urea cycle and aa defects

Question 1

How is PKU tested for

Answer 1

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

Question 2

Which conditions are screened for in newborn screening

Answer 2

aminoacidopathies (PKU, tyrosinemias, MSUD), acidemias, carb metabolism disorders, fatty acid oxidation disorders, urea cycle disorders, other (CF, hemoglobinopathies, hearing loss, hypothyroid)

Question 3

3. 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

Answer 3

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

Question 4

5. Understand the limitations, controversies, and obstacles to NBS in specific disorders

Answer 4

In VLCAD deficiency, 21% are true positives while 69% are false positives.

Question 5

causes of hyperphenylalaninemia

Answer 5

PKU and BH4 deficiency

Question 6

enzyme deficiency in PKU

Answer 6

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.

Question 7

consequences of decreased tyrosine in PKU

Answer 7

Tyrosine is required for conversion to catecholamines and melanin

Question 8

Labs in untreated phenylketonuria (PKU)

Answer 8

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).

Question 9

6. List the signs and symptoms of untreated phenylketonuria (PKU)

Answer 9

Mental retardation, musty body odor, eczema, decreased pigmentation, autistic behaviors, white matter hyperintensities (pseudoleukodystrophy) and seizure. Decreased myelin, and catecholamine formation

Question 10

PKU diagnosis

Answer 10

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)

Question 11

7. Describe three approaches to treating a patient with PKU/hyperphenyalaninemia

Answer 11

1. 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?

Question 12

8. Define maternal PKU syndrome

Answer 12

microcephaly, low birth weight, mental retardation, and malformations in infants of mothers with poorly controlled PKU

Question 13

9. Know the biochemistry and basic pathophysiology of maple syrup urine disease (MSUD)

Answer 13

Autosomal recessive Deficiency in branched chain ketoacid dehydrogenase complex leads to elevated alpha-ketoacids. Mutations have been found in all four subunit genes

Question 14

Presentation of MSUD

Answer 14

1. 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

Question 15

MSUD progression in untreated neonate

Answer 15

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

Question 16

Diagnosis of MSUD

Answer 16

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

Question 17

MSUD treatment

Answer 17

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

Question 18

10. Describe the pathophysiology and clinical symptoms of tyrosinemia type 1

Answer 18

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

Question 19

3 presenting forms of tyrosinemia type 1

Answer 19

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)

Question 20

What causes porphyria like attack in tyrosinemia type 1

Answer 20

succinylacetone accumulation inhibits delta-aminolevulinic acid dehydratase activity which leads to decreased heme production (similar to porphyria)

Question 21

what causes damage to liver and kidneys in tyrosinemia type 1

Answer 21

buildup of fumarylacetoacetate

Question 22

tyrosinemia type 1 treatment

Answer 22

1. 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

Question 23

clinical features of tyrosinemia type 1

Answer 23

palmoplantar keratosis, corneal lesions

Question 24

clinical signs of alkaptonuria

Answer 24

black urine, black pigmentation of cartilage and collagen and degenerative arthritis from fourth decade

Question 25

Cause of homocystinuria

Answer 25

deficiency in cystathione B-synthase which catalyzes homocysteine > cystathionine.

Question 26

diagnosis of homocystinuria

Answer 26

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

Question 27

Clinical features of untreated homocystinuria

Answer 27

1. 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

Question 28

What percentage of CBS mutations are B6 responsive

Answer 28

50%

Question 29

homocystinuria treatment

Answer 29

1. 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

Question 30

Urea cycle disorders- pathophys and presentation

Answer 30

Ammonia rises- toxic to CNS. Results in encephalopathy, coma, neurological damage, or death. Can present at any age

Question 31

Ornithine transcarbamylase deficiency- presentation/labs

Answer 31

Most common urea cycle disorder. X linked. Plasma: low citrulline, elevated glutamine. Urine: elevated organic acids (orotic acid)

Question 32

Diagnosis of OTC deficiency

Answer 32

genetic testing, plasma ammonia elevated with normal anion gap and normal plasma glucose

Question 33

List ammonia scavenging agents

Answer 33

sodium phenylacetate and sodium benzoate

Question 34

MOA of ammonia scavenging agents

Answer 34

Bind to glutamine (phenylacetate) or glycine (benzoate) to scavenge nitrogen

Question 35

Treatment of urea cycle disorder

Answer 35

1. 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

Question 36

Which disorders are not included in newborn screening

Answer 36

aminoacidopathies, urea cycle disorders, organic acid metabolism disorders

Question 37

carbamoylphosphat synthetase 1 deficiency

Answer 37

most severe of urea cycle disorders. Rapidly develop hymerammonemia as newborn. At risk for repeat boutts.