A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders

Ortigoza‐Escobar, Juan Darío

doi:10.3389/fneur.2020.582160

Cited by 19 publications

(24 citation statements)

References 163 publications

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“…While metabolic abnormalities have been found in patients with such NDDs as ASD (an increase in lactate and creatine and a decrease in creatinine are among many suggested changes that have been reported [ 127 , 139 , 142 , 143 , 144 ]), Rett syndrome (MIM# 312750; metabolites associated with urea and the Krebs cycle and the metabolism of certain amino acids [ 145 ]) and Down syndrome (MIM# 190685; alterations to methylation metabolism, carnitine/O-acetylcarnitine, dimethyl sulfone, and myo-inositol [ 143 ]), the group of disorders where metabolomics has the most obvious diagnostic application is that of inborn errors of metabolism (IEM), affecting 1:1000 to 1:2000 newborns [ 137 , 146 ]. To date, there are 1615 known IEM and over a half of them show neurologic involvement, including at least 231 presenting with a movement disorder and at least 116 treatable IEMs causing intellectual disability [ 147 , 148 , 149 , 150 , 151 ]. It has also been suggested that ASD patients, at least those born outside of high income countries, are underdiagnosed for IEM [ 148 ].…”

Section: Integrating Omics To Understand Functional Effects and Impro...mentioning

confidence: 99%

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

Kadlubowska

Schrauwen

2022

Genes

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During the last decade, genetic testing has emerged as an important etiological diagnostic tool for Mendelian diseases, including pediatric neurological conditions. A genetic diagnosis has a considerable impact on disease management and treatment; however, many cases remain undiagnosed after applying standard diagnostic sequencing techniques. This review discusses various methods to improve the molecular diagnostic rates in these genomic cold cases. We discuss extended analysis methods to consider, non-Mendelian inheritance models, mosaicism, dual/multiple diagnoses, periodic re-analysis, artificial intelligence tools, and deep phenotyping, in addition to integrating various omics methods to improve variant prioritization. Last, novel genomic technologies, including long-read sequencing, artificial long-read sequencing, and optical genome mapping are discussed. In conclusion, a more comprehensive molecular analysis and a timely re-analysis of unsolved cases are imperative to improve diagnostic rates. In addition, our current understanding of the human genome is still limited due to restrictions in technologies. Novel technologies are now available that improve upon some of these limitations and can capture all human genomic variation more accurately. Last, we recommend a more routine implementation of high molecular weight DNA extraction methods that is coherent with the ability to use and/or optimally benefit from these novel genomic methods.

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Section: Integrating Omics To Understand Functional Effects and Impro...mentioning

confidence: 99%

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

Kadlubowska

Schrauwen

2022

Genes

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“…Acute-onset MDs are a possible presentation of various genetic disorders in children, mostly in the setting of the acute decompensation of IEM, often with accompanying encephalopathy [ 197 ].…”

Section: Inborn Errors Of Metabolism and Genetic Disordersmentioning

confidence: 99%

“…Treatment relies on a low-lysine and carbohydrate-enriched diet with carnitine supplementation [ 198 ]. Other organic acidurias that may present with acute encephalopathy with dystonia, dyskinesias and choreoathetosis include maple syrup urine disease, propionic, 3-methylglutaconic and methylmalonic acidemias, and cobalamin C defects [ 197 , 198 , 199 ]. Early diagnosis and the initiation of appropriate dietary and pharmacologic interventions prevents further neurological deterioration.…”

Section: Inborn Errors Of Metabolism and Genetic Disordersmentioning

confidence: 99%

Acute Movement Disorders in Childhood

Garone

Graziola

Grasso

et al. 2021

JCM

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Acute-onset movement disorders (MDs) are an increasingly recognized neurological emergency in both adults and children. The spectrum of possible causes is wide, and diagnostic work-up is challenging. In their acute presentation, MDs may represent the prominent symptom or an important diagnostic clue in a broader constellation of neurological and extraneurological signs. The diagnostic approach relies on the definition of the overall clinical syndrome and on the recognition of the prominent MD phenomenology. The recognition of the underlying disorder is crucial since many causes are treatable. In this review, we summarize common and uncommon causes of acute-onset movement disorders, focusing on clinical presentation and appropriate diagnostic investigations. Both acquired (immune-mediated, infectious, vascular, toxic, metabolic) and genetic disorders causing acute MDs are reviewed, in order to provide a useful clinician’s guide to this expanding field of pediatric neurology.

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“…The IEM base database ( (accessed on 25 September 2022) currently contains about 1450 inborn errors of metabolism (IEM) [ 3 ], accounting for nearly 20% of all rare diseases, and incidence rates are 1 in 800–2500 live births [ 4 , 5 ]. From a pathophysiological point of view, IMDs can be divided into three diagnostically useful groups: (i) defects of small molecules; (ii) disorders involving energy metabolism; and (iii) disorders involving complex molecules [ 6 ]. IMDs can present with very varied symptoms and signs, affecting any organ at any stage of life between the prenatal period and adulthood.…”

Section: Introductionmentioning

confidence: 99%

Proteomics in Inherited Metabolic Disorders

Chantada-Vázquez

Bravo

Gouveia

et al. 2022

IJMS

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Inherited metabolic disorders (IMD) are rare medical conditions caused by genetic defects that interfere with the body’s metabolism. The clinical phenotype is highly variable and can present at any age, although it more often manifests in childhood. The number of treatable IMDs has increased in recent years, making early diagnosis and a better understanding of the natural history of the disease more important than ever. In this review, we discuss the main challenges faced in applying proteomics to the study of IMDs, and the key advances achieved in this field using tandem mass spectrometry (MS/MS). This technology enables the analysis of large numbers of proteins in different body fluids (serum, plasma, urine, saliva, tears) with a single analysis of each sample, and can even be applied to dried samples. MS/MS has thus emerged as the tool of choice for proteome characterization and has provided new insights into many diseases and biological systems. In the last 10 years, sequential window acquisition of all theoretical fragmentation spectra mass spectrometry (SWATH-MS) has emerged as an accurate, high-resolution technique for the identification and quantification of proteins differentially expressed between healthy controls and IMD patients. Proteomics is a particularly promising approach to help obtain more information on rare genetic diseases, including identification of biomarkers to aid early diagnosis and better understanding of the underlying pathophysiology to guide the development of new therapies. Here, we summarize new and emerging proteomic technologies and discuss current uses and limitations of this approach to identify and quantify proteins. Moreover, we describe the use of proteomics to identify the mechanisms regulating complex IMD phenotypes; an area of research essential to better understand these rare disorders and many other human diseases.

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A Proposed Diagnostic Algorithm for Inborn Errors of Metabolism Presenting With Movements Disorders

Cited by 19 publications

References 163 publications

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

Acute Movement Disorders in Childhood

Proteomics in Inherited Metabolic Disorders

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