Inborn Errors of Metabolism: AAs and Urea Cycle

Question 1

urine ferric chloride spot test

Answer 1

pku

Question 2

Phe levels in severe, moderate, and benign phenylketonuria

Answer 2

severe: >1200
Moderate: 600-1200
Mild:

Question 3

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

Answer 3

maternal PKU

Question 4

3 Actions to manage metabolic encephalopathies

Answer 4

Remove Offending agent

1. NPO
2. STOP catabolism
3. Dialysis

Question 5

Urine DNPH Positive

Answer 5

MSUD

*will also be positive in PKU

Question 6

Plasma MSUD findings

Answer 6

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

Question 7

enzyme deficient in MSUD

Answer 7

branched chain ketoacid dehydrogenase (BCKD)

autosomal recessive

Question 8

BCKD structure and its relationship to treatment

Answer 8

4 subunits

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

Question 9

3 presentations MSUD

Answer 9

1. Severe Neonatal
2. Acute Intermittent
   - ataxia, hypoglycemia with ketoacids
3. Subacute Chronic
   - failure to thrive, plastic paraplegia, hypotonia

Question 10

case presentation:
newborn infant
poor feeding, progressive lethargy
coma and seizures 6 days of age
mild hypoglycemia
mild metabolic acidosis
ketonuria

Answer 10

MSUD

Question 11

acute treatment MSUD

Answer 11

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

Question 12

chronic MSUD therapy

Answer 12

• 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

Question 13

case presentation:
1month old infant
direct hyperbilirubinemia
prolonged PTT, elevated transaminases
hepatomegaly
edema (low albumin)
no hypoglycemia; no acidosis

Answer 13

Tyrosinemia type 1

Question 14

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

Answer 14

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

Question 15

enzyme deficient in tyrosinemia type 1

Answer 15

fumarylacetoacetate hydrolase (FAH)
autosomal recessive

Question 16

Presenting forms of tyrosinemia type 1

Answer 16

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

Question 17

specific chemical elevated in tyrosinemia type 1

Answer 17

Succinylacetone

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

*tyrosine is proximal to block so only modestly elevated

Question 18

Cellular effects liver and kidneys, tyrosinemia type 1

Answer 18

hepatocellular damage

• cirrhosis
• hepatocellular carcinoma
• high alpha feto protein

Renal tubular disease

• renal fanconi syndrome
• hypophosphatemic rickets

Question 19

tyrosinemia type 1 treatment

Answer 19

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

Question 20

alkaptonuria deficiency

Answer 20

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

Question 21

alkaptouria symptoms

Answer 21

• 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

Question 22

alkaptouria treatment

Answer 22

Treatment: diet low in phenylalanine and tyrosine

Question 23

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

Answer 23

homocystinuria

Question 24

most common enzyme deficiency in homocystinuria

Answer 24

CBS

which converts homocysteine to cystathione

Question 25

labs in homocystinuria

Answer 25

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

Question 26

positive urine cyanide-nitroprusside

Answer 26

homocystinuria -tests for sulfur containing AA

Question 27

Untreated homocystinuria

Answer 27

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

Question 28

50% of CBS mutations are responsive to what?

Answer 28

pyridoxine = vitamin B6

Question 29

How to know if CBS mutation is responsive to B6?

Answer 29

Pyridoxine (B6) Challenge - 750mg oral per day for a week - monitor plasma methionine, total homocysteine - If B6 responsive: plasma hyperhomocysteinemia will normalize

Question 30

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

Answer 30

B6 sensitive: -B6, Folic Acid, B12 B6 Insensitive: - low methionine diet - betaine supplementation

Question 31

pattern of transmission of most common urea cycle disorder

Answer 31

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

Question 32

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

Answer 32

OTC deficiency

Question 33

OTC deficiency acute emergency labs

Answer 33

VBG: pH 7.55, pCO2 24 Plasma Ammonia: 470 Respiratory alkalosis

Question 34

OTC family history

Answer 34

maternal uncle died at 6 days after progressive lethargy and coma

Question 35

OTC deficiency normal labs

Answer 35

Plasma AA: - low citrulline - elevated glutamine >1200 Urine Organic Acids: -orotic acid*****

Question 36

Genetic test OTC

Answer 36

Diagnostic: | hemizygote for p.T178M mutation

Question 37

urea cycle defect treatment strategies

Answer 37

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

Question 38

succinylacetone role in kidney

Answer 38

- mitochondrial toxin in kidney and inhibits Krebs cycle | - membrane dysfxn in kidney

Question 39

succinylacetone role in liver

Answer 39

- 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

Question 40

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

Answer 40

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

Question 41

what is citrulline?

Answer 41

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

Question 42

what is orotic acid?

Answer 42

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!

Question 43

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

Answer 43

OTC is mitochondrial hepatic enzyme with rapid postmortem degradation -instead use mutational analysis: also lower risk

Question 44

alkaptonuria symptom appearance

Answer 44

- all symptoms except dark stained diapers appear later in life - HGO deficiency is present at birth

Question 45

3 possible pathways impaired that lead to homocystinuria

Answer 45

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

Question 46

clinical use of betaine

Answer 46

- part of alternative re-methylation pathway of homocysteine -->MET - Betaine supplementation will help convert homocysteine -->met

Question 47

vitamin supplementation in homocystinemia

Answer 47

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 ```