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Metabolism Flashcards

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1
Q

True or false: inborn errors of metabolism only present in childhood

A

false–can present in adulthood as well

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2
Q

A _______ should be suspected as the cause in any case of neonatal death, especially if it was attributed to sepsis.

A

inborn error of metabolism

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3
Q

Name the 3 functional categories of inborn errors of metabolism. Give examples of disorders in each of these categories.

A
  1. Disorders that give rise to intoxication
    - ex AA catabolism disorders
  2. Disorders that involve energy metabolism
    - mitochondrial
  3. Disorders involving complex molecules
    - lysosomal storage disorders
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4
Q

What does C0 represent?

A

carnitine

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5
Q

Elevated alanine on plasma amino acids may reflect _____?

A

=elevated chronic lactic acid

  • elevated in mitochondrial, pyruvic acid disorders
  • also elevated in some UCDs
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6
Q

The presence of alloisoleucine on PAA is diagnostic for what condition?

A

MSUD

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7
Q

Elevated arginine on PAA can suggest what disorder?

A

Argininemia

-low in other UCDs

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8
Q

The presence of arginosuccinic acid on PAA is diagnostic for what condition?

A

ASL deficiency

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9
Q

Name 2 situations where branched chain amino acids can be elevated on PAA?

A
  1. MSUD (normal ratios of leucine, valine, and isoleucine are perturbed), leucine levels very elevated
  2. diet
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10
Q

Elevated citrulline can be seen on PAA under what circumstances?

A 
Argininosuccinic aciduria (200–300 µM)
Citrullinemia (2000–3000 µM)
Citrin deficiency (50–300 µM)
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11
Q

Elevated glutamine on PAA can be associated with what group of conditions?

A

Urea Cycle Defects

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12
Q

Elevated glycine on PAA can be associated with what 2 conditions?

A
  1. Glycine encephalopathy

2. Organic acidemias (MMA & PA)

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13
Q

Methionine can be very elevated on PAA in what condition?

A

Homocystinuria

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14
Q

Phenylalanine is elevated on PAA in what condition

A

PKU

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15
Q

Tyrosine is elevated on PAA in what condition?

A

Hepatorenal tyrosinemia (type I)

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16
Q

Name 3 amino acids that can be elevated in liver disease/dysfxn

A
  1. Methionine
  2. Phenylalanine
  3. Tyrosine

Also : Orn, Lys, Pro, Ala, Gln
Thr:Ser ratio >2
↓ BCAAs

Elevations not as striking as when related to an IEM

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17
Q

What are the artifactual findings on PAA if the sample is hemolyzed?

A

↑ Glu

↓ Gly, Orn, Arg, Gln

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18
Q

What does urine organic acids look at?

A

Intermediates in the degradation of amino acids, carbohydrates, and lipids
Not reabsorbed by the kidney -> excreted in the urine

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19
Q

Elevated actetoacetate and 3-hydroxybutyrate on urine organic acids suggest what?

A

-Fasting or ketosis

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20
Q

What are some history questions to ask regarding hy poglycemia?

A
  1. Measured BG was (POC vs serum)
  2. time since last meal?
  3. Prolonged fasting?
  4. Viral illness
  5. Symptomatic? malaise, lethargy, seizures, abd pain, N/V
  6. Medications
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21
Q

What neonatal factors are on the differential for hypoglycemia along with IEM?

A
  1. sepsis
  2. severe systemic illness
  3. SGA
  4. Maternal diabetes
  5. hyperinsulinism
  6. hypopituitarism
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22
Q

What is ketotic hypoglycemia?

A

=condition characterized by symptomatic hypoglycemia, with evidence of ketones in blood or urine

  • usually occurs in thin, young children (18 months-6 years)
  • Occurs in setting of food disruption (viral illness, vomiting, prolonged fasting–skipped inner night before)
  • Symptoms early AM of ketosis (abd pain, anorexia, N/V) +/- neuroglycopenia (lethargy, malaise, unresponsiveness, seizures)
  • labs will have mild acidosis, otherwise normal
  • responds to carbs or IV dextrose
  • can recur early in childhood
  • diagnosis of exclusion
  • some disorders–GSD 0 can look similar
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23
Q

Name 5 categories of metabolic disease that can have decompensation with excessive exercise

A
  1. Fatty acid oxidation disorders
  2. glycolysis disorders
  3. muscle glycogenolysis disorders
  4. purine and pyrimidine metabolism disorders
  5. respiratory chain metabolism disorders
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24
Q

Name 2 categories of metabolic disorders that can behave metabolic decompensation triggered by drugs.

A
  1. Porphyrias

2. Glucose 6 phosphate dehydrogenase deficiency

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25
Q

Name 3 ketone bodies

A
  1. beta hydroxybutyrate
  2. acetone
  3. acetoacetatic acid
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26
Q

What is a ketone body?

A

water soluble molecule produced by the liver from fatty acids under certain conditions including fasting, carbohyrate restrictive diets, starvation, prolonged intense exercise, inadequately or untreated diabetes mellitus

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27
Q

What happens to ketone bodies after they are produced in the liver?

A

They are released into the blood stream and taken up by:

  1. extra-hepatic tissues (not the brain): converted to acetyl-coA -> Krebs cycle -> etc -> energy
  2. the brain: convert acetyl-CoA into long chain fatty acids
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28
Q

What is the purpose of ketone bodies?

A

Ketone bodies are an alternative energy fuel source when glucose stores are low

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29
Q

What is MPS I?

Name enzyme deficiency and accumulated metabolite,

A

Hurler syndrome

  • alpha-L-iduronidase deficiency
  • accumulate dermatan sulfate and heparan sulfate
  • Due to IDUA mutations
30
Q

What is MPS II?

Name enzyme deficiency and accumulated metabolilte.

A

Hunter syndrome

  • iduronate 2-sulfatase deficiency
  • accumulate dermatan sulfate and heparin sulfate
  • Due to mutations in IDS gene on X chromosome
31
Q

What is MPS III?

Name enzyme deficiency and accumulated metabolite.

A

SanFilipo syndrome

-4 different enzyme deficiencies (classified into 4 different subtypes), all result in accumulation of heparan sulfate

32
Q

What is MPS IV?

Name enzyme deficiency and accumulated metabolite

A

Morquio syndrome
-2 different enzyme deficiencies, both result in accumulation of keratin sulfate. In type A also accumulate chondroitin-6-sulfate

33
Q

Name 3 reasons for an unsatisfactory NBS sample.

A
  1. hemolysis
  2. contamination with blood spots with other samples
  3. irregular thickness of blood samples
34
Q

A child has a Phe level >1200 with reduced tyrosine and elevated phe/tyrosine ratio. What are the 2 major disorders on your differential?

A

=c/w phenylketonuria (PKU)
2 causes:
1. phenylalanine hydroxylase deficiency (98% of PKU)
2. Defects in biopterin synthesis (2% PKU)

35
Q

What study should you obtain to determine the cause of an elevated Phe level on NBS after it is verified?

A

urine biopterin or pterins

36
Q

What is the goal Phe level for treated PKU?

A

Phe 120-360 (for all ages)
Tx with Phe free formula and low protein diet
Can add Bh4 (sapropterin) if difficult to control with diet alone

37
Q

What are the features of maternal PKU?

A

= fetal abnormalities due to teratogenic effects of elevated Phe levels during pregnancy

-miscarriage, IUGR, microcephaly, intellectual disability, congenital heart defects, cleft lip/palate, and pyloric stenosis

38
Q

There are 2 types of tyrosinemia. Which type manifests mostly with liver/renal disease and which type mainly with cutaneous and ocular features?

A
  1. Tyrosinemia Type I (hepatorenal)
    - liver failure/cirrhosis and liver cancer, renal fanconi syndrome
  2. Tyrosinemia Type II (oculocutaneous)
39
Q

You have a newborn screen with elevated tyrosine and methionine. Follow-up studies confirm these features and there is +succinylacetone on urine organic acids. What disorder?

A

=tyrosinemia type 1

  • due to defect in FAH
  • sx: liver failure, renal fanconi syndrome, FTT, neurologic crises
40
Q

You have a newborn screen with a methionine level > 100 and elevated plasma methionine and homocysteine. What’s the diagnosis? What’s the enzymatic defect?

A

=classical homocystinuria

-deficiency of cystathione beta synthetase

41
Q

Name 5 treatments for homocystinuria

A
  1. pyroxidine and folate
  2. low methionine diet
  3. betaine
  4. dypridamole
  5. aspirin (for thrombosis)
42
Q

Newborn screening demonstrates elevated branched chain amino acids. Alloisoleucine is detected. What’s the diagnosis? What’s the enzymatic deficiency?

A

=Maple syrup urine disease

due to defect in branched chain ketoacid decarboxylase

43
Q

What is the treatment for maple syrup urine disease?

A
  1. diet with low branched chain amino acids

2. thiamine (vitamin B1)

44
Q

Newborn screen shows elevated C6, C8, and C8/C10 ratio. What’s the diagnosis?

A

=MCAD (medium chain acyl-CoA dehydrogenase deficiency)

45
Q

What is the treatment for MCAD?

A
  1. Avoidance of fasting (cornstarch at night)

2. carnitine

46
Q

What metabolic disorder has the following features? What type of disorder?

cardiomyopathy, hypotonia, rhabdomylosis. Moms can have HELLP. NBS shows elevated C14-OH, C16-OH, and C18-OH and C18:1-OH

A

=LCHAD

-Disorder of fatty acid oxidation

47
Q

A child presents from a country with no newborn screening with seizures, hypotonia, developmental delay, hearing loss, alopecia, and an eczematous rash. What biochemical disorder should you suspect? How is this tested for on NBS?

A

=biotinidase deficiency

-screened for on NBS by colorimetric test to detect biotinidase activity

rash and alopecia are characteristic features

48
Q

What is the treatment for biotinidase deficiency?

A

=supplementation with oral biotin

49
Q

What is the defect in 3MCC deficiency? What can precipitate a metabolic crisis in this disorder?

A

3MCC deficiency=3 methylcrotonyl CoA carboxylase deficiency

  • defect in one of the enzymes needed to breakdown leucine
  • metabolic decompensation/crisis can be triggered by catabolic state / reduced food intake (fasting, infection, exertion) because there is increased breakdown of amino acids and fatty acids in an attempt to make ketones for the body
50
Q

3MCC can be detected on NBS by elevated _________.

A 
=C5-OH
-impt to note there are multiple other disorders that can show up on NBS with elevated C5-OH so need to follow ACT to determine which one
Beta-ketothiolase deficiency
Biotinidase deficiency
Holocarboxylase deficiency
HMG-CoA lyase deficiency
2M3HBA
3MGA
51
Q

A child comes in with a history of poor oral intake due to a viral illness. He has lethargy and vomiting. Labs show hypoglycemia, metabolic acidosis (with elevated anion gap), elevated ammonia. There are no ketones in the urine but UOA detects 3 methylcrotonylglycine. What is the disorder? How do you treat it?

A

=3MCC or 3 methylcrotonyl CoA Carboxylase deficiency

  • when decompensates presents with acidosis and hypoketotic hypoglycemia
  • triggered by catabolism

-Treatment for acute crisis: Start 10% glucose continuous infusion at 1.5x maintenance to provide 7-
8mg/kg/min +/- D25 2/kg if hypoglycemia, bicarbonate if acidotic, + carnitine

52
Q

A baby has a significantly elevated C3 on NBS. What are the 2 disorders on the differential? Does this finding need immediate action?

A

Elevated C3 ->

  1. Methylmalonic acidemia
  2. Proprionic academia
    - baby needs immediate evaluation, stop oral intake, IV fluids and labs to evaluate
53
Q

A baby has elevated galactose and galactose 1 phosphate on NBS. What should you do?

A
  1. immediately get repeat levels
  2. put baby on lactose free formula

Untreated galactosema commonly presents with feeding problems, failure to thrive, hepatocellular damage, bleeding, and E. coli sepsis.

Initiation of diet in first 10 days can reverse most of manifestations.

54
Q

What labs should be monitored as response to treatment of galactosemia at appointments?

A
  1. Erythrocyte galactose 1 phosphate levels
  2. urinary galactitol

Increase in either of these suggests galactose consumption/possible non-compliance with diet

55
Q

There is elevated 17-OH progesterone on NBS. What disorder should you suspect? What are the key deficient chemicals that can make the infant symptomatic?

A

=CAH (usually due to 21 hydroxylase deficiency)

  • deficient in aldosterone and cortisol can lead to hyponatremic hyperkalemic dehydration and shock
  • ACTH stimulates overproduction of testosterone -> virilization of females
56
Q

True or false: breastfeeding should be avoided in a child with SCID.

A

True–could transmit CMV in breastmilk
screened for on NBS
22q11.2 kids can be picked up because of this

57
Q

True or false: urine orotic acid will be able both chronically and in an acute crisis in a child with OTC deficiency.

A

=false-usually abnormal in acute crisis
-if suspect pt has OTC deficiency and not in acute crisis (esp if pt is female), best way to confirm is with gene sequencing

58
Q

True or false: serum hexA levels are usually for screening for Tay Sachs carrier status in a pregnant female.

A

False-serum HexA level is not reliable during pregnancy
Best assay (esp if non-Ashkenazi Jewish) is WBC hexA level
Molecular testing not helpful for non-Ashkenazi Jewish population because most mutations will not be detected

59
Q

What screening test can be used to look for X-linked adrenoleukodystrophy?

A

=VLFCA (tend to accumulate)

-due to a defect in a protein on the surface of peroxisomes that transports VLFCA into the peroxisome for degredation. Impaired transport and therefore impaired degredation of these VLCFA and the disorder.

60
Q

You have a child detected on NBS with elevated tyrosine level and +succinylacetone. What treatment should be initiated?

A
  1. low tyrosine diet
  2. nitisinone or NTBC
    1.0 mg/kg/day, usually divided into 2 doses
    blocks formation of succinylacetone, which is toxic to the liver and kidneys
  3. liver transplant (now NTBC and diet are first line)
61
Q

Name the disorder and the key biochemical defects:
-rhizomelic shortening of the lumbs with punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities, coronal clefts in vertebral bodies, cataracts, seizures.

A

=rhizomelic chrondroplasia punctate

  • autosomal recessive peroxisome biogenesis disorder
  • characterized by elevated plasma phytanic acid, deficient RBC plasmogens, normal VLCFA
62
Q

N-acetylaspartic acid (NAA) is the key biochemical finding for what disorder. Name 2 ways to detect it.

A
  1. Canavan disease

Absence of Aspartoacylase -> inability to break down NAA -> NAA builds up in the brain -> demyelination and disease

  1. Detect NAA on urine organic acids
  2. NAA peak on MR-spec
63
Q

Nitisinone (or NTBC) can be used to treat what 2 disorders?

A
  1. tyrosinemia type 1

2. alkaptonuria

64
Q

True or false: acute intermittent porphyria is inherited in an autosomal recessive manner.

A

false. It’s autosomal dominant, nmost asymptomatic

65
Q

True or false: the enzyme glucose-6 phosphatase (the enzyme that is defective in GSD 1a) is expressed only in the liver.

A

=true

-diagnosis by enzymatic assay of liver biopsy or molecular testing

66
Q

What disorder is caused by deficiency of alpha galactosidase?

A

=Fabry disease

67
Q

What disorder is caused by cerebrosidase B galactosidase deficiency?

A

=Krabbe disease

68
Q

Name 2 urea cycle disorders characterized by undetectable levels of citrulline. How do you tell the difference between the 2?

A

2 disorders with undetectable citrulline levels (in males)

  1. OTC deficiency
    - will have elevated orotic acid level in urine
  2. CPS deficiency
    - nl orotic acid level
69
Q

Name 3 mucopolysaccharidoses that can have preserved cognitive function?

A
  1. Morquio (MPS IV)
  2. Maroteaux-Lamy (MPS VI)
  3. Hurler-Scheie variant of MPS I
70
Q

Why are patients with PA or MMA intermittently treated with metronidazole?

A

reduces gut bacterial load because gut bacteria produce proprionate which can also be converted to methyl malonic acid

71
Q

What disorder is characterized by elevated levels of arylsulfatase A and B glucouronidase in the blood? What are the other characteristic features?

A

= I cell disease (or mucolipidosis type II)

Characterized by:

  • coarse facial features
  • hepatomegaly
  • dysostosis multiplex on skeletal survey and joint contractures

unlike other lysosomal storage disorders, multiple enzymes are elevated in the plasma

Genetics (16 decks)

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