Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

Abstract

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.

<p>Urinary Metabolomic Profiling Reveals Biological Pathways and Predictive Signatures Associated with Childhood Asthma</p>

“…Therefore, metabolomic studies have been applied to discover biomarkers/therapeutic targets and reveal underlying mechanisms of various diseases. 33 Similarly, in the current study we provided an overview of metabolic changes in asthma during childhood based on a GC-MS metabolomic approach, which broadens our knowledge of pathobiological pathways involved in childhood asthma and sheds light on the prevention, diagnosis, and treatment of asthma at an early age. Moreover, asthma diagnosis relies on clinical manifestations and confirmed expiratory-airflow limitation, but symptoms and pulmonary function measurements may not always reflect the underlying airway inflammation and are insensitive to small variations in inflammatory status.…”

Altered Plasma Mitochondrial Metabolites in Persistently Symptomatic Individuals after a GBCA-Assisted MRI

“…Definitive MD diagnosis usually requires biopsy and/or genetic testing; no specific metabolic markers can reliably identify a particular defect, and while conventional urine or plasma abnormalities sometimes correlate, their diagnostic sensitivity and specificity remain poor [15,16]. Small molecules are increasingly globally interrogated in clinically heterogeneous conditions involving mitochondria, e.g., inborn errors of metabolism (IEMs) [37], and to characterize and differentiate primary MDs [19,20], thereby greatly expanding biomarker identification. Our discovery-based MS metabolomics analyses identified 45 plasma biochemicals as provisionally altered in this small GDD cohort, with the proportion of plasma biochemicals from nucleotide and energy superpathways notably higher than expected.…”

Diagnostic approach in adult-onset neurometabolic diseases

“…In addition, biochemical phenotyping could also be enlarged by metabolomics, establishing a comprehensive biochemical profile. 59 The high-dimensional nature of the data amassed through metabolomics requires the use of dedicated preprocessing platforms and multivariate analysis or even machine learning tools to classify the findings. 60 This untargeted approach has the potential to direct the diagnosis among varied and unspecific manifestations and to diminish the number of specific biochemical tests, thus reducing the overall cost.…”