Inborn Errors of Metabolism: AAs and Urea Cycle Flashcards
urine ferric chloride spot test
pku
Phe levels in severe, moderate, and benign phenylketonuria
severe: >1200
Moderate: 600-1200
Mild:
presentation: infant born with microcephaly, congenital cardiac lesion, mental retardation, low birth weight
maternal PKU
3 Actions to manage metabolic encephalopathies
Remove Offending agent
- NPO
- STOP catabolism
- Dialysis
Urine DNPH Positive
MSUD
*will also be positive in PKU
Plasma MSUD findings
Increased: leucine, valine, isoleucine
Alloisoleucine present
Branched chain ketoacids on urine analysis
Urine DNTH +
enzyme deficient in MSUD
branched chain ketoacid dehydrogenase (BCKD)
autosomal recessive
BCKD structure and its relationship to treatment
4 subunits
mutations in E2 subunit: most likely to be B1 (thiamine) responsive
3 presentations MSUD
- Severe Neonatal
- Acute Intermittent
- ataxia, hypoglycemia with ketoacids - Subacute Chronic
- failure to thrive, plastic paraplegia, hypotonia
case presentation: newborn infant poor feeding, progressive lethargy coma and seizures 6 days of age mild hypoglycemia mild metabolic acidosis ketonuria
MSUD
acute treatment MSUD
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
chronic MSUD therapy
- 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
case presentation: 1month old infant direct hyperbilirubinemia prolonged PTT, elevated transaminases hepatomegaly edema (low albumin) no hypoglycemia; no acidosis
Tyrosinemia type 1
lab results tyrosinemia type 1 (US, plasma, urine)
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
enzyme deficient in tyrosinemia type 1
fumarylacetoacetate hydrolase (FAH) autosomal recessive
Presenting forms of tyrosinemia type 1
- early infancy (1-6mths): liver disease
- late infancy: rickets from renal tubulopathy, no obvious liver failure
- porphyria like attack at any age
specific chemical elevated in tyrosinemia type 1
Succinylacetone
Acts in liver, kidney and nerves:
-porphyria like pain crises
peripheral neuropathy
*tyrosine is proximal to block so only modestly elevated
Cellular effects liver and kidneys, tyrosinemia type 1
hepatocellular damage
- cirrhosis
- hepatocellular carcinoma
- high alpha feto protein
Renal tubular disease
- renal fanconi syndrome
- hypophosphatemic rickets
tyrosinemia type 1 treatment
- NTBC
- inhibits 4-hydroxyphenylpyruvic acid deoxygenate
- increases plasma tyrosine
- decreases FAA and succinylacetone
- may not prevent hepatocellular carcinoma - Phe and Tyr restriction to avoid hypertyrosinemia
- decreased risk of keratitis and palmoplantar keratosis - Liver transplant if hepatocellular carcinoma develops
alkaptonuria deficiency
- Deficiency of hepatic enzyme homogentisate oxidase (HGO) in degredative pathway of tyrosine to fumate
- homogentistic acid accumulates and is cleared by kidney and excreted
alkaptouria symptoms
- 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
alkaptouria treatment
Treatment: diet low in phenylalanine and tyrosine
case presentation:
14 day old infant
newborn screen shows methionine= 210 (cutoff = 100)
homocystinuria
most common enzyme deficiency in homocystinuria
CBS
which converts homocysteine to cystathione
labs in homocystinuria
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
positive urine cyanide-nitroprusside
homocystinuria
-tests for sulfur containing AA
Untreated homocystinuria
- Skeletal Malformations: most common in B6 resistant forms
- Recurrent thromboembolism
- Atherosclerotic Disease
- Eye abnormalities
- Developmental Disability/ Neuropsychiatric
50% of CBS mutations are responsive to what?
pyridoxine = vitamin B6
How to know if CBS mutation is responsive to B6?
Pyridoxine (B6) Challenge
- 750mg oral per day for a week
- monitor plasma methionine, total homocysteine
- If B6 responsive: plasma hyperhomocysteinemia will normalize
Homocystinuria treatment to reduce homocysteine levels in B6 sensitive vs. B6 Insensitive
B6 sensitive:
-B6, Folic Acid, B12
B6 Insensitive:
- low methionine diet
- betaine supplementation
pattern of transmission of most common urea cycle disorder
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
case presentation:
4 day old male
lethargy, poor feeding, emesis
altered mental status, minimally responsive
hypertonic, hyperreflexic, possible seizures
OTC deficiency
OTC deficiency acute emergency labs
VBG: pH 7.55, pCO2 24
Plasma Ammonia: 470
Respiratory alkalosis
OTC family history
maternal uncle died at 6 days after progressive lethargy and coma
OTC deficiency normal labs
Plasma AA:
- low citrulline
- elevated glutamine >1200
Urine Organic Acids:
-orotic acid*****
Genetic test OTC
Diagnostic:
hemizygote for p.T178M mutation
urea cycle defect treatment strategies
- dietary protein restriction
- ammonia scavenging meds
- l-argenine or l-citruline supplementation (depends on specific defect)
- acute severe hyperammonemia may require hemodialysis or iv scavengers
- consider liver transplant for patients with recurrent hyper ammonia or brittle disease refractory to medical management
succinylacetone role in kidney
- mitochondrial toxin in kidney and inhibits Krebs cycle
- membrane dysfxn in kidney
succinylacetone role in liver
- 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
why is there an increased risk of HCC with tyrosinemia type 1?
abnormal FAH inhibits DNA glycosylases which remove mutagenic base substituents in genes
what is citrulline?
-product of condensation between carbamyl phosphate and ornithine
Enzyme: OTC
what is orotic acid?
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!
how can liver biopsies with enzyme analysis lead to misdiagnosis of OTC deficiency?
OTC is mitochondrial hepatic enzyme with rapid postmortem degradation
-instead use mutational analysis: also lower risk
alkaptonuria symptom appearance
- all symptoms except dark stained diapers appear later in life
- HGO deficiency is present at birth
3 possible pathways impaired that lead to homocystinuria
1. re-methylation: Homocysteine --> Met -THF and B12 2. trans-sulfuration: CBS homocysteine--> crystathione -B6 3. alternative re-methylation: -uses betaine as methyl donor
clinical use of betaine
- part of alternative re-methylation pathway of homocysteine –>MET
- Betaine supplementation will help convert homocysteine –>met
vitamin supplementation in homocystinemia
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
