13.1 Overview of Inborn Errors of Metabolism

Inborn errors of metabolism are genetic disorders that disrupt normal metabolic processes. These conditions result from enzyme deficiencies, leading to toxic buildup or essential nutrient shortages. Understanding their genetic basis and metabolic consequences is crucial for proper diagnosis and management.

Diagnosis often begins with newborn screening, followed by confirmatory tests like biochemical analysis and genetic testing. Early detection enables timely intervention, potentially preventing severe complications. Prenatal diagnosis and genetic counseling are important for at-risk families planning future pregnancies.

Genetic Basis of Inborn Errors of Metabolism

Understanding Inborn Errors of Metabolism

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• Inborn errors of metabolism result from genetic defects affecting metabolic pathways
• Occur when enzymes responsible for specific biochemical reactions are absent or deficient
• Lead to accumulation of toxic substances or deficiency of essential metabolites
• Can affect various metabolic processes including carbohydrate, protein, and fat metabolism
• First described by Sir Archibald Garrod in early 1900s, identifying alkaptonuria as an inherited disorder

Enzyme Deficiencies and Genetic Mutations

• Enzyme deficiencies stem from genetic mutations altering protein structure or function
• Mutations can occur in coding regions, regulatory regions, or splice sites of genes
• Types of mutations include missense, nonsense, frameshift, and splice site mutations
• Single nucleotide polymorphisms (SNPs) can also contribute to enzyme deficiencies
• Severity of enzyme deficiency depends on the type and location of the genetic mutation

Inheritance Patterns and Genetic Transmission

• Most inborn errors of metabolism follow autosomal recessive inheritance pattern
• Requires two copies of the mutated gene, one from each parent, for disease manifestation
• Carriers (heterozygotes) typically do not show symptoms but can pass the mutation to offspring
• Some disorders follow X-linked inheritance patterns (Lesch-Nyhan syndrome)
• Mitochondrial inheritance occurs in disorders affecting mitochondrial DNA (MELAS syndrome)
• De novo mutations can cause sporadic cases without family history

Metabolic Consequences and Manifestations

Disruption of Metabolic Pathways

• Metabolic pathways comprise series of enzyme-catalyzed reactions
• Enzyme deficiencies disrupt normal flow of metabolites through pathways
• Can lead to accumulation of substrates or intermediates upstream of the block
• May result in deficiency of products downstream of the enzymatic block
• Affects major metabolic processes (glycolysis, fatty acid oxidation, amino acid metabolism)

Biochemical Abnormalities and Metabolite Accumulation

• Abnormal accumulation of metabolites occurs due to pathway disruptions
• Toxic metabolites can damage various organs and tissues (brain, liver, kidneys)
• Metabolite accumulation detectable in blood, urine, or cerebrospinal fluid
• Examples include elevated phenylalanine in phenylketonuria (PKU) and elevated very long-chain fatty acids in adrenoleukodystrophy
• Deficiency of essential metabolites can also occur (lack of thyroid hormones in congenital hypothyroidism)

Clinical Manifestations and Disease Progression

• Acute metabolic crisis characterized by sudden onset of severe symptoms
• Can be triggered by stress, infection, or dietary changes
• Symptoms include vomiting, lethargy, seizures, and coma
• Chronic progressive disease develops over time with gradual accumulation of toxic metabolites
• Can lead to developmental delays, intellectual disability, and organ dysfunction
• Specific clinical features vary depending on the affected metabolic pathway and organs involved

Diagnosis and Detection

Newborn Screening and Early Detection

• Newborn screening programs test for various inborn errors of metabolism
• Utilizes dried blood spots collected shortly after birth
• Tandem mass spectrometry (MS/MS) allows simultaneous screening for multiple disorders
• Detects abnormal levels of specific metabolites indicative of metabolic disorders
• Enables early diagnosis and intervention before symptom onset
• Screening panels vary by country and region, but typically include disorders like PKU, galactosemia, and maple syrup urine disease

Diagnostic Methods and Confirmatory Testing

• Suspected cases identified through newborn screening require confirmatory testing
• Biochemical analysis of blood, urine, and cerebrospinal fluid to measure metabolite levels
• Enzyme activity assays to determine the presence and function of specific enzymes
• Genetic testing to identify specific mutations responsible for the disorder
• Imaging studies (MRI, CT) to assess organ involvement and structural abnormalities
• Specialized tests like skin fibroblast culture for certain disorders (peroxisomal disorders)

Prenatal Diagnosis and Genetic Counseling

• Prenatal diagnosis available for families with known genetic risk
• Methods include chorionic villus sampling and amniocentesis
• Genetic counseling crucial for families with affected individuals or carriers
• Discusses inheritance patterns, recurrence risks, and available testing options
• Preimplantation genetic diagnosis offers option for at-risk couples undergoing in vitro fertilization