Inborn Errors of Metabolism Inborn Errors of MetabolismIEM Disorders in which a gene defect causes a clinically significant block in a metabolic pathwayenzyme deficiency or transport protein ID: 1047326
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1. Dr Lucy MungaiUniversity of NairobiInborn Errors of Metabolism
2. Inborn Errors of Metabolism(IEM) Disorders in which a gene defect causes a clinically significant block in a metabolic pathway(enzyme deficiency or transport protein defect). Resulting either in accumulation of substrate before the block or deficiency of the product.Genetically transmitted
3. What is a metabolic disease?Garrod’s hypothesis product deficiency Substrate excess toxic metaboliteADBC
4. Pathophysiologic classification Disorders that result in toxic accumulation Disorders of protein metabolism (eg, amino acidopathies, organic acidopathies, urea cycle defects)Disorders of carbohydrate intoleranceLysosomal storage disordersDisorders of energy production, utilization Fatty acid oxidation defectsDisorders of carbohydrate utilization, production (ie, glycogen storage disorders, disorders of gluconeogenesis and glycogenolysis)Mitochondrial disordersPeroxisomal disorders
5. PROTEINGLYCOGENFATAMINO ACIDSFRUCTOSEGALACTOSEFREE FATTY ACIDSAMMONIAUREAUREA CYCLEORGANIC ACIDSGLUCOSEPYRUVATEACETYL CoAKREBS CYCLENADHKETONESATPLACTATEAn integrated view of the metabolic pathways
6. Classification of IEMsAminoacidopathies e.g., phenylketonuria, hereditary tyrosinemia, nonketotic hyperglycinemia, maple syrup urine disease and homocystinuria. Hereditary tyrosinemia can present in the neonate with a bleeding diathesis due to liver disease, or later in infancy with a renal Fanconi syndrome. nonketotic hyperglycinemia presents as unremitting seizures with hypotonia and hiccoughs. MSUD classically presents at the end of the first week of life with feeding difficulties, lethargy, coma, seizures and the characteristic odor. Urea cycle defects (e.g., citrullinemia, ornithine transcarbamylase deficiency, and arginosuccinic aciduria) result from the inability to detoxify nitrogen and are characterized by severe hyperammonemia and respiratory alkalosis, with a typical onset after 24 hours of age
7. Classification of IEMs Disorders of carbohydrate metabolism (e.g., galactosemia, hereditary fructose intolerance, fructose 1,6-diphosphatase deficiency and the glycogen storage diseases) inability to metabolize specific sugars, aberrant glycogen synthesis, or disorders of gluconeogenesis. manifest with hypoglycemia, hepatosplenomegaly, lactic acidosis or ketosis.Lysosomal storage disorders (e.g., mucopolysaccharidosis, Tay-Sachs, Niemann-Pick disease, Gaucher’s disease) caused by accumulation of glycoproteins, glycolipids, or glycosaminoglycans within lysosomes in various tissues. present later infancy, not with a specific laboratory abnormality, but with organomegaly, facial coarseness ,neurodegeneration and show a progressively degenerative course.
8. Classification of IEMsOrganic acidemias (e.g. propionic acidemia, multiple carboxylase deficiency) abnormal metabolism of proteins, fats or carbohydrates with marked metabolic acidosis with ketosis, elevated lactate &hyperammonemia. Common signs include vomiting, signs of encephalopathy, neutropenia and thrombocytopenia. Fatty acid oxidation defects/Beta-oxidation defectse.g., short, medium, and long- chain acyl-CoA dehydrogenase deficiencies characterized by hypoketotic hypoglycemia, hyperammonemia & cardiomyopathy.(MCAD) is among the most common of all IEMs and may account for 5% of SIDS cases.Primary Lactic Acidoses present with severe lactic acidosis(e.g., pyruvate dehydrogenase, pyruvate carboxylase and cytochrome oxidase deficiencies).
9. Clinical PresentationFetal development may have been normal, provided that the metabolites are able to cross the placenta and metabolized by mom. neonates may be asymptomatic, and may only become symptomatic after the initiation of feedsNewborn crashMultiple stillbirths or early childhood deaths suggestive, consanguinity unusual odor of urine or sweat
10. Clinical PresentationToddlers and preschool-aged children present with stagnation or loss of cognitive milestones-language,attention developmental regression growth retardation seizures. History of growth disturbances, lethargy, recurrent emesis, poor feeding, rashes, seizures, hiccoughs, apnea, tachypnea.
11. History and PhysicalSubtle signs or symptomsFeeding difficulty, odd cry, vomiting, diarrhea, tachypnea, dyspnea, hypotonia/hypertonia, tachycardia, mental status changesOvert signs or symptomsPersistent hypoglycemia, acidosis, dehydration, shock, apnea, seizures, abnormal mental status, temperature instability, arrhythmia, cardiomyopathy, sudden deathDysmorphic features, strange odor, rashes, jaundice, organomegaly
12. Abnormal odorsBurnt sugar,maple syrup — MSUD Sweaty socks /cheese-like — Isovaleric acidemiaFruity/ammoniacal — Methylmalonic acidemia or propionic acidemiaMouse urine/musty — PhenylketonuriaCabbage-like/rotten eggs — TyrosinemiaMalt/hops — Methionine malabsorptionCat urine — 3-Methylcrotonic acidemia, 3-hydroxy-3-methylglutaric aciduriaFish-like — Trimethylaminuria and carnitine excess
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16. Laboratory findingsMetabolic acidosis with increased anion gap, Primary respiratory alkalosis, hyperammonemia Hypoglycemia, ketosis or ketonuria, low BUN,Hyperbilirubinemia, elevated liver function tests including PT and PTT, lactic acidosis, high lactate/pyruvate ratio Non-glucose-reducing substances in urine, neutropenia and thrombocytopenia.
17. Approach to treatmentReduce precursor substrate load Removal of toxic compounds – hemodialysis, chelators, trapping agents Enhancement of the activity of the deficient enzymeDecreasing the flux through the deficient pathway by restricting precursors in the diet. If an inborn error of metabolism is suspected in a neonate they should be kept NPO but given IV fluids containing dextrose so as to keep the infant anabolic.Provide caloric supportProvide fluid supportDivert metabolitesSupplement with cofactor(s)
18. Hunter syndrome,mucopolysaccharidosis type 2 Mucopolysacchridoses –disorder in breakdown of glycosaminoglycans(GAG) due to deficiency of lysosomal enzymesGAG- oligosaccharide components to protein skeleton in extracellular matrixDeficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S) The lack of this enzyme causes heparan sulfate and dermatan sulfate to accumulate in all body tissues.Exhibit X-linked recessive inheritance
19. EpidemiologyThere are estimated to be approximately 2,000 people afflicted with Hunter syndrome worldwide, 500 of whom live in the United States.A study in the United Kingdom indicated an incidence among males of approximately 1 in 130,000 male live births.In severe cases, death usually occurs by age 15. In attenuated cases, patients may survive into their 50s
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23. Clinical Presentation:Categorized as either "mild" or "severe" depending on the presence of central nervous system symptomsThe symptoms not apparent at birth. As the buildup of GAGs continues throughout the cells of the body, signs of Hunter syndrome become more visible. distinctive coarseness in their facial features, prominent forehead, a nose with a flattened bridge, and an enlarged tongue. Communicating hydrocephalus can developThe gastrointestinal system is also affected via autonomic dysregulation , mucosal dysfunction.
24. Clinical Presentation:Valvular heart leaflets with GAG accumulation. A thickened myocardium eventually leads to coronary artery compromise, The walls of the airway may become thickened, as well, leading to obstructive airway disease.All major joints may be affected by Hunter syndrome, leading to joint stiffness and limited motion. carpal tunnel syndrome,short stature Pebbly, ivory-colored skin lesions may be found on the upper arms, legs, and upper back :pathognomic for the disease. After 18 months, children with severe MPS II may suffer from developmental decline
25. Investigations:Urine spot tests are readily available to screen for mucopolysaccharidoses (MPSs). ELISA technique has recently been shown to accurately quantify GAGs in urine (eg, dermatan and heparan sulfate excretion) and in blood.Lysosomal enzymes are present in all cells except mature erythrocytes. Iduronate sulfatase deficiency is determined by the direct enzymatic assay of leucocytes and fibroblasts as skin biopsy.Prenatal diagnosis is routinely available by measuring I2S enzymatic activity in amniotic fluid or in chorionic villus tissueA full skeletal surveyOphthalmologic examination with slit lamp: visual acuity and corneal and retinal .Cardiac echocardiography and ECGAirway evaluation: Assess for upper airway obstruction and sleep apnea and determine pulmonary function. [30
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30. IEM- Index of Suspicion:Rapid deterioration in an otherwise well infant.Septic appearing infant or abnormal sepsis such as E.coli. Failure to thrive, Regression in milestones. Recurrent emesis or feeding difficulty, alterations in respirations, abnormal urine/body smell, changing MS/lethargy, jaundice, seizures, intractable hiccups. Can masquerade like pyloric stenosis.Dietary aversion- proteins, carbs.