urea cycle and aa defects Flashcards
How is PKU tested for
guthrie bacterial inhibition assay- blood from patient put on agar plate containing bacteria that require phenylalanine for growth. Pts with PKU will have bacterial growth around their blood spot due to elevated phenylalanine
Which conditions are screened for in newborn screening
aminoacidopathies (PKU, tyrosinemias, MSUD), acidemias, carb metabolism disorders, fatty acid oxidation disorders, urea cycle disorders, other (CF, hemoglobinopathies, hearing loss, hypothyroid)
- Understand and describe the original rationale for newborn screening and the basic concepts of current criteria underlying decisions applied to individual diseases considered for inclusion in newborn screening panels
The modified wilson jungner criteria is applied to conditions to determine feasibility of inclusion in NBS. For example, PKU receives a 10/10 score but Krabbe disease only gets a 6/10 score
- Understand the limitations, controversies, and obstacles to NBS in specific disorders
In VLCAD deficiency, 21% are true positives while 69% are false positives.
causes of hyperphenylalaninemia
PKU and BH4 deficiency
enzyme deficiency in PKU
phenylalanine hydroxylase deficiency- normally converts phenylalanine into tyrosine, so Phe builds up and is converted to phenyllactic acid and phenylacetic acid, and Pts have lack of tyrosine.
consequences of decreased tyrosine in PKU
Tyrosine is required for conversion to catecholamines and melanin
Labs in untreated phenylketonuria (PKU)
Autosomal recessive- effects are due to elevated total body Phe. Elevated Phe: >1200mM is severe, 600-1200 is moderate, <600 is mild (non-PKU hyperPhe).
- List the signs and symptoms of untreated phenylketonuria (PKU)
Mental retardation, musty body odor, eczema, decreased pigmentation, autistic behaviors, white matter hyperintensities (pseudoleukodystrophy) and seizure. Decreased myelin, and catecholamine formation
PKU diagnosis
Elevated plasma Phe and normal BH4- measured during newborn screenings via: 1. guthrie bacterial inhibition assay. 2. fluorometric analysis (fewer false positives). 3. tandem mass spectrometry (can be used to detect multiple disorders at same time)
- Describe three approaches to treating a patient with PKU/hyperphenyalaninemia
- Restrict dietary protein – Phe tolerance depends on residual enzyme activity. Supplement with Phe-free beverage. 2. Biopterin (BH4 supplementation of deficient). 3. Large neutral amino acid supplement (Phe shares transporter with LNAA at BBB). 4. phenylalanine ammonia lyase (degrades Phe). 5. macroglycoprotein. 6. liver cell transplant?
- Define maternal PKU syndrome
microcephaly, low birth weight, mental retardation, and malformations in infants of mothers with poorly controlled PKU
- Know the biochemistry and basic pathophysiology of maple syrup urine disease (MSUD)
Autosomal recessive Deficiency in branched chain ketoacid dehydrogenase complex leads to elevated alpha-ketoacids. Mutations have been found in all four subunit genes
Presentation of MSUD
- severe neonatal form (<1% activity): labs normal, maple syrup odor in urine. 2. Acute intermittent form (residual activity): late onset, ataxia, ketoacidotic coma +/- hypoglycemia, aa and keto acids normal btw attacks. 3. subacute chronic form (residual activity): hypotonia/ developmental delay, failure to thrive, spastic paraplegia
MSUD progression in untreated neonate
12-24hrs after birth: maple syrup odor in cerumen, elevated plasma BCAAs. 2-3 days: ketonuria, irritability, poor feeding. 4-5 days: encephalopathy (lethargy, apnea, movements such as fencing and bicycling). 7-10 days: coma, respiratory failure
Diagnosis of MSUD
labs: elevated leucine, valine and isoleucine with leucine > valine. Urine dinitrophenylhydrazin test positive (precipitates with BC ketoacids). 2-hydroxyisoleucine in urine gives it a mapl syrup smell. 3. genetic testing
MSUD treatment
Acute: Eliminate dietary protein intake, supplement valine and isoleucine, provide non-BCAA aa, avoid hypotonic fluids. Chronic: Protein restriction, BCAA free medical foods, supplement valine and isoleucine, supplement leucine, thiamin supplementation if E2 deficiency
- Describe the pathophysiology and clinical symptoms of tyrosinemia type 1
AR Fumarylacetoacetate hydrolase deficiency- causes elevated tyrosine ( range 25-105) and methionine (range 5-34 mM), and urine organic acids (succinylacetone and delta-aminolevulinic acid). Also hepatomegaly with multinodular disease due to damage
3 presenting forms of tyrosinemia type 1
- Early in infancy (1 to 6 months): Liver disease (hepatic failure or cholestatic jaundice or cirrhosis with renal tubulopathy). 2. Late infancy: Rickets due to renal tubulopathy (Fanconi syndrome) with no obvious liver failure. 3. Porphyria-like attack at any age (can be presenting sign)
What causes porphyria like attack in tyrosinemia type 1
succinylacetone accumulation inhibits delta-aminolevulinic acid dehydratase activity which leads to decreased heme production (similar to porphyria)
what causes damage to liver and kidneys in tyrosinemia type 1
buildup of fumarylacetoacetate
tyrosinemia type 1 treatment
- NTBC- inhibits production of fumarylacetoacetate and succinylacetone by inhibiting enzyme in tyrosine metabolism (4-hydroxyphenylpyruvic acid dioxygenase). 2. Phe and Tyr restriction. 3. liver transplant if hepatocellular carcinoma
clinical features of tyrosinemia type 1
palmoplantar keratosis, corneal lesions
clinical signs of alkaptonuria
black urine, black pigmentation of cartilage and collagen and degenerative arthritis from fourth decade
Cause of homocystinuria
deficiency in cystathione B-synthase which catalyzes homocysteine > cystathionine.
diagnosis of homocystinuria
Elevated plasma methionine, homocysteine and total homocysteine. Elevated urine homocysteine. Urine organic acids normal (no MMA) and urine cyanide-nitroprusside test is positive. Genetic testing
Clinical features of untreated homocystinuria
- skeletal malformations: marfanoid habitus, osteoporosis, scoliosis. Most common in B6 non responsive forms. 2. Recurrent thromboembolism (triggered by anesthesia, catabolism, smoking, contraceptives), may be isolated sign in late onset B6 responsive forms. 3. Atherosclerotic dz, 4. eye abnormalities, 5. developmental and neuropsychiatric sx
What percentage of CBS mutations are B6 responsive
50%
homocystinuria treatment
- pyridoxine (B6) challenge: 75mg orally per day for 1 week. Homocysteine will normalize in B6 responsive pts. 2. restric dietary protein. 3. Methionine free foods. 4. oral betaine. 5. Supplement with B12, folate, and/or cysteine
Urea cycle disorders- pathophys and presentation
Ammonia rises- toxic to CNS. Results in encephalopathy, coma, neurological damage, or death. Can present at any age
Ornithine transcarbamylase deficiency- presentation/labs
Most common urea cycle disorder. X linked. Plasma: low citrulline, elevated glutamine. Urine: elevated organic acids (orotic acid)
Diagnosis of OTC deficiency
genetic testing, plasma ammonia elevated with normal anion gap and normal plasma glucose
List ammonia scavenging agents
sodium phenylacetate and sodium benzoate
MOA of ammonia scavenging agents
Bind to glutamine (phenylacetate) or glycine (benzoate) to scavenge nitrogen
Treatment of urea cycle disorder
- dietary protein restriction. 2. ammonia scavenging meds. 3. L-arginine or L-citrulline supplementation. 4. hyperammonia (acute/severe) may require hemodialysis or IV scavengers. 5. Liver transplant if recurrent
Which disorders are not included in newborn screening
aminoacidopathies, urea cycle disorders, organic acid metabolism disorders
carbamoylphosphat synthetase 1 deficiency
most severe of urea cycle disorders. Rapidly develop hymerammonemia as newborn. At risk for repeat boutts.
