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Biochemical Genetics PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "BIOCHEMICAL GENETICS" by Greg Enns, MB, ChB, FAAP.

This medical PowerPoint presentation talks about Biochemical genetics is the study of the relationship between genes and the biochemical processes that they control. It focuses on how genes affect the structure, function, and regulation of proteins, which are the building blocks of living organisms.

Biochemical genetics involves studying the interactions between genes and the environment, as well as the effects of genetic mutations on biochemical pathways. This field also investigates the role of enzymes, hormones, and other molecules in the regulation of gene expression and the inheritance of traits.

Some of the areas of research within biochemical genetics include Metabolic disorders, Molecular genetics, Pharmacogenetics, and Evolutionary genetics, etc.

Tags : Biochemical genetics, biochemical pathways, Metabolic disorders, Molecular genetics, Pharmacogenetics, Evolutionary genetics, endocrinology, endocrinology PowerPoint presentation

Published on : Apr 18, 2023 | Views : 946 | Downloads : 0

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Slide 1-

BIOCHEMICAL GENETICS Greg Enns, MB, ChB, FAAP Professor of Pediatrics Director, Biochemical Genetics Program Lucile Packard Children’s Hospital
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2 Learning Goals Develop abilities to recognize signs and symptoms associated with inborn errors of metabolism Become aware of clues to an underlying inborn error of metabolism by using simple lab tests
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Lecture Outline Inborn Errors of Metabolism Signs and Symptoms Diagnostic Tests Routine labs Biochemical profiling
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So what exactly is a Biochemical Geneticist anyway?
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5 Inborn Errors of Metabolism “Metabolic Disorders” Inherited disorders of intermediary metabolism Autosomal recessive Autosomal dominant X-linked Maternal (mitochondrial) inheritance Metabolic imbalance most commonly secondary to an enzyme deficiency Toxic metabolites Deficiency states Altered energy production
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6 Who, What, & How? Common presentations Neurologic decompensation Multi-organ system involvement Lysosomal storage disorders Types of tests Basic Complex Newborn screening Test interpretations Common mistakes Case examples
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7 Who to TestClinical Features Neurologic symptoms Altered Mental Status Developmental regression Mental retardation Psychiatric illness Autism? Failure to thrive SIDS Non-immune hydrops Eye findings Cataracts Pigmentary retinopathy Hepatosplenomegaly Cardiomyopathy Bone/joint disease Contractures Dysostosis multiplex Osteonecrosis Unusual odor
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8 Signs and Symptoms of Inborn Errors of Metabolism Appear after an interval of good health (hours, days) in a usually previously healthy full-term infant Unmasked by “stressors” that lead to catabolism (e.g. infection, fasting, dehydration, excessive protein, birth) Non-specific (limited response to stress in neonates)
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9 Signs and Symptoms of Inborn Errors of Metabolism Failure to thrive, feeding difficulties Respiratory distress Hypotonia, seizures, lethargy Hypothermia (especially neonates)
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10 Signs and Symptoms of Inborn Errors of Metabolism Ocular findings Hepatosplenomegaly Cardiomyopathy Renal tubular disease Abnormal odor Unusual skin, hair Dysostosis multiplex Dysmorphic features
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11 Signs and Symptoms of Inborn Errors of Metabolism Typically patients who have metabolism disorders display a constellation of features Isolated failure to thrive, cardiomyopathy, etc. in the absence of other organ system involvement or other clinical features (e.g. developmental delay) would be unusual
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12 Signs and Symptoms of Inborn Errors of Metabolism MAY PRESENT AT ANY AGE
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13 Case #1 A 4-day-old boy is taken to the emergency room on Christmas eve because of poor feeding and lethargy. He is hypothermic and is tachypneic. He has elevated (3+) ketones in his urine and a metabolic acidosis (anion gap 25 with normal lactate). His ammonia is 735 M (normal 5-35).
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14 Case #1 This presentation is most suggestive of …? A) Maple syrup urine disease B) Urea cycle defect C) Fatty acid oxidation defect D) Glycogen storage disease E) Organic acidemia
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15 Your answer? E) Organic acidemia
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16 THE ANION GAP Na+ - [Cl- + HCO3-]
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17 THE ANION GAP Total serum cations: Na + UC Total serum anions: Cl + HCO3 + UA So… NA + UC = UA + Cl + HCO3
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18 THE ANION GAP UA – UC = Na+ - [Cl- + HCO3-] = the anion gap
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19 Concentrations of “unmeasured” cations and anions(mEq/L) Unmeasured Cations K 4.5 Ca 5.0 Mg 1.5 Total 11 Unmeasured Anions Protein 15 PO4 2 SO4 1 Organic acids 5 Total 23
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20 Metabolic Acidosis with Increased Anion Gap Increased Unmeasured Anion: Methanol, metformin Uremia Diabetic ketoacidosis Paraldehyde, phenformin Inborn errors of metabolism Lactic acidemia Ethanol, ethylene glycol Salicylates, solvents, strychnine
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21 Metabolic Acidosis with Increased Anion Gap Decreased Unmeasured Cation*: Hypokalemia Hypocalcemia Hypomagnesemia *Possible in theory, but rarely encountered
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22 Metabolic Acidosis with Normal Anion Gap Renal tubular acidosis Intestinal loss of bicarbonate
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23 A B C D A TA EAB EBC ECD F G Negative Feedback A, B, C, D – substrate and products of major pathway F, G – products of minor pathway T – transporter ; E - enzymes Prototypical Metabolic Pathway Cell membrane
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24 The Laboratory specimen results
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25 Organic Acids(GC-MS) Urine only Qualitative screen 100’s of compounds 3 hour prep 30 min run
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26 Methylmalonic Acidemia Total Ion Chromatogram Ion Abundance Time (min)
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27 Case #1 Initial methylmalonic acid (MMA) level 1,200 uM (nl <0.3 uM) Treated with: High dextrose intravenous fluids + insulin Intravenous “nitrogen scavenging” medications Sodium benzoate + sodium phenylacetate Intravenous carnitine Intramuscular hydroxocobalamin Dialysis is often needed to decrease MMA and ammonium levels, but avoided in this case
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28 TC II OH-Cbl TC II OH-Cbl OH-Cbl+3 Cbl+3 Me Cbl Homocysteine Methionine Methionine Synthase Cbl+2 L-Methylmalonyl CoA Succinyl CoA Ado Cbl Cbl+1 TC II OH-Cbl+3 Methylmalonyl CoA Mutase F A,H B C,D E,G The Cobalamin Pathway
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29 Methylmalonic Acidemia Common signs/symptoms: lethargy intermittent vomiting dehydration failure to thrive respiratory distress hypotonia Matsui et al. NEJM 308:857, 1983
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30
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31 BRAIN INJURY IN ORGANIC ACIDEMIAS Pediatr Res 40:404-9, 1996 caudate and putamen hyperintensity delayed myelination
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32 Case #2 You are called about a 55-year-old male who became confused and lethargic a few days after endoscopic sinus surgery to remove nasal polyps that were causing chronic sinusitis. He had been discharged home on steroids to prevent swelling. His wife took him to the emergency room after he became more confused and disoriented. He progressed to a coma and was placed on mechanical ventilation in the intensive care unit.
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33 Case #2 The ICU physician upon reviewing the initial laboratory studies noted a respiratory alkalosis and normal complete blood count, glucose, and liver enzymes. Cerebrospinal fluid studies and urinalysis are normal. Blood, urine, and cerebrospinal fluid cultures are obtained. A urine toxicology screen was also normal. Initial head CT scan and CXR were normal.
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34 Case #2 Your differential diagnosis includes which of the following? A) Steroid psychosis B) Occult infection C) Intoxication D) Inborn error of metabolism E) All of the above
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35 Your answer? E) All of the above
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36 Case #2 Although most metabolic studies take days to weeks to obtain results, you recall that ammonia is a central respiratory stimulant and urea cycle disorders often are associated with tachypnea. Moreover, unlike many metabolic disorders, a metabolic acidosis is typically not present initially in urea cycle disorders. You look at the lab results again and notice the blood urea nitrogen is low.
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37 Case #2 So…you check an ammonia (obtained on ice and sent to the lab quickly) and find an abnormal elevation. The ammonia level is 281 M (normal 5-35).
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38 Case #2 The most likely diagnosis is: A) Urea cycle disorder B) Mitochondrial disease C) Propionic acidemia D) Medium-chain acyl-CoA dehydrogenase deficiency E) Proteus mirabilis urinary tract infection
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39 Your diagnosis? A) Urea cycle disorder
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40 Quantitative Amino Acids(HPLC) Plasma, urine, CSF 40 amino acids (sometimes more) 10 minute prep 3 hour run per sample
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41
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42 Case #2 Metabolic labs:  glutamine citrulline 3 uM (8-47) orotic acid <1 g/mg creatinine (<4.7)
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43
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44 Urea Cycle Disorders Clinical Features Term birth ~DOL 2 poor feeding, vomiting, lethargy progressing to coma, apnea Seizures may occur with cerebral edema Often mistaken for sepsis Later onset with ataxia, altered mental status (post-partum)
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45 Late-Onset Urea Cycle Disorders Behavioral problems Agitation Delirium Aggression Confusion Ataxia Headache Hemiparesis Nassogne et al. JIMD 28:407-14, 2005
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46 Lysosomal Storage Disorders Family of > 40 disorders; collective prevalence ~1:8,0001 Enzyme deficiency causes lysosomes to become engorged1 Each disease is a consequence of type of substrate and where it accumulates1 Progressive accumulation of substrate may result in irreversible damage2 Meikle P et al. JAMA. 1999;281:249-254. Wraith JE et al. J Pediatr. 2004;144:581-588.
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47 MPS ENZYME BLOCKS iduronate sulfatase -L-iduronidase HURLER (MPS I) COOH COOH S-O O NAc O COOH O NAc O S-O O-S HUNTER (MPS II) O S-O NAc O COOH O S-O NAc O
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48 Normal Cell Abnormal Cell Lysosomal Storage Disorders
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49 CNS Involvement Metachromatic Leukodystrophy 8% Sanfilippo A 7% Hunter Severe 5% Krabbe 6% Sandhoff 2% GM 1 Gangliosidosis 2% Mucolipidosis type II / III 2% Niemann-Pick A 2% Niemann-Pick C 4% Tay-Sachs 4% Sanfilippo B 4% Gaucher type 2 & 3 1% Niemann-Pick B 2% Maroteaux-Lamy 3% Cystinosis 4% Morquio 5% Pompe 5% Hurler/Scheie (MPS I) 4% Gaucher type I 13% Scheie (MPS I) 1% Hurler (MPS I) 4% Hunter Mild 1% Fabry 7% Significant or severe CNS involvement (~ 54%) No or minimal CNS involvement (~ 46%) Adapted from Meikle P et al. JAMA. 1999;281:249-254. Other 2% -Mannosidosis Sanfilippo D 1% 1%
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50 Mucopolysaccharidosis type I Disease-at-a-Glance 1. Meikle P et al. JAMA. 1999;281:249-254.
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51 MPS I Umbilical/inguinal hernia Cardiovascular disease Obstructive airway disease Corneal clouding Hepatosplenomegaly Chronic rhinitis/otitis Joint stiffness Developmental delay Hearing loss Enlarged tongue Look for unusual symptoms or clusters of more common symptoms Carpal tunnel syndrome Skeletal deformities Signs &Symptoms Macrocephaly Neufeld EF, Muenzer J. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:3421-3452.
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52 Disease Progression: Severe MPS I 10 months 12 months 22 months 34 months 39 months
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53 Disease Progression: Mild MPS I 3 years 4 years 6 years 8 years 11 years
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54 “Scheie” MPS I S “Hurler” MPS I H All patients typically have < 1% of normal enzyme levels, but only MPS l H involves the CNS “Hurler-Scheie” MPS I HS MPS I Clinical Heterogeneity Severe Attenuated Courtesy of Emil Kakkis, MD.
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55 Peripheral Nervous System Involvement Carpal tunnel syndrome nerve entrapments/nerve compressions Most patients lack typical symptoms until severe compression occurs
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56 Contractures of the Arm
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57 Skeletal Abnormalities (Clarke LA, 1997) Photo reproduced by permission of Hodder/Arnold Publishers.
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58 Gibbus in MPS I
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Dimethylmethylene Blue Binding Assay For Glycosaminoglycans Blank 5 µg/ml 17.5 µg/ml 35 µg/ml 50 µg/ml Urine + DMB reagent  Blue product Courtesy T. Cowan
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60 Normal MPS I Hurler MPS I Scheie MPS II Hunter MPS III Sanfilippo MPS IV Morquio MPS VI Maroteaux- Lamy MPS VII Sly Dermatan, Heparan Dermatan, Heparan Dermatan, Heparan Dermatan, Heparan Heparan Keratan Dermatan Thin-layer chromatography Courtesy of T. Cowan
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61 SUMMARY High index of suspicion – consider IEM in parallel with more common conditions Presentations are non-specific Simple screening tests yield critical diagnostic clues
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62 InterventionalGeneticist Anesthesiologist Primary Care Physician Neurologist Otorhinolaryngologist Genetic Counselor Cardiologist Gastroenterologist Surgeon Pulmonologist Dentist Ophthalmologist Orthopedist Hematologist Nephrologist Palliative Care Specialist Metabolic Disease Treatment Team