Lecture 8 Inborn Errors of Metabolism PDF

Advanced Clinical Chemistry Dr. Ayman Mustafa Abu Mustafa Lecture 8: Inborn Errors of Metabolism 1 Definition and...

Advanced Clinical Chemistry Dr. Ayman Mustafa Abu Mustafa Lecture 8: Inborn Errors of Metabolism 1 Definition and Importance of Inborn Errors of Metabolism ❑ Overview of Inborn Errors of Metabolism (IEM( ▪ Rare genetic disorders that affect metabolic pathways, leading to disruptions in normal biochemical processes. ❑ Importance of Early Detection and Treatment ▪ Early intervention can prevent severe outcomes such as neurological damage, organ failure, or death. ▪ Screening and diagnosis are key to managing these disorders effectively. ❑ Clinical Significance ▪ Pediatrics: Most IEM manifest in infancy or early childhood. ▪ Neurology: Many IEM affect the nervous system, leading to developmental delays, seizures, and intellectual disabilities. ▪ Genetics: IEM are inherited in various patterns, and genetic testing helps in diagnosis and family planning. 2 Dr. Ayman Mustafa Abu Mustafa 1  Classification of Inborn Errors of Metabolism ❑ Classification of Inborn Errors of Metabolism ▪ Disorders of carbohydrate metabolism. ▪ Disorders of amino acid metabolism. ▪ Disorders of fatty acid metabolism. ▪ Organic acidemias. ▪ Lysosomal storage diseases. ▪ Mitochondrial diseases. ▪ Urea cycle disorders 3 I. Inborn Errors of Carbohydrate Metabolism ▪ Galactosemia ▪ Hereditary Fructose Intolerance ▪ Glycogen Storage Diseases 4 Dr. Ayman Mustafa Abu Mustafa 2  1. Galactosemia ❑ Pathophysiology ▪ Deficiency in galactose-1-phosphate uridylyltransferase. ▪ This enzyme defect leads to the accumulation of galactose-1-phosphate in tissues. ❑ Clinical Features: ▪ Failure to thrive: Poor growth and feeding issues in infants. ▪ Liver damage: Hepatomegaly, jaundice, and cirrhosis. ▪ Cataracts: Clouding of the lens in the eye leading to vision impairment 5 1. Galactosemia 6 Dr. Ayman Mustafa Abu Mustafa 3  1. Galactosemia ❑ Diagnosis: ▪ Blood tests: Elevated galactose levels. ▪ Enzyme assays: Low galactose-1-phosphate uridylyltransferase activity. ❑ Management: ▪ Galactose-free diet: Avoidance of milk and dairy products. ▪ Early dietary management prevents long-term complications. 7 2. Hereditary Fructose Intolerance ❑ Pathophysiology: ▪ Deficiency in aldolase B, an enzyme involved in fructose metabolism. ▪ Inability to break down fructose-1-phosphate, leading to toxic accumulation in the liver, kidneys, and small intestine. ❑ Clinical Features: ▪ Hypoglycemia: Low blood sugar levels, especially after fructose intake. ▪ Liver dysfunction: Jaundice, hepatomegaly, and potential liver failure following fructose ingestion. 8 Dr. Ayman Mustafa Abu Mustafa 4  2. Hereditary Fructose Intolerance 9 2. Hereditary Fructose Intolerance ❑ Diagnosis: ▪ Enzyme assays: Reduced aldolase B activity in liver tissue. ▪ Genetic testing: Identification of mutations in the aldolase B gene. ❑ Management: ▪ Avoidance of fructose, sucrose, and sorbitol: Strict dietary control to prevent symptoms. ▪ Lifelong dietary modification is essential to prevent acute episodes. 10 Dr. Ayman Mustafa Abu Mustafa 5  3. Glycogen Storage Diseases (GSD) ❑ GSD Type I (Von Gierke’s Disease): ▪ Deficiency in glucose-6-phosphatase. ▪ Leads to accumulation of glycogen in the liver and kidneys, causing hypoglycemia and hepatomegaly. ❑ GSD Type II (Pompe Disease): ▪ Deficiency in acid alpha-glucosidase (lysosomal enzyme). ▪ Glycogen accumulates in lysosomes, leading to muscle weakness, cardiomyopathy, and respiratory issues. 11 3. Glycogen Storage Diseases (GSD) ❑ Diagnosis: ▪ Enzyme assays: Measurement of specific enzyme activities (e.g., glucose-6-phosphatase, acid alpha-glucosidase). ▪ Liver biopsy: To assess glycogen accumulation and enzyme deficiency. ❑ Management: ▪ GSD Type I: Glucose supplementation to prevent hypoglycemia and maintain normal blood glucose levels. ▪ GSD Type II (Pompe Disease): Enzyme replacement therapy (ERT) to restore enzyme function and manage symptoms. 12 Dr. Ayman Mustafa Abu Mustafa 6  II. Inborn Errors of Amino Acid Metabolism 13 1. Phenylketonuria (PKU) ❑ Pathophysiology: ▪ Deficiency in phenylalanine hydroxylase. ▪ Leads to the accumulation of phenylalanine in blood and tissues, which is toxic to the brain. ❑ Clinical Features: ▪ Intellectual disability: Progressive cognitive decline if untreated. ▪ Hypopigmentation: Lighter skin and hair color. ▪ Eczema and seizures: Other neurological and dermatological manifestations. 14 Dr. Ayman Mustafa Abu Mustafa 7  1. Phenylketonuria (PKU) 15 1. Phenylketonuria (PKU) ❑ Diagnosis: ▪ Elevated phenylalanine levels in blood via neonatal screening. ❑ Management: ▪ Strict low-phenylalanine diet: Avoid foods rich in phenylalanine (e.g., meat, dairy, nuts). ▪ Tyrosine supplementation: To provide an alternative pathway for melanin production and other metabolic functions. 16 Dr. Ayman Mustafa Abu Mustafa 8  2. Alkaptonuria ❑ Pathophysiology: ▪ Deficiency in homogentisate 1,2-dioxygenase. ▪ Leads to the accumulation of homogentisic acid, which deposits in tissues and causes damage. ❑ Clinical Features: ▪ Dark urine: Urine turns black upon standing due to homogentisic acid. ▪ Ochronosis: Blue-black discoloration of connective tissues, especially in the ears, nose, and eyes. ▪ Arthritis: Due to the deposition of homogentisic acid in joints, leading to joint pain and stiffness. 17 Phenylalanine and tyrosine metabolism 18 Dr. Ayman Mustafa Abu Mustafa 9  2. Alkaptonuria ❑ Diagnosis: ▪ Elevated homogentisic acid in urine detected through urine organic acid analysis. Urine becomes black on exposure to air ❑ Management: ▪ Symptomatic treatment for arthritis: Pain management, physical therapy. ▪ Dietary restrictions: Limiting phenylalanine and tyrosine intake to reduce homogentisic acid accumulation. 19 3. Albinism ❑ Pathophysiology: ▪ Genetic mutations affecting melanin production, often involving defects in the tyrosinase enzyme or other enzymes in the melanin biosynthesis pathway. ❑ Clinical Features: ▪ Lack of pigmentation in skin, hair, and eyes. ▪ Sensitivity to light: Vision problems due to lack of pigmentation in the retina. ▪ Increased risk of skin cancer due to lack of UV protection in the skin. 20 Dr. Ayman Mustafa Abu Mustafa 10  3. Albinism ❑ Diagnosis: ▪ Genetic testing: Identifies mutations in genes related to melanin production. ▪ Low melanin levels in skin and hair. ❑ Management: ▪ Sun protection: Avoidance of sun exposure, use of sunscreen to prevent skin damage. ▪ Regular eye exams: To manage vision problems. ▪ Skin cancer surveillance: Regular skin checks due to increased risk of malignancies. 21 4. Homocystinuria ❑ Pathophysiology: ▪ Deficiency in cystathionine β-synthase, an enzyme involved in the conversion of homocysteine to cysteine. ▪ Accumulation of homocysteine in plasma and tissues, leading to damage in various organs. ❑ Clinical Features: ▪ Marfanoid features: Tall stature, long limbs, and arachnodactyly (long, thin fingers). ▪ Mental retardation: Intellectual disabilities and developmental delays. ▪ Thromboembolic events: Increased risk of blood clots, leading to stroke, deep vein thrombosis (DVT), and pulmonary embolism. 22 Dr. Ayman Mustafa Abu Mustafa 11  Methionine metabolism 23 4. Homocystinuria ❑ Diagnosis: ▪ Elevated homocysteine levels in plasma. ▪ Genetic testing can confirm the deficiency of cystathionine β- synthase. ❑ Management ▪ Vitamin B6, B12, and folate supplementation: To help reduce homocysteine levels. ▪ Dietary restrictions: Low methionine diet to reduce homocysteine buildup. 24 Dr. Ayman Mustafa Abu Mustafa 12  5. Maple Syrup Urine Disease (MSUD) ❑ Pathophysiology: ▪ Deficiency in branched-chain α-keto acid dehydrogenase, an enzyme responsible for metabolizing branched-chain amino acids (BCAAs). ▪ Leads to the accumulation of BCAAs (valine, leucine, and isoleucine) and their toxic metabolites. ❑ Clinical Features: ▪ Neonatal encephalopathy: Severe neurological symptoms such as lethargy, poor feeding, seizures, and developmental delays. ▪ Sweet-smelling urine: A distinctive odor of maple syrup, caused by the buildup of branched-chain amino acids. 25 5. Maple Syrup Urine Disease (MSUD) ❑ Diagnosis: ▪ Elevated branched-chain amino acids in plasma: Diagnostic marker for MSUD. ▪ Genetic testing may confirm the specific enzyme deficiency. ❑ Management: ▪ Restriction of branched-chain amino acids in the diet: Special low-protein foods to limit BCAA intake. ▪ Lifelong dietary management to prevent metabolic crises. 26 Dr. Ayman Mustafa Abu Mustafa 13  III. Inborn Errors of Fatty Acid Metabolism 27 1. Carnitine/Acylcarnitine Translocase Deficiency ❑ Pathophysiology: ▪ Defect in mitochondrial carnitine transporter. ▪ Impairs the transport of long-chain fatty acids into the mitochondria for β-oxidation, leading to an energy deficit. ❑ Clinical Features: ▪ Hypoglycemia: Due to impaired fatty acid oxidation, leading to low blood sugar. ▪ Muscle weakness: Decreased energy production in muscles, resulting in fatigue and weakness. ▪ Cardiomyopathy: Heart muscle dysfunction due to lack of energy substrates. 28 Dr. Ayman Mustafa Abu Mustafa 14  1. Carnitine/Acylcarnitine Translocase Deficiency ❑ Diagnosis: ▪ Plasma acylcarnitine profile: Detection of abnormal acylcarnitine levels, particularly long-chain acylcarnitines. ❑ Management: ▪ Carnitine supplementation: To bypass the transporter defect and promote fatty acid metabolism. ▪ Low-fat diet: To reduce the reliance on fatty acids as an energy source and manage metabolic stress. 29 2. Medium-chain Acyl-CoA Dehydrogenase Deficiency (MCAD) ❑ Pathophysiology: ▪ Impairment in the β-oxidation of medium-chain fatty acids. ▪ Deficiency in MCAD enzyme prevents proper breakdown of medium-chain fatty acids, leading to an accumulation of these fatty acids and reduced energy production during fasting. ❑ Clinical Features: ▪ Fasting hypoglycemia: Inability to mobilize fatty acids for energy during periods of fasting, leading to low blood sugar. ▪ Vomiting and lethargy: Due to energy deficits and metabolic disturbances 30 Dr. Ayman Mustafa Abu Mustafa 15  2. Medium-chain Acyl-CoA Dehydrogenase Deficiency (MCAD) ❑ Diagnosis: ▪ Elevated C6-C10 acylcarnitines in blood: The presence of these medium-chain fatty acid metabolites in the blood confirms the diagnosis of MCAD deficiency. ❑ Management: ▪ Avoidance of fasting: Frequent meals to maintain blood glucose levels. ▪ Regular meals: High carbohydrate diet to prevent hypoglycemia. ▪ Emergency glucose administration: Immediate treatment during episodes of metabolic crisis. 31 3. Very-long-chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) ❑ Pathophysiology: ▪ Defect in long-chain fatty acid oxidation. ▪ Inability to properly break down long-chain fatty acids, resulting in an accumulation of these fatty acids and energy deficits during periods of fasting or metabolic stress. ❑ Clinical Features: ▪ Hypoglycemia: Due to impaired fatty acid oxidation and energy production. ▪ Cardiomyopathy: Heart muscle dysfunction due to the inability to use fatty acids as an energy source. ▪ Rhabdomyolysis: Breakdown of muscle tissue, leading to muscle pain, weakness, and release of muscle proteins into the bloodstream. 32 Dr. Ayman Mustafa Abu Mustafa 16  3. Very-long-chain Acyl-CoA Dehydrogenase Deficiency (VLCAD) ❑ Diagnosis: ▪ Elevated long-chain acylcarnitines: Detected in blood plasma, confirming the impairment in fatty acid oxidation. ❑ Management: ▪ Avoidance of fasting: Prevents the onset of metabolic crises by ensuring consistent energy intake. ▪ Dietary fat management: Low-fat diet to reduce the burden on the impaired oxidation pathway. 33 IV. Organic Acidemias 34 Dr. Ayman Mustafa Abu Mustafa 17  Organic Acidemias ❑ Examples of Organic Acidurias: ▪ Methylmalonic Acidemia (MMA): Defect in methylmalonyl- CoA mutase. ▪ Propionic Acidemia: Defect in propionyl-CoA dehydrogenase. ▪ Isovaleric Acidemia: Defect in isovaleryl-CoA dehydrogenase. ❑ Clinical Features: ▪ Acute metabolic crises: Rapid onset of symptoms often triggered by illness or fasting. ▪ Vomiting and lethargy: Common signs of metabolic decompensation. ▪ Neurological symptoms: Seizures, developmental delay, and cognitive issues due to metabolic imbalance. 35 Organic Acidemias 36 Dr. Ayman Mustafa Abu Mustafa 18  Organic Acidemias ❑ Diagnosis: ▪ Urine organic acids: Elevated levels of organic acids specific to each disorder. ▪ Blood ammonia levels: Often elevated in metabolic crises, indicating a buildup of toxic metabolites. ❑ Management: ▪ Low-protein diet: Restriction of protein intake to prevent the buildup of toxic metabolites. ▪ Metabolic supplementation: Use of supplements such as carnitine, coenzyme Q10, or specific cofactors to aid in metabolic pathways. ▪ Emergency care: Rapid glucose administration and other interventions during acute metabolic crises to stabilize the patient. 37 V. Mitochondrial Disorders ▪ Mitochondrial Myopathy ▪ Mitochondrial Diseases 38 Dr. Ayman Mustafa Abu Mustafa 19  1. Mitochondrial Myopathy ❑ Pathophysiology: ▪ Defects in mitochondrial DNA or nuclear genes affecting energy production. ▪ Mitochondria fail to produce adequate ATP, leading to energy deficits in cells with high energy demands, particularly muscle cells. ❑ Clinical Features: ▪ Muscle weakness: Progressive weakness, especially in proximal muscles. ▪ Exercise intolerance: Difficulty in performing physical activities due to insufficient muscle energy. ▪ Lactic acidosis: Accumulation of lactic acid due to impaired oxidative phosphorylation. 39 1. Mitochondrial Myopathy ❑ Diagnosis: ▪ Muscle biopsy: Histological examination reveals ragged red fibers, indicating mitochondrial dysfunction. ▪ Mitochondrial DNA analysis: Identifies mutations in mitochondrial or nuclear genes responsible for mitochondrial function. ❑ Management: ▪ Supportive care: Includes physical therapy, respiratory support, and symptom management. ▪ Coenzyme Q10 supplementation: Helps enhance mitochondrial function and energy production. 40 Dr. Ayman Mustafa Abu Mustafa 20  2. Examples of Mitochondrial Diseases ❑ Leber's Hereditary Optic Neuropathy (LHON): ❑ Pathophysiology: ▪ Mitochondrial DNA mutations affecting optic nerve function. ❑ Clinical Features: ▪ Progressive vision loss, starting with central vision, often leading to blindness. 41 2. Examples of Mitochondrial Diseases ❑ MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes): ❑ Pathophysiology: ▪ Mutations in mitochondrial DNA leading to defective oxidative phosphorylation. ❑ Clinical Features: ▪ Recurrent stroke-like episodes, lactic acidosis, seizures, and muscle weakness. 42 Dr. Ayman Mustafa Abu Mustafa 21  2. Examples of Mitochondrial Diseases ❑ Diagnosis: ▪ Genetic testing: Identification of mitochondrial DNA mutations specific to each disease. ▪ Mitochondrial enzyme assays: Measure the activity of mitochondrial enzymes to assess mitochondrial dysfunction. ❑ Management: ▪ Symptomatic treatment: Pain management, anticonvulsants for seizures, and rehabilitation. ▪ Avoiding triggers: Preventing metabolic stress, avoiding fasting, and managing infections or other triggers that can exacerbate symptoms. 43 VI. Lysosomal Storage Diseases (LSD) 44 Dr. Ayman Mustafa Abu Mustafa 22  VI. Lysosomal Storage Diseases (LSD) ❑ Types of Lysosomal Storage Disorders ▪ Gaucher's Disease: Glucocerebrosidase deficiency. ▪ Tay-Sachs Disease: Hexosaminidase A deficiency. ▪ Niemann-Pick Disease: Sphingomyelinase deficiency. ▪ Sandhoff’s Disease: Hexosaminidase B deficiency. ❑ Clinical Features: ▪ Organomegaly, neurodegeneration, developmental delay. ❑ Diagnosis: ▪ Enzyme activity assays, genetic testing. ❑ Management: ▪Enzyme replacement therapy (ERT), substrate reduction therapy (SRT), supportive care 45 VII. Urea Cycle Disorders 46 Dr. Ayman Mustafa Abu Mustafa 23  VII. Urea Cycle Disorders ❑ Overview of Urea Cycle ▪ Pathways involved in ammonia detoxification. ▪ Key enzymes: Carbamoyl-phosphate synthetase I, Ornithine transcarbamylase. ❑ Common Urea Cycle Disorders ▪ Ornithine transcarbamylase deficiency (OTC). ▪ Argininosuccinate synthetase deficiency. ▪ Clinical Features: Hyperammonemia, vomiting, lethargy, and potential coma. ❑ Diagnosis: ▪ Elevated ammonia levels, blood amino acid analysis. ❑ Management: ▪ Protein restriction, ammonia scavengers (e.g., sodium benzoate, phenylbutyrate), liver transplant in severe cases 47 48 Dr. Ayman Mustafa Abu Mustafa 24  Diabetes Mellitus Type 1 ❑ Pathophysiology: ▪ Autoimmune destruction of insulin-producing β-cells in the pancreas. ▪ Leads to insulin deficiency, causing elevated blood glucose levels (hyperglycemia). ❑ Clinical Features: ▪ Polyuria: Excessive urination due to high glucose levels in the blood that spill over into the urine. ▪ Polydipsia: Increased thirst as the body attempts to compensate for fluid loss due to polyuria. ▪ Weight loss: Despite increased food intake, the body breaks down fat and muscle for energy due to the lack of insulin. ▪ Diabetic Ketoacidosis (DKA): Severe complication with symptoms like nausea, vomiting, abdominal pain, and fruity- smelling breath due to the buildup of ketones. 49 Diabetes Mellitus Type 1 ❑ Diagnosis: ▪ Blood glucose tests: Elevated fasting blood glucose (>126 mg/dL) or random blood glucose >200 mg/dL. ▪ HbA1c: Long-term blood glucose control measurement; ≥6.5% indicates diabetes. ▪ Autoantibody testing: Identifies antibodies against β-cells (e.g., GAD65, IA-2), supporting autoimmune origin. ❑ Management: ▪ Insulin therapy: Administered through injections or pumps to regulate blood glucose levels. ▪ Blood glucose monitoring: Regular checks to track glucose levels and adjust insulin doses. ▪ Dietary management: Tailoring carbohydrate intake with insulin therapy to maintain stable blood glucose levels. 50 Dr. Ayman Mustafa Abu Mustafa 25  Advanced Medical Biochemistry Dr. Ayman Mustafa Abu Mustafa 26