inherited metabolic disorders - flashcards

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  • Title: UCI Inborn errors of metabolism

  • Author: Dr. Leila Zeinab Asgarian

  • Date: October 2024

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Metabolism

  • Definition: Sum of all chemical reactions in the body.

  • Functions:

    • Energy Production: Enzymes break down food for immediate fuel or storage.

    • Substance Management: Processes create necessary substances and break down waste.

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Cellular Components in Metabolism

  • Transporter Proteins: Move substances across cell membranes.

  • Mitochondria: Breakdown glucose and fatty acids to produce ATP through:

    • Krebs cycle

    • Electron transport chain

  • Lysosomes: Contain digestive enzymes (proteases, lipases, glycosidases, phosphatases) for macromolecule degradation.

  • Peroxisomes: Detoxify harmful byproducts of metabolism.

  • Smooth ER: Involved in lipid synthesis and carbohydrate metabolism.

  • Transcription Factors: Regulate gene expression related to metabolism.

  • Energy and Nutritional Sensors:

    • AMP-K: Stimulates glucose uptake and lipid oxidation.

    • mTOR: Promotes biosynthesis.

  • Kinases and Phosphatases: Modulate the activity of metabolic enzymes.

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Key Metabolic Pathways and Substances

  • Glycogen Storage: Multiple related diseases and pathways.

  • Amino Acid Metabolism: Overview of biochemical compounds, their pathways, and metabolic diseases based on enzyme deficiencies.

  • Diseases: Tyrosinaemia, Phenylketonuria (PKU), and various glycogen storage diseases (GSD).

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Peroxisomal Defects and Organic Acidurias

  • Discusses links between various fatty acids and their functions.

  • Overview of organic acidurias and related enzyme deficiencies.

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Inborn Errors of Metabolism (IEM)

  • Definition: Conditions caused by genetic changes affecting metabolism, leading to enzyme deficiencies.

  • Symptoms can result from toxic substance accumulation, impacting cellular functions.

  • Prevalence: Approximately 1 in 800-2500 at birth. Presentation varies from infancy to adulthood.

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Classification of IEM

  • Discusses classical IEMs and metal disorders such as Wilson's disease and hemochromatosis.

  • Notes on neurodegeneration associated with metal metabolism disorders.

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Distribution of Metabolic Disorders

  • Pie-chart representation of categories:

    • Mitochondrial disorders (19%)

    • Disorders of metal metabolism (3%)

    • Peroxisomal disorders (3%)

    • Disorders of steroid metabolism (5%)

    • Glycosylation disorders (12%)

    • Other disorders percentage distributions.

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Genetics of Metabolic Disorders

  • Enzymatic deficiencies arise from genetic mutations, impacting metabolic pathways.

  • Consequences of enzyme inactivity leading to metabolite accumulation and toxicity.

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Specific Genetic Disorders

  • Urea Cycle Disorders: Focus on nitrogen compound disorders affecting ammonia processing.

  • Glycogen Metabolism Disorders: Diseases like Gierke disease, Pompe disease, etc., related to glucose storage and utilization.

  • Fatty Acid Breakdown Disorders: Impacts of mutations in key enzymes on fatty acid metabolism.

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Case Study: Maple Syrup Urine Disease (MSUD)

  • BCAAs essential amino acids, enzyme mutations causing MSUD.

  • Neurochemical implications and dietary treatment options.

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Genetic Diversity in IEMs

  • Discussion of allele frequencies, causative mutations, and familial transmission.

  • Importance of genomic studies in identifying metabolic disorders.

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Diagnostic Procedures and Challenges

  • Overview of newborn screening for IEMs in the UK.

  • Diagnostic challenges due to biomarker overlap among metabolic pathways.

  • Importance of integrated genomic analysis for accurate diagnosis.

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Diagnostic Complexity in IEM

  • Diagnosis can extend beyond neonatal period; understanding effector transcripts is crucial.

  • GWAS significance in connecting genetic variations to disease mechanisms.

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Genetic Architecture of Metabolic Traits

  • Discussion on examples of genetic obesity as a form of IEM.

  • Involvement of specific genes (LEP, MC4R) in metabolic pathways.

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Treatment and Management of IEMs

  • Emotional and financial burden: Symptoms linked to IEMs and their management strategies.

  • Overview of dietary and regenerative treatment options, including gene therapy prospects.

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Acknowledgments

  • List of contributors from UCL Institute of Child Health and other affiliated institutions.