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MHG II > Biochemical Genetics > Flashcards

Biochemical Genetics Flashcards

1
Q

Genetic changes can result in complete, partial, enhanced, or conditional defects

A
  1. many enzymes are part of complexes
  2. some changes effect kinetics that won’t appear until stress is applied
  3. Difference btwn polymorphisms and mutations is not clear cut
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2
Q

Reasons why newborns are the most vulnerable (3)

A
  1. Just came off 9 months of life support, therefore most biochemical processes were not functioning at full capacity
  2. Extremely catabolic: vascular changes, breathing, feeding
    * Increased consumption and decreased capacity for energy (biochemical enzymes are not at mature levels)
  3. Secondary energy sources are used; leads to more complex processes with greater room for error
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3
Q

Inborn errors of metabolism: Generalities (3)

A
  1. increased incidence of neurodevelopmental and behavior problems, most due to general neurotoxicity
  2. brain is affected first b/c it uses the most genes and requires the most biochemical intermediates
  3. Most common finding is global delay
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4
Q

4 types of metabolic processes

A
  1. Production: ATP energy
  2. Toxin clearance: ammonia –> urea
  3. Conversion: into a useable product
    (Gal-1-P–> Glc-1-P)
  4. Degradation: remove extra material
    Glucosyl ceramide –> Glc + ceramide
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5
Q

Acutely toxic biomolecules (5)

A
  1. Ammonia: especially bad for brain
  2. Glycine: NT
  3. Lactic acid: inflammation in muscles
  4. Organic acids: block urea cycle, glycine clearance, shuts down glucose production, prevent cofactor binding
  5. Galactose: conversion to galactitol –> neurotoxin & hepatotoxin, cataracts in eyes
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6
Q

Clinical clues for Acute Inborn Errors of Metabolism (2)

A
  1. patients usually normal and stable at birth
  2. Symptoms result when metabolites build up/drop (24hours - 2 weeks) *can also be triggered by illness, fasting, surgery, growth, stress (increased by catabolic processes)
  3. Patients appear to have SEPSIS
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7
Q

Symptoms as brain is increasingly affected

A
  1. Initial: anorexia, sleepiness, vomiting, temperature instability, hiccups (signal gly), hypotonia
  2. Advanced: lethargy, coma, seizures, respiratory arrest, cerebral edema, immune impairment, hepatic dysfxn, decorticate posturing, cardiomyopathy, death
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8
Q

Affects on brain (4)

A
  1. toxin destruction of neurons (Phe –> Phe-acetic acid)
  2. toxin disruption of neuron fxn (ammonia causes tissue swelling and slow NT)
  3. accumulation or deficiency of metabolite that is also a NT (Gly)
  4. Not enough fuel (FA oxid disorders)
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9
Q

Common lab: Complete blood count

A

Detects pancytopenia from bone marrow suppresion (caused particularly from organic acids)

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10
Q

Common lab: Urinalysis

A

Detect ketones (FA oxid) and reducing substances (Gal, Frc)

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11
Q

Common lab: blood gas

A

acidosis (metabolic) or alkalosis

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12
Q

Common lab: electrolytes

A

Detect anion gap (Na - Cl - CO2) <15 normal

*Above 15, reflects unexplained acids in blood

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13
Q

Common lab: Blood glucose

A

Detects defects in gluconeogenesis and energy substrate production or substrate storage

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14
Q

Common lab: Blood ammonia and (blood urea nitrogen) BUN

A

detects primary and secondary defects in urea cycle

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15
Q

Common lab: lactate and pyruvate

A

Detect defects in pyruvate metabolism, energy production/use, ETC, inefficient metabolism, and stress

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16
Q

Specialty Lab: Plasma AA

A

Detects breaks in normal AA metabolism (PKU, MSUD)

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17
Q

Specialty lab: urine organic acid

A

Detects metabolites of unprocessed organic acids from protein and FA metabolism

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18
Q

Specialty lab: carnitine (acyl-profile)

A

Detects most organic acids bound as CoA products to carnitine. Detects unprocessed fatty acid intermediates
*Carnitine can bind to make intermediates water soluble –> excretion

19
Q

Specialty lab: very long chain FA

A

Detects peroxisomal defects

20
Q

Specialty lab: urine mucopoly/oligo saccharide

A

Detects unprocessed compounds from lysosomal failure

21
Q

Red Herring disease that can be mistaken as biochemical diseases (4)

A
  1. Heart disease: massive lactic acidosis
  2. Seizures & Code: lactic acidosis (burn a lot of energy quickly)
  3. Starvation: ketosis, abnormal AA levels, lactic acidosis
  4. liver disease: hypoglycemia, AA elevations for F,I, M,V,L,Y, homocysteine
22
Q

Red Herring drugs that can be mistaken as biochemical diseases (3)

A
  1. Valproate (seizures): elevated ammonia, glycine *interferes with nitrogen metabolism
  2. TPN: if sample is drawn from IV, high levels of AA will be detected (not representative)
  3. Penicillin: false positive reducing substance
23
Q

Urea Cycle disorders

A
  1. build up of ammonia (only way to excrete)
  2. Decrease in Arginine metabolite leads to inability to make nitric oxide. Arginine can become an essential AA
  3. Elevation of ammonia and glutamine
    * Primary toxicity to brain
24
Q

Newborn symptoms

A
  1. Hyperammonemia (trigger nausea reflex)
  2. Vomiting
  3. lethargy or coma
  4. Respiratory alkalosis: hyperventilation (trapping CO2 in brain), anion gap
25
Q

Diagnosis of Urea Cycle disorders

A
  1. Identify hyperammonemia
  2. Determine specific enzyme lacking/deficient by measuring intermediate levels in plasma AA (high Gln, low Arg)
    * patient presents with respiratory alkalosis & lethargy
    * high ammonia –> cerebral edema (swelling in brain) –> high CO2 –> rapid breathing
26
Q

Treatment of Urea Cycle Disorders (6)

A
  1. Decrease protein content in diet
  2. Since ammonia is water soluble, dialysis
  3. Scavenger sodium benzoate: combines with gly –> hypurate –> excreted
    * Also excreting gly causes excess N to be used ot make more gly
  4. Scavenger phenylacetate: traps Gln –> phenyl-Gln (can be toxic since Glu is a NT)
  5. Long term: liver transplant
  6. Suppress catabolism
27
Q

Disruption of the urea cycle (4)

A
  1. Genetic defect in enzyme
  2. Damage to the liver- from chemical toxins or infectious processes
  3. Drug effects: valproic acid, chemotherapy
  4. overload system: massive hemolysis or protein catabolism
28
Q

Laboratory presentation of UCD

A
  1. Normal: anion gap, WBC, glucose, urine
  2. pH elevated initially (respiratory alkalosis)
  3. LOW blood BUN, high ammonia
  4. Low arginine, high glutamine
29
Q

Maple Syrup urine disease

A

Defect in BRANCHED CHAIN KETO-ACID DH

  1. Build up of Leu, Ile, Val (2-oxo-keto acid)
  2. Leucine is toxic
  3. Isoleucine has smell
  4. large ketones on urinalysis
30
Q

Maple syrup disease management (3)

A
  1. Dialysis to rapidly decrease Leu levels
  2. high energy, low protein feeding
    * Leu restriction, Ile and Val supplementation to promote anabolism
  3. Thiamine suplementation
31
Q

Maple syrup disease prognosis

A
  1. Episodic decompensations (cerebral edema)
  2. long term disability (inversely correlated with duration of Leu elevation)
  3. Pancreatitis
  4. Epidermolysis; secondary to Ile deficiency
32
Q

MMA: methylmalonyl-coA mutase
PA: propionyl-coA carboxylase

A
  1. Deficiency of succinyl-CoA

2. build up of methymalonyl-CoA & propionyl-CoA and other organic acids

33
Q

MMA/PA presentation

A
  1. History of poor feeding, abnormal muscle tone, respiratory distress, vomiting, seizures
  2. Toxic encephalopathy: metabolite build up, hyperammonemia, hypoglycemia, hyerglycinemia, ketosis, anion gap, rapid breathing –> acidotic
    neutropenia, thrombocytopenia, elevated amylase/lipase
34
Q

Effects of organic acids on biochemical pathways

A
  1. Shut down glucose production
  2. prevent cofactor from binding in CPS I
  3. interferes with TCA –> high lactate
  4. Interferes with Gly clearance (hyper)
35
Q

MMA/PA treatment

A
  • rehydration & promotion of anabolism
    1. Buffer acidosis
    2. Remove precursors w/ carnitine and dialysis
    3. manage diet: restriction of Val, odd-chain FA, Met, Ile, Thr)
    4. Biotin and cobalamin supplementation (cofactors)
36
Q

MMA/PA outcomes

A
  1. Good if response to vitamines
  2. Unresponsive: severe decompensations, neurological outcomes
  3. Chronic renal failure (MMA), cardiomyopathy, risk of pancreatitis, epidermolysis
  4. Liver transplant prevents hyperammonemia, but not secondary effects
37
Q

Isovaleric acidemia (IVA)

A

Deficiency in ISOVALERYL-COA DH

  1. highly toxic: incr isovaleric acid & leu
  2. “sweaty feet” odor
  3. Similar to MMA/PA, but milder
38
Q

Isovaleric acidemia management

A
  1. Rehydration, promotion of anabolism
  2. Gly and carnitine supplementation for alternative disposal
  3. Leucine restriction
    * easy to treat
39
Q

Criteria for newborn screening (5)

A
  1. screen for disorder that is well defined and has reasonable frequency
  2. not reliably detected clinically and if untreated causes irreversible damage
  3. If there is a rapid test with high sensitivity and specificity
  4. Interventions are feasible and can improve outcome
  5. screening and treatment is cost effective
    * use of tandem mass spectrometry (one test, multiple diseases)
40
Q

Phenylketonuria (PKU)

A

Deficiency in PHENYLALANINE HYDROXYLASE

  1. high Phe
  2. mental retardation, autistic behavior, seizures, white matter hyperintesntities
41
Q

PKU dietary therapy

A
  1. Restrict dietary protein & decrease Phe intake
  2. Supplement with synthetic AA
  3. maternal PKU: treatment must be more aggressive b/c toxic for fetuses
42
Q

urea cycle

A
  1. ammonia –> carbamoyl phosphate
  2. Carbamoyl phospate + ornithine –> citrulline (exits mito to cyto)
  3. Citrulline + asp–> argininosuccinate
  4. argininosuccinate –> fumarate + ARG
    * becomes an essential AA in UCD
  5. Arg –> urea & ornithine
    * Arg –> citrulline creates NITRIC OXIDE
43
Q

UCD in adults

A
  1. Caused by environmental trigger (auto-selective vegetarians) –> eat more carbs, no protein (commonly leads to obesity b/c lack of protein signals hunger)
  2. Feeding disruption, seizures, neurological posturing due to cerebral edema, hyperventilation, lethargy –> death
  3. More severe: can’t accommodate to brain swelling like newborns (w/ skull not yet fused) –> brain herniates

MHG II (8 decks)

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