ABSTRACT
Inborn errors of metabolism constitute a set of hereditary diseases that impose severe medical and physical challenges in the affected individual, in particular, for the pediatric patient population. Timely diagnosis is crucial for these patients, as any delay could result in irreversible health damage, underscoring the importance of early initiation of personalized treatment. Current routine diagnostic screening for inborn errors of metabolism relies on various targeted analyses of established biomarkers. However, this approach is time-consuming, focuses on a limited number of tests (based on clinical information) with a relatively small number of biomarkers, and does not facilitate the identification of new markers. In contrast, untargeted metabolomics-based screening offers a more efficient diagnostic solution, by assessing thousands of metabolites across multiple metabolic pathways in a single test. This not only saves time but also conserves resources for clinicians, the diagnostic laboratory, and for patients.This chapter describes the computational workflow of our "Next Generation Metabolic Screening" approach, which is a metabolomics-based method that is currently applied at the Translational Metabolic Laboratory of the Radboud University Medical Center (the Netherlands) for the diagnosis of inborn errors of metabolism.
Subject(s)
Metabolism, Inborn Errors , Metabolomics , Workflow , Humans , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/metabolism , Metabolomics/methods , Biomarkers , Computational Biology/methods , Software , MetabolomeABSTRACT
Aberrant or dysfunctional cellular enzymes are responsible for a wide range of diseases including cancer, neurodegenerative conditions, and metabolic disorders. Deficiencies in enzyme level or biofunction may lead to intracellular accumulation of substrate to toxic levels and interfere with overall cellular function, ultimately leading to cell damage, disease, and death. Marketed therapeutic interventions for inherited monogenic enzyme deficiency disorders include enzyme replacement therapy and small molecule chaperones. Novel approaches of in vivo gene therapy and ex vivo cell therapy are under clinical evaluation and provide promising opportunities to expand the number of available disease-modifying treatments. To support the development of these different therapeutics, assays to quantify the functional activity of protein enzymes have gained importance in the diagnosis of disease, assessment of pharmacokinetics and pharmacodynamic response, and evaluation of drug efficacy. In this review, we discuss the technical aspects of enzyme activity assays in the bioanalytical context, including assay design and format as well as the unique challenges and considerations associated with assay development, validation, and life cycle management.
Subject(s)
Biomarkers , Drug Development , Metabolism, Inborn Errors , Humans , Biomarkers/metabolism , Metabolism, Inborn Errors/drug therapy , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , Drug Development/methods , Enzyme Assays/methods , Animals , Enzyme Replacement Therapy/methodsABSTRACT
Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme Gfpt1 are critical for T cell expansion and function. Further, T helper (TH1) cells synthesized uridine diphosphate N-acetylglucosamine more rapidly and were more impaired by Gfpt1 deficiency than TH17 cells. Screening IEI genes found that Bcl11b promotes the CD4 T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.
Subject(s)
Metabolism, Inborn Errors , Animals , Metabolism, Inborn Errors/immunology , Metabolism, Inborn Errors/genetics , Humans , Mice , Mice, Inbred C57BL , T-Lymphocytes/immunologyABSTRACT
BACKGROUND: Inherited glycosylphosphatidylinositol (GPI) deficiency is an autosomal recessive disease and a set of syndromes caused by different genes involved in the biosynthesis of phosphatidylinositol characterized by severe cognitive disability, elevated serum alkaline phosphatase (ALP) levels, and distinct facial features. This report presents a patient with inherited GPI deficiency caused by a homozygous frameshift variant of PGAP3 due to uniparental isodisomy (UPiD) on chromosome 17. METHOD: Clinical characteristics of the patient were collected. Microarray analysis followed by adaptive sampling sequencing targeting chromosome 17 was used for the identification of variants. Sanger sequencing was used to confirm the variant in the target region. RESULTS: The patient was born at 38 weeks of gestation with a birthweight of 3893 g. He had a distinctive facial appearance with hypertelorism, wide nasal bridge, and cleft soft palate. Postnatal head magnetic resonance imaging revealed a Blake's pouch cyst. The serum ALP level was 940 IU/L at birth and increased to 1781 IU/L at 28 days of age. Microarray analysis revealed region of homozygosity in nearly the entire region of chromosome 17, leading to the diagnosis of UPiD. Adaptive sampling sequencing targeting chromosome 17 confirmed the homozygous variant NM_033419:c.778dupG (p.Val260Glyfs*14) in the PGAP3 gene, resulting in a diagnosis of inherited GPI deficiency. CONCLUSION: This is the first report of inherited GPI deficiency caused by UPiD. Inherited GPI deficiency must be considered in patients with unexplained hyperphosphatasemia.
Subject(s)
Glycosylphosphatidylinositols , Uniparental Disomy , Humans , Male , Carboxylic Ester Hydrolases , Frameshift Mutation , Glycosylphosphatidylinositols/deficiency , Glycosylphosphatidylinositols/genetics , Homozygote , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/pathology , Phosphorus Metabolism Disorders/genetics , Phosphorus Metabolism Disorders/pathology , Receptors, Cell Surface , Seizures , Uniparental Disomy/genetics , Uniparental Disomy/pathology , Infant, NewbornABSTRACT
Inherited metabolic diseases (IMDs) are a group of heterogeneous genetic disorders resulting in substrate accumulation, energy deficiency, or complex molecular defects due to the failure of specific molecules to act as enzymes, cofactors, transporters, or receptors in specific metabolic pathways. The pathophysiological changes seen in IMDs are sometimes associated with intellectual disability (ID) or neurocognitive decline, necessitating multidisciplinary input. We here describe our experience at one tertiary metabolic centre in the UK. We reviewed the case prevalence and existing service provision in one adult IMD service covering a multi-ethnic population of 10 million in North England. In our cohort of 2268 IMD patients, 1598 patients had general metabolic conditions (70.5%), and 670 had lysosomal storage disease/disorders (LSD)s (29.5%). The overall prevalence of ID and neurocognitive decline was found to be 15.7% (n = 357), with patients with LSDs accounting for 23.5% (n = 84) of affected patients. Given the prevalence of ID in adults with IMDs, access to multidisciplinary input from neuropsychology and neuropsychiatry services is important. Education of healthcare professionals to diagnose IMDs in patients with ID, in addition to neurocognitive and neuropsychiatric presentations, will avoid missed diagnoses of IMD and will have a positive effect on patient outcomes.
Subject(s)
Intellectual Disability , Humans , Intellectual Disability/genetics , Intellectual Disability/epidemiology , Adult , Female , Male , United Kingdom/epidemiology , Middle Aged , Adolescent , Young Adult , Prevalence , Metabolic Diseases/genetics , Metabolic Diseases/epidemiology , Neurocognitive Disorders/epidemiology , Neurocognitive Disorders/etiology , Aged , Cognitive Dysfunction/genetics , Cognitive Dysfunction/epidemiology , Lysosomal Storage Diseases/epidemiology , Lysosomal Storage Diseases/genetics , Metabolism, Inborn Errors/complications , Metabolism, Inborn Errors/epidemiology , Metabolism, Inborn Errors/geneticsABSTRACT
BACKGROUND: Malonyl-CoA decarboxylase (MLYCD) deficiency, also known as malonic aciduria (MAD), is a rare autosomal recessive inherited metabolic defect. In this study, we aimed to investigate the clinical and molecular features of five patients with MAD in order to increase clinicians' awareness of the disease. METHODS: Sanger sequencing was used to detect and genetically analyze the MLYCD variations in the preexisting patients and their parents. RESULTS: Five patients with MAD (5 months to 9.6 years old; two males and three females) rarely exhibited metabolic decompensation episodes or seizures. All patients exhibited varying degrees of developmental delay and hypotonia. Our study expands the spectrum of variants of the MLYCD gene. MLYCD gene variations were detected in all five patients, and five new variants were identified: c.60delG (p.Arg21Glyfs*52), c.928C > T (p.Arg310*), c.1293G > T (p.Trp431Cys), c.721T > C (p.Ser241Pro), and Exons 4-5 deletion. Additionally, there is no correlation between various genotypes and phenotypes. CONCLUSION: A high-medium-chain triglyceride and low-long-chain triglyceride diet supplemented with L-carnitine was effective in most patients and may improve cardiomyopathy and muscle weakness. Newborn screening may aid in the early diagnosis, treatment, and prognosis of this rare disorder.
Subject(s)
Carboxy-Lyases , Metabolism, Inborn Errors , Child , Child, Preschool , Female , Humans , Infant , Male , Carboxy-Lyases/genetics , Carboxy-Lyases/deficiency , Follow-Up Studies , Malonyl Coenzyme A , Metabolism, Inborn Errors/genetics , Metabolism, Inborn Errors/diagnosis , Methylmalonic Acid , PhenotypeABSTRACT
There are many different genetic diseases called inborn errors of metabolism (IEM) which result from defective enzymes in the metabolic pathway. As a result, these defects either cause a harmful accumulation of substances or lead to a lack of certain types of molecule. The present review traces the origin and development of IEMs from Sir Archibald Garrod's theory in the early 20th century to current diagnostic and therapeutic approaches. It also involves a systematic literature review complying with PRISMA which included studies sourced from PubMed, Scopus, Web of Science and Google Scholar. It points out that high rates of consanguinity are associated with high prevalence rates for IEMs especially in the Eastern Mediterranean area. IEMS are classified as energy deficiency disorders, intoxication disorders, and storage disorders. Each category has a variety of clinical manifestations. This study incorporates different diagnostic methods ranging from simple biochemical tests to tandem mass spectrometry and next generation sequencing; while management approaches such as dietary modifications, enzyme replacement therapy and gene therapy were assessed for their efficacy. Specific attention is paid to Pakistan where there exists considerable consanguinity among people coupled with inadequate health care services which have seriously affected delivery of health care services thereby leading to numerous challenges for the country healthcare system during service provision.
Subject(s)
Metabolism, Inborn Errors , Humans , Metabolism, Inborn Errors/therapy , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/genetics , History, 20th Century , Genetic Therapy , Enzyme Replacement Therapy , History, 21st CenturyABSTRACT
La clorhidrorrea congénita es un trastorno genético infrecuente pero importante caracterizado por una alteración grave del balance hidroelectrolítico como resultado de un defecto en la absorción intestinal de cloruros. Los niños afectados presentan diarrea persistente, deshidratación y malnutrición; el control médico y del desarrollo son complejos. Mejorar la detección prenatal es esencial para facilitar la atención del paciente, las intervenciones tempranas y el asesoramiento genético informado. Sin embargo, a pesar de los avances de la medicina, la naturaleza compleja y la escasa frecuencia de esta entidad, constituyen un desafío para la detección prenatal. En este estudio, se reporta el caso de una embarazada donde los estudios por imágenes de resonancia magnética fetales identificaron en forma efectiva las características típicas de la clorhidrorrea congénita. Se proveen conocimientos sobre las complejidades del diagnóstico y se sugieren caminos para las estrategias de detección temprana de esta enfermedad.
Congenital chloride diarrhea (CCD) is a rare but significant genetic disorder characterized by severe electrolyte imbalances resulting from impaired intestinal chloride absorption. Affected children experience persistent diarrhea, dehydration, and malnutrition, complicating medical and developmental care. The enhancement of prenatal detection is crucial for improved patient management, early interventions, and informed genetic counseling. However, despite advancements in medicine, the complex nature and rarity of CCD make prenatal detection challenging. In this study, we report a fetal case where prenatal magnetic resonance imaging (MRI) effectively identified the distinctive characteristics of CCD, providing insights into the complexities of diagnosis and suggesting avenues for enhanced early detection strategies.