FFP1-IEM-2024-25-Final.pptx - Inborn Errors of Metabolism

Royal College of Surgeons in Ireland – Medical University of Bahrain Inborn Errors of Metabolism Module :FFP1 Code :MEDI-101-FFP1 Class: MedYear1 semester 1 Lecturer: Dr Jeevan Shetty Date : 20th Oct 2024  Royal College of Surgeons in Ireland – Medical University of Bahrai...

Royal College of Surgeons in Ireland – Medical University of Bahrain Inborn Errors of Metabolism Module :FFP1 Code :MEDI-101-FFP1 Class: MedYear1 semester 1 Lecturer: Dr Jeevan Shetty Date : 20th Oct 2024  Royal College of Surgeons in Ireland – Medical University of Bahrain Learning Outcomes  Describe the classification of IEMs  Describe new-born screening to detect inborn errors  Discuss disorders of amino acid metabolism – Phenylketonuria, tyrosinemia, organic aciduria, alkaptonuria, maple syrup urine disease  Discuss disorders of lipid metabolism (MCAD)  Discuss disorders of energy metabolism and mitochondrial disorders  Discuss disorders of gluconeogenesis  Discuss disorders of carbohydrate metabolism (galactosemia, hereditary fructose intolerance and fructosuria)  Outline disorders involving complex molecules, including Inborn Errors of Metabolism Genetic disorders of metabolism involve single genes – enzymes involved in metabolic pathways or – transport proteins. Clinical presentation usually arises due to: Diversion to alternate product C – accumulation of toxic substances which interfere with normal function – deficiency of product of a metabolic pathway Deficiency of product B Accumulation of substrate A Metabolic consequences Inborn errors of metabolism (IEMs) Individually rare but collectively common Mode of inheritance Presentation – at any age, even in adulthood Diagnosis – “does not necessarily require extensive knowledge of biochemical pathways or individual metabolic diseases.” – understanding of broad clinical manifestations of IEMs provides the basis for knowing when to consider the diagnosis – high ‘index of suspicion is most important in making a diagnosis Emergency treatment – depends on prompt institution of therapy aimed at metabolic stabilization Age of onset of IEMs Age at clinical presentation varies for individual IEM and variants. Timing of presentation depends on: – significant accumulation of toxic metabolites – deficiency of the product Onset and severity may be exacerbated by environmental factors: – diet – intercurrent illness Disorders of carbohydrate or protein metabolism and energy production tend to: – present in the neonatal period or early infancy – to be unrelenting and rapidly progressive – less severe variants usually present later and are episodic Fatty acid oxidation, glycogen storage, and lysosomal storage disorders tend to: – present insidiously in infancy or childhood with subtle neurological – or psychiatric features often undiagnosed until adulthood Newborn screening- Rationale Early detection, before the onset of any clinical manifestations. Early introduction of treatment, leads to better clinical outcomes, Reduces morbidity or prevent premature mortality. “Heel-prick” test @3-5 days old “Guthrie” small blood sample taken from heel and tested – biochemical abnormalities, genetic tests, mass-spectrometry National Newborn Screening Programme for inherited metabolic and congenital disorders (Ireland) Classification of IEM Group 1: disorders which give rise to intoxication: –IEMs leading to progressive accumulation of toxic compounds, proximal to block PKU, MSUD, organic acidurias Group 2: disorders involved in energy metabolism –IEM of intermediary metabolism, symptoms due in part to energy deficiency Mitochondrial or cytoplasmic energy defects Group 3: disorders involving complex molecules –Involves cellular organelles ,including diseases associated with disturbed synthesis or catabolism of complex molecules Lysosomal storage disorders, peroxisomal disorders and intracellular trafficking (congenital disorders of glycosylation) - Jean-Marie Saudubray Group 1: disorders which give rise to intoxication Share clinical similarities: Amino acidopathies: Do not interfere with embryo-foetal Phenylketonuria, Maple Syrup Urine development Disease, Homocystinuria, Tyrosinemia Present after a symptom-free interval Organic acidurias: Methylmalonic aciduria, Propionic aciduria, Glutaric aciduria Type l Urea cycle disorders Clinical signs of intoxication may be: – Acute – vomiting, coma, liver Ornithine TransCarbamylase (OTC) failure deficiency, Citrullinaemia – Chronic – failure to thrive, Sugar intolerances developmental delay, ectopia Classical Galactosaemia, Hereditary lentis (dislocation of lens) Fructose Intolerance Metal intoxication Wilson’s disease, Menkes disease, Many are treatable with the removal Haemochromatosis of toxin Porphyria's  Classical PKU Metabolism of Phenylalanine and Tyrosine Albinism Hypopigmentation PHENYLALANINE PKU Phenylalanine hydroxylase TYROSINE MELANIN Tyrosine aminotransferase 4-HYDROXYPHENYLPYRUVIC ACID 4-hydroxyphenylpyruvic acid oxidase HOMOGENTISIC ACID musty Alkaptonuria Homogentisic acid oxidase (“mousy”) odor MALEYLACETOACETIC ACID Maleylacetoacetate isomerase FUMARYLACETOACETIC ACID Fumarylacetoacetate hydrolase Tyrosinaemia Type I FUMARATE + ACETOACETATE CO2 + H2O BH4 – Tetrahydrobiopterin BH2 - Dihydrobiopterin Glucogenic & ketogenic Phenylketonuria – PKU (hyperphenylalaninaemia) Clinical symptoms: irritability, vomiting, fits. mental Inheritance Autosomal recessive retardation by 4 - 6 Incidence = 1 in 4,500 (Ireland) – 1 in 11,000 USA ~ 97% due to PAH enzyme defect months ~ 3% due to defective synthesis of cofactor, reduced melanin production tetrahydrobiopterin pale skin, fair hair, blue eyes Diagnosis: Newborn screen (Heel-prick / Guthrie) test frequently, generalised Biochemical – amino acid analysis eczema Management: Diet low in Phenylalanine; supplement with Tyrosine Cofactor-related form (dihydrobiopterin reductase deficiency) Neurotransmitter supplementation Tyrosinemia Type -1 Defect: Deficiency in fumarylacetoacetate hydrolase Biochemistry: Accumulation of fumaryl acetoacetate and its metabolites in the Urine, particularly succinyl acetone Symptoms: Characteristic cabbage-like odor Liver failure and renal tubular acidosis Treatment: dietary restriction of Phe and Tyr Alkaptonuria One of the first diseases to be recognized as IEM Defect: accumulation of homogentisic acid due to deficiency of Homogentisic acid oxidase Clinical Presentation Pigmentation phenotype called ochronosis – pigmentation of ears and eyes Dark urine that turns black on standing- homogentisic aciduria Arthritis associated with calcification of joints Maple syrup urine disease(MSUD) Defect: metabolism of leucine, isoleucine & valine. (deficiency in branched chain α-keto acid dehydrogenase) Biochemistry: α-amino acids and their α-keto analogs are elevated in plasma & urine. Symptoms: X vomiting, dehydration, severe metabolic acidosis and characteristic maple syrup odor in Ketogenic the urine. Severe neurological complications if left untreated Treatment: Dietary restriction of branched-chain amino acids Ketogenic & Glucogenic Case study A 5-year-old is brought to her pediatrician because her mother notices that she is having difficulty with her sight. Her mother explains that she has had slow mental and physical development compared to her peers. The girl has long ”spidery” fingers and is tall for her age. She has a downward dislocation of her lens in one of her eyes. Laboratory tests reveal that she has elevated levels of methionine. She also has elevated levels of homocysteine in her urine. Homocystinuria Defect in cystathionine synthase Accumulation of homocysteine in the urine Methionine and metabolites elevated in the blood Cardiovascular disease, deep vein thrombosis, thromboembolism & stroke, mental retardation, osteoporosis, dislocation of the lens. 17  Organic Aciduria Glutaric aciduria type I (GA1) Organic acids: Defect: metabolism of lysine, include carboxylic acids, with or without hydroxylysine & tryptophan keto, hydroxyl or other non-amino (deficiency in glutaryl CoA functional groups dehydrogenase) common features – water soluble, acids Biochemistry: harmful organic and ninhydrin stain negative (No N group) acids accumulate Derived from dietary protein, fat and Symptoms: Dystonia, dyskinesia, carbohydrate. excretion of glutaric and 3-hydroxy glutaric acids in urine, neuronal Organic Aciduria degeneration, Some IEMs “giving rise to intoxication” can be classified as organic aciduria’s seizures untreated => brain Derived mainly from branched-chain amino damage & possibly death acids and Lysine and Tryptophan Diagnosis: excess metabolites excreted Causes accumulation of organic acids in urine and analyzed by capillary gas in blood and urine. chromatography-mass spectrometry (GC- Autosomal recessive MS) Treatment: Dietary restriction of https://www.ncbi.nlm.nih.gov/pmc/ protein. articles/PMC3210240/ 18 Medium Chain Acyl dehydrogenase deficiency (MCAD) Disorder of fatty acid oxidation due to impaired break down medium chain fatty acids into acetyl-CoA. MCAD is responsible for the dehydrogenation step of fatty acids with chain lengths between 6 and 12 carbons as they undergo beta- oxidation in the mitochondria Main clinical signs: – intolerance to prolonged fasting – due to huge loss of energy (unable to effectively use stored triglycerides) – Impaired ketogenesis – Hypoglycaemia-SIDS (higher dependence on carbohydrates for energy) – recurrent episodes of hypoglycaemic coma with an associated medium-chain dicarboxylic aciduria Management via diet – avoid fasting – glucose supplements 19 ENERGY FROM FATTY ACID OXIDATION Beta-oxidation of long chain fatty acids produces two carbon units, acetyl- CoA and the reducing equivalents NAD and FADH2. 20 Group 2: disorders involved in energy metabolism Diagnosis often difficult Common symptoms Hypoglycaemia, lactic acidaemia, hypotonia, cardiomyopathy, hepatomegaly, sudden unexpected death (SIDs). Some may cause dysmorphism Mitochondrial defects: Congenital lactic acidemias: – Pyruvate dehydrogenase deficiency, – pyruvate carboxylase deficiency, – Krebs cycle enzyme deficiencies Respiratory chain disorders Fatty Acid Oxidation and ketone body disorders Cytoplasmic defects: –Glycolysis, Gluconeogenesis and Glycogen metabolism 21 Disorders of gluconeogenesis - associated with hypoglycaemia Pyruvate carboxylase deficiency Glucose Glucose-6-P Glucose-1-P Glycogen Presentation Galactose Severe neonatal - seizures, coma, lactic acidosis, mild hypoglycaemia, Fructose-6-P Mild infantile – psychomotor retardation, mild lactic acidosis Fructose-1,6-bisphosphatase Phosphofructokinase Diagnosis Fructose-1,6-bisP ↑ lactate, ketosis Fructose-1,6-bisphosphatase deficiency Glyceraldehyde-P Presentation Acute onset with hepatomegaly, ase K Hypoglycaemia, seizures, coma EPC Phosphoenolpyruvate P Oxaloacetate Malate Diagnosis Alanine Pyruvate Malate ↑ lactate, ketosis carboxylase Oxaloacetate Lactate Pyruvate TCA PEP carboxykinase deficiency Pyruvate cycle 2-oxo glutarate Extremely rare dehydrogenase Gluconeogenesis- Synthesis of glucose by non- carbohydrate ssubstrates lactate (from anaerobic glycolysis), Glycerol(from hydrolysis of triacylglycerols in fasting state) & Amino acids. 22 Mitochondrial diseases Mitochondrial Disorders include Disorders of enzymes or enzyme complexes involved in the generation deficiencies of of chemical energy by Oxidative Phosphorylation Pyruvate dehydrogenase (PDH) complex Diagnostic criteria TCA cycle Type of inheritance Electron transport chain (ETC) ATP synthase Clinical symptoms encephalopathies myopathies cardiomyopathies Biochemical features Lactic acidosis Lactate often elevated in both blood and CSF Electron Transport Chain deficiency – Enzyme activity of specific RC complex often Blockage of ETC due to O2 deficiency, genetic decreased Morphological features – Ragged red fibers (RRF) in muscle biopsy defects or inhibitors causes a rise in NADH+/NAD – DNA analysis ratio and inhibits PDH and TCA. 23 CASE: A ‘THREE-PARENT BABY’ 2 siblings died at 6 and 8 months due to a genetic defect in the mtDNA Diagnosed with Leigh syndrome:- failure to thrive, Progressive neuropathy, muscle weakness, psychomotor regression. Children usually die within 2-3 years of respiratory failure. Caused by defects in ETC proteins and some pyruvate dehydrogenase. Maternal nucleus was removed from her egg and inserted into a donor egg that had had its nucleus removed. This was then fertilized with the father’s sperm. Using this procedure, some mitochondria can be transferred with the nuclear transfer. 24 Pyruvate dehydrogenase deficiency (PDH) Presentation: Progressive encephalopathy, brain malformation, psychomotor retardation, muscular hypotonia, epilepsy Diagnosis: Increased plasma lactate and pyruvate Enzyme analysis in Fibroblasts and muscle 25 STORAGE DISORDER Genetic diseases characterised by abnormal accumulation of lipids or carbohydrates Glycogen Storage Disorders (GSDs) - abnormal synthesis or degradation of glycogen - due to a defect in the genes coding for enzymes involved in glycogen metabolism GSDs affect liver & muscle disease presentation & severity depend on the role played by the enzyme & its tissue-specificity Signs: - Hypoglycaemia - Muscle pain / cramps / weakness 26  Galactose metabolism 1. Phosphorylation to Galactose-1-P by galactokinase 2. Formation of UDP-galactose, Transfer of UDP from UDP-Glucose by Galactose-1-phosphate uridyl transferase (GALT). (Glucose-1-P is formed ) 3. UDP Galactose can be converted to UDP- Glucose by UDP-hexose-4-epimerase Galactokinase deficiency: 4. UDP-Glucose converted to Glucose-1-P by Autosomal recessive Gal-1-P uridyl transferase Elevation of galactose in blood & urine Excess galactose converted to galctitol Elevated galactitol can cause cataracts. Rx- Dietary restriction Major source of galactose in the diet is lactose from milk products. Lactose is cleaved by the enzyme lactase into glucose and galactose 27  Classic Galactosemia - Autosomal recessive Galactose 1-phosphate uridyltransferase (GALT) deficiency: Symptoms: Most present as neonates: Galactosaemia, galactosuria, vomiting diarrhoea, jaundice, failure to thrive Gal-1-P & galactitol accumulate in nerve, lens, liver & kidneys – liver damage, mental retardation, cataracts, verbal dyspraxia, motor abnormalities. Therapy: Rapid detection & removal of galactose from the diet. Galactitol is a sugar alcohol formed by the reduction of galactose. This pathway is more active in galactosemic patients 28 Fructose metabolism Sucrose is ingested & Entry of fructose into cells is not cleaved in intestine. insulin-dependant Phosphorylated by fructokinase to Free fructose – fruit, honey Fructose-1-P & high fructose corn syrup. Then cleaved by aldolase B Western diets – approx 10% calories from fructose Products: Metabolised much faster 1. DHAP – enters glycolysis or than glucose gluconeogenesis (Bypasses phosphofructokinase, rate 2. Glyceraldehyde has several fates limiting step in glycolysis) including conversion to: Get accumulation of Acetyl - Glyceraldehyde-3-phosphate, and CoA hence to glycolysis or gluconeogenesis Promotes FA synthesis -Glycerol-3-phosphate and hence to triglycerides and phosphoglycerides OBESITY 29 Fructosuria and hereditary fructose intolerance Essential Fructosuria – Genetic deficiency of fructokinase – Fructose found in urine – Benign condition, often discovered due to positive test for reducing sugars in urine Hereditary fructose intolerance – Genetic deficiency of aldolase B – Accumulation of fructose-1-P in the cell – Reduced production of ATP (why?), reduced release of glucose from glycogen – Hypoglycemia, vomiting, jaundice, liver damage, kidney damage, growth abnormalities, coma if untreated – Treatment: removal of fructose from the diet 30 Group 3: disorders involving complex molecules Symptoms: Permanent, progressive, independent of intercurrent events, unrelated to food intake Treatment: Limited to enzyme replacement or bone marrow transplant. Lysosomal disorders Sphingolipidoses -- – Gaucher’s disease, – Niemann-Pick disease, – Tay-Sachs disease, – Krabbe’s disease, – Metachromatic leukodystrophy, – Fabry’s disease Mucopolysaccharidosis (glycosaminoglycans) – Hurler’s disease, – Hunter’s disease (XR) Peroxisomal disorders – Zellweger Syndrome, – X linked-adrenoleucodystrophy Congenital disorders of glycosylation  SUMMARY OF IEM Group 1: disorders which give rise to intoxication: Revision exercise Group 2: disorders involved in energy metabolism Group 3: disorders involving complex molecules - Jean-Marie Saudubray Extra In-depth Information for reference-when studying for the USMLE exam Sphingolipidoses Accumulated Disease Deficient enzyme products Symptoms Inheritance Sphingomyelinase Sphingomylen Niemann-Pick Brain, RBC Mental retardation, Spasticity, AR disease* Seizures, Ataxia, Death by 2–3 yr infancy AR Galactocerebrosidase Glycolipid Spasticity, hypertonia, hyperreflexia, infancy Krabbe disease Oligodendrocytes blindness, deafness, decerebration neurodenegeration Glucocerebrosidase Glucocerebrosides Hepatosplenomegaly, Anemia, AR Gaucher disease RBC, liver, spleen Ashkenazi Jews Thrombocytopenia, Bone pain Infancy – adult Neurodegeneration AR Hexosaminidase A GM2 gangliosides Tay-Sachs disease* Ashkenazi Jews (Sandhoff) neurons Developmental delay Infant - child Early death Demyelination Mental retardation AR Metachromatic Arylsulphatase A Sulphatides Motor dysfunction 1st yr - adult leukodystrophy neural tissue Ataxia Seizures α galactosidase A Glycolipids Paraesthesia limbs, stroke, X-linked Fabry disease adults brain, heart, kidney cardiomyopathy, renal failure *degradation of sphingomyelin – figure 17.12 glycosphingolipid disorders- figure 17.20 Lippincott’s Biochemistry  Mucopolysaccharide disorders (MPS) Disorder Enzyme defect Typical presentation MPS I Hurler AR α-iduronidase Developmental regression, cloudy HS, DS cornea, organomegaly, heart valve disease, Coarse facial features, humpback, life expectancy 10 yr MPS II Hunter X-linked Iduronate Similar to Hurler but no cloudy cornea HS, DS sulphatase Distinctive facial features, hearing loss, thickening of heart valves,obstructive airway disease, life expectancy dependant on severity