatty acids, eicosanoids and cholesterol. Additionally, they play roles in bile acid biosynthesis, steroid synthesis and metabolism, and vitamin D3 synthesis and metabolism. Mutations in many CYP genes cause inborn errors of metabolism and contribute to increased risk of cancer. MS provides a convenient method for the identification and quantification of CYP enzymes, and in the present paper we will review the current state of the technology for such an analysis.

Screening Newborns for Inborn Errors of Metabolism by Tandem Mass Spectrometry

2003 ◽  
Vol 348 (23) ◽  
pp. 2304-2312 ◽  
Author(s):  
Bridget Wilcken ◽  
Veronica Wiley ◽  
Judith Hammond ◽  
Kevin Carpenter
Keyword(s):  
Mass Spectrometry ◽  
Tandem Mass Spectrometry ◽  
Inborn Errors Of Metabolism ◽  
Tandem Mass ◽  
Inborn Errors

scholarly journals 4th Rare Disease South Eastern Europe (See) Meeting Skopje, Macedonia (November 14th, 2015)

PRILOZI ◽  
2015 ◽  
Vol 36 (3) ◽  
pp. 154-159
Author(s):  
Zoran Gucev ◽  
Velibor Tasic ◽  
Momir Polenakovic
Keyword(s):  
Mass Spectrometry ◽  
Eastern Europe ◽  
Rare Disease ◽  
Laboratory Diagnosis ◽  
Gm1 Gangliosidosis ◽  
Pharmacological Chaperone ◽  
Screening Programs ◽  
South Eastern ◽  
Wide Range ◽  
South Eastern Europe

Abstract The 4th meeting on rare diseases in South Eastern Europe (SEE) was held in Skopje, at the Macedonian Academy of Sciences and Arts (MASA) on the 14th of November 2015. The focuses were metabolic, rare brain diseases as well as the rare dysmorphic syndrome. The authors of the report are particularly keen on stating that one of the main goals of the meeting, namely to help the treatment of patients with rare disease has begun to bear fruits. The talk on an iminosugar-based pharmacological chaperone compound as a drug candidate for the treatment of GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B) was enlightening. To date, there is no treatment available to be offered to patients, but chaperones lead mutated proteins to adopt a native-like conformation and to successfully traffic to their normal cellular destination. DORPHAN is developing an iminosugar-based pharmacological chaperone compound for the treatment of GM1-gangliosidosis and mucopolysaccharidosis IVB. A talk on recent developments in the laboratory diagnosis of mucopolysaccharidoses (MPS) was particularly interesting, covering the laboratory diagnosis of the MPS diseases by a strategy of clinical examination, biochemical analysis of urine samples, enzyme tests and genetic characterization of underlying mutations. New techniques were developed, including analysis of urinary glycosaminoglycans with tandem mass spectrometry, miniaturized enzyme tests or novel synthetic substrates for enzyme assays using mass spectrometry detection of products using dried blood spots. Feasibility and cost-effectiveness of these methods in newborn screening programs have been demonstrated. Neuromuscular RDs, and especially familial amyloid polyneuropathy (FAP) were a topic of the Bulgarian colleagues. Diagnosis, screening and the role of microglia were also topics of particular interest. In summary, this year RD meeting was exciting and productive on a wide range of diseases and on a novel insights on diagnosis and treatment. New methods are expanding our capabilities for a fast and precise diagnosis. Novel knowledge offers better distinction on whom to treat with which medications (e.g. steroid dependent nephrotic syndrome). Novel diseases or variants are published (segmental overgrowth). The authors of the report are particularly keen on stating that one of the main goals of the meeting, namely to help the treatment of patients with rare disease has begun to bear fruits. Namely, the Health Fund of Macedonia for the first time treats the patients with Gaucher′s disease. We are hopeful that the number of patients treated for Gaucher′s disease and the number of treated patients with other treatable RDs diseases will continue to grow.

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