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Dems Unit 2 Part 2 YAAAY > Inborn Errors of Metabolism: AAs and Urea Cycle > Flashcards

Inborn Errors of Metabolism: AAs and Urea Cycle Flashcards

1
Q

urine ferric chloride spot test

A

pku

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2
Q

Phe levels in severe, moderate, and benign phenylketonuria

A

severe: >1200
Moderate: 600-1200
Mild:

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3
Q

presentation: infant born with microcephaly, congenital cardiac lesion, mental retardation, low birth weight

A

maternal PKU

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4
Q

3 Actions to manage metabolic encephalopathies

A

Remove Offending agent

  1. NPO
  2. STOP catabolism
  3. Dialysis
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5
Q

Urine DNPH Positive

A

MSUD

*will also be positive in PKU

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6
Q

Plasma MSUD findings

A

Increased: leucine, valine, isoleucine
Alloisoleucine present
Branched chain ketoacids on urine analysis
Urine DNTH +

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7
Q

enzyme deficient in MSUD

A

branched chain ketoacid dehydrogenase (BCKD)

autosomal recessive

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8
Q

BCKD structure and its relationship to treatment

A

4 subunits

mutations in E2 subunit: most likely to be B1 (thiamine) responsive

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9
Q

3 presentations MSUD

A
  1. Severe Neonatal
  2. Acute Intermittent
    - ataxia, hypoglycemia with ketoacids
  3. Subacute Chronic
    - failure to thrive, plastic paraplegia, hypotonia
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10
Q 
case presentation:
newborn infant
poor feeding, progressive lethargy
coma and seizures 6 days of age
mild hypoglycemia
mild metabolic acidosis
ketonuria
A

MSUD

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11
Q

acute treatment MSUD

A

eliminate dietary protein
supplement valine and isoleucine
provide non protein energy and non branched chain amino acids

avoid hypotonic fluids
treat cerebral edema if develops
maybe hemodialysis

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12
Q

chronic MSUD therapy

A
  • protein restricted diet with foods free of branched chain AA
  • Child leucine intake 400-600mg/day; after adolescence 600-800mg/day
  • supplement valine and isoleucine: rapid depletion with dietary exclusion
  • thiamine supplementation if E2 subunit deficient
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13
Q 
case presentation:
1month old infant
direct hyperbilirubinemia
prolonged PTT, elevated transaminases
hepatomegaly
edema (low albumin)
no hypoglycemia; no acidosis
A

Tyrosinemia type 1

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14
Q

lab results tyrosinemia type 1 (US, plasma, urine)

A

US: hepatomegaly with multi nodular disease

Plasma: Tyrosine 440 (NL 25-105); Methionine 160 (NL 5-34)

Urine Organic Acids: succinylacetone and a-aminolevulinic acid

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15
Q

enzyme deficient in tyrosinemia type 1

A 
fumarylacetoacetate hydrolase (FAH)
autosomal recessive
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16
Q

Presenting forms of tyrosinemia type 1

A
  1. early infancy (1-6mths): liver disease
  2. late infancy: rickets from renal tubulopathy, no obvious liver failure
  3. porphyria like attack at any age
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17
Q

specific chemical elevated in tyrosinemia type 1

A

Succinylacetone

Acts in liver, kidney and nerves:
-porphyria like pain crises
peripheral neuropathy

*tyrosine is proximal to block so only modestly elevated

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18
Q

Cellular effects liver and kidneys, tyrosinemia type 1

A

hepatocellular damage

  • cirrhosis
  • hepatocellular carcinoma
  • high alpha feto protein

Renal tubular disease

  • renal fanconi syndrome
  • hypophosphatemic rickets
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19
Q

tyrosinemia type 1 treatment

A
  1. NTBC
    - inhibits 4-hydroxyphenylpyruvic acid deoxygenate
    - increases plasma tyrosine
    - decreases FAA and succinylacetone
    - may not prevent hepatocellular carcinoma
  2. Phe and Tyr restriction to avoid hypertyrosinemia
    - decreased risk of keratitis and palmoplantar keratosis
  3. Liver transplant if hepatocellular carcinoma develops
20
Q

alkaptonuria deficiency

A
  • Deficiency of hepatic enzyme homogentisate oxidase (HGO) in degredative pathway of tyrosine to fumate
  • homogentistic acid accumulates and is cleared by kidney and excreted
21
Q

alkaptouria symptoms

A
  • Dark connective tissue, brown pigmented sclerae, urine black on prolongued exposure to air
  • Debilitating arthralgias because homogentisic acid is toxic to cartilage
  • takes years for homogenistic to be deposited into cartilage and be converted to pigment like polymer in collagenous tissues
22
Q

alkaptouria treatment

A

Treatment: diet low in phenylalanine and tyrosine

23
Q

case presentation:
14 day old infant
newborn screen shows methionine= 210 (cutoff = 100)

A

homocystinuria

24
Q

most common enzyme deficiency in homocystinuria

A

CBS

which converts homocysteine to cystathione

25
Q

labs in homocystinuria

A

Plasma AA

  • Methionine 180 (NL 10-35)
  • Homocystine 2 (NL 0)
  • Total homocysteine 150

Urine AA

  • Homocysteine 20mmol/mg creatinine
  • normally undetectable

Urine organic acids normal

Positive urine cyanide-nitorprusside

26
Q

positive urine cyanide-nitroprusside

A

homocystinuria

-tests for sulfur containing AA

27
Q

Untreated homocystinuria

A
  1. Skeletal Malformations: most common in B6 resistant forms
  2. Recurrent thromboembolism
  3. Atherosclerotic Disease
  4. Eye abnormalities
  5. Developmental Disability/ Neuropsychiatric
28
Q

50% of CBS mutations are responsive to what?

A

pyridoxine = vitamin B6

29
Q

How to know if CBS mutation is responsive to B6?

A

Pyridoxine (B6) Challenge

  • 750mg oral per day for a week
  • monitor plasma methionine, total homocysteine
  • If B6 responsive: plasma hyperhomocysteinemia will normalize
30
Q

Homocystinuria treatment to reduce homocysteine levels in B6 sensitive vs. B6 Insensitive

A

B6 sensitive:
-B6, Folic Acid, B12

B6 Insensitive:

  • low methionine diet
  • betaine supplementation
31
Q

pattern of transmission of most common urea cycle disorder

A

OTC deficiency = x-linked

  • male hemizygotes with no enzyme may not survive past newborn
  • female heterozygotes have clinical symptoms range depending of pattern of x-inactivation
32
Q

case presentation:
4 day old male
lethargy, poor feeding, emesis
altered mental status, minimally responsive
hypertonic, hyperreflexic, possible seizures

A

OTC deficiency

33
Q

OTC deficiency acute emergency labs

A

VBG: pH 7.55, pCO2 24
Plasma Ammonia: 470

Respiratory alkalosis

34
Q

OTC family history

A

maternal uncle died at 6 days after progressive lethargy and coma

35
Q

OTC deficiency normal labs

A

Plasma AA:

  • low citrulline
  • elevated glutamine >1200

Urine Organic Acids:
-orotic acid*****

36
Q

Genetic test OTC

A

Diagnostic:

hemizygote for p.T178M mutation

37
Q

urea cycle defect treatment strategies

A
  1. dietary protein restriction
  2. ammonia scavenging meds
  3. l-argenine or l-citruline supplementation (depends on specific defect)
  4. acute severe hyperammonemia may require hemodialysis or iv scavengers
  5. consider liver transplant for patients with recurrent hyper ammonia or brittle disease refractory to medical management
38
Q

succinylacetone role in kidney

A
  • mitochondrial toxin in kidney and inhibits Krebs cycle

- membrane dysfxn in kidney

39
Q

succinylacetone role in liver

A
  • inhibits a-aminolevulinic dehydratase activity which mediates formation of porphobilinogen in heme synthesis
  • Mitochondria toxicity + Membranes + heme biosynthesis –> nodular cirrhosis
  • no evidence for involvement with cancerous mutations
40
Q

why is there an increased risk of HCC with tyrosinemia type 1?

A

abnormal FAH inhibits DNA glycosylases which remove mutagenic base substituents in genes

41
Q

what is citrulline?

A

-product of condensation between carbamyl phosphate and ornithine
Enzyme: OTC

42
Q

what is orotic acid?

A

If OTC is deficient, carbamyl phosphate and ornithine will be in excess.

-carbamyl phosphate goes to cytosol and is a substrate for carbamoyl phosphate synthase II in pyrimidine synthesis

–> orotic acid is an intermediate in pyrimidine biosynthesis

Most helpful diagnostic for OTC deficiency!

43
Q

how can liver biopsies with enzyme analysis lead to misdiagnosis of OTC deficiency?

A

OTC is mitochondrial hepatic enzyme with rapid postmortem degradation

-instead use mutational analysis: also lower risk

44
Q

alkaptonuria symptom appearance

A
  • all symptoms except dark stained diapers appear later in life
  • HGO deficiency is present at birth
45
Q

3 possible pathways impaired that lead to homocystinuria

A 
1. re-methylation: 
Homocysteine --> Met
-THF and B12
2. trans-sulfuration: CBS 
homocysteine--> crystathione
-B6
3. alternative re-methylation:
-uses betaine as methyl donor
46
Q

clinical use of betaine

A
  • part of alternative re-methylation pathway of homocysteine –>MET
  • Betaine supplementation will help convert homocysteine –>met
47
Q

vitamin supplementation in homocystinemia

A

High homocysteine associated with vascular risk

-folic acid supplements lower plasma homocysteine levels

Folic acid/ B12: 
-re-methylation
Betaine:
-alternative re-methylation
B6:
-trans-sulfuration

Dems Unit 2 Part 2 YAAAY (23 decks)

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