Amino Acid Metabolism and Urea Cycle Defects

Question 1

Phenylalanine hydroxylase (PAH) deficiency can be diagnosed by newborn screening in virtually 100% of cases based on detection of the presence of hyperphenylalaninemia using the _______ or other assays on a blood spot obtained from a heel prick.

Answer 1

Guthrie microbial

Question 2

what is the treatment of Classic PKU:

Answer 2

a low natural protein diet through use of a Phe-free medical formula and a regular infant formula as soon as possible after birth to achieve plasma Phe concentrations of 120-360 µmol/L (2-6 mg/dL). A significant proportion of patients with PKU may benefit from adjuvant therapy with 6R-BH4 stereoisomer.

Question 3

The diagnosis of primary phenylalanine hydroxylase deficiency (PAH deficiency) is based on the detection of an elevated plasma phenylalanine (Phe) concentration and evidence of normal ______ metabolism. Individuals with PAH deficiency show plasma phenylalanine (Phe) concentrations that are persistently higher than _______ in the untreated state

Answer 3

BH4 cofactor,

120 µmol/L (2 mg/dL)

Question 4

Untreated children with persistent severe hyperphenylalaninemia (i.e., PKU) show impaired brain development. Signs and symptoms include: _______

Answer 4

microcephaly, epilepsy, severe intellectual disability, and behavior problems. Hypopigmentation,
Eczema, Hypomyelination on brain MR

Question 5

Phe concentrations of _____ are generally regarded as safe.

Answer 5

120-360 µmol/L (2-6 mg/dL) or 40-240 µmol/L (1-4 mg/dL)

Question 6

Ultimate IQ of a patient with PKU is directly related to ______

Answer 6

the age of initiation of therapy and the Phe levels achieved in childhood

Question 7

Some PKU patients have residual enzyme activity that can be further increased with supplementation of the _____

Answer 7

BH4 cofactor

Question 8

Women with PAH deficiency who are off diet and are planning a pregnancy should start a Phe-restricted diet prior to conception and should maintain plasma Phe concentrations between ______, ideally over several months, before attempting conception .

Answer 8

120 and 360 µmol/L (2-6 mg/dL)

Question 9

Infants born to mothers with uncontrolled PKU have _______

Answer 9

growth restriction, microcephaly, intellectual disability and heart malformations

Question 10

Maple Syrup Urine Disease Results from deficiency of the __________

Answer 10

branched chain ketoacid dehydrogenase complex

Question 11

Maple syrup urine disease (MSUD) in untreated neonates is characterized by what features at 12-24 hours after birth;

Answer 11

maple syrup odor in cerumen,
Elevated plasma concentrations of branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine) and allo-isoleucine, as well as a generalized disturbance of plasma amino acid concentration ratios

Question 12

what may occur by age 7-10 days in Maple syrup urine disease (MSUD) in untreated neonates

Answer 12

coma and central respiratory failure

Question 13

In untreated Maple syrup urine disease (MSUD) what clinical manifestations can be seen by age 4-5 days.

Answer 13

deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as “fencing” and “bicycling”

Question 14

In untreated Maple syrup urine disease (MSUD) what is the phenotype by age 2-3 days;

Answer 14

ketonuria, irritability, and poor feeding

Question 15

The three genes associated with MSUD are ______

Answer 15

BCKDHA (E1a subunit gene, MSUD type 1A),
BCKDHB (E1b subunit gene, MSUD type 1B),
DBT (E2 subunit gene, MSUD type 2)

Question 16

Treatment of MSUD includes

Answer 16

dietary leucine restriction, high-calorie BCAA-free formulas, judicial supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring

Question 17

Adolescents and adults with MSUD are at increased risk for __________ . Orthotopic liver transplantation is an effective therapy for classic MSUD.

Answer 17

ADHD, depression, and anxiety disorders and can be treated successfully with standard psychostimulant and antidepressent medications

Question 18

how is MSUD diagnosed

Answer 18

Elevation of leucine,
Presence of allo-isoleucine,
Presence of urine ketones in a neonate,
Assessment of lactate, alpha-ketoglutarate for combined enzyme deficiencies (DLD),
Branched chain ketoacid dehydrogenase complex enzyme activity,
Gene sequencing
BCKDHA, BCKDHB, DBT, DLD
BCKDHB patients may be thiamine-responsive

Question 19

Untreated tyrosinemia type I usually presents either in young infants with ______ or later in the first year with liver dysfunction and renal tubular dysfunction associated with _______

Answer 19

severe liver involvement ,

growth failure and rickets.

Question 20

Untreated children with tyrosinemia type 1 may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include _________

Answer 20

change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation.

Question 21

Diagnostic metabolite in tyrosinemia type 1 is ______

Answer 21

succinylacetone in urine

Question 22

Tyrosinemia type I results from deficiency of the enzyme _______

Answer 22

fumarylacetoacetate hydrolase (FAH),

Question 23

what is the treatment of tyrosinemia?

Answer 23

Nitisinone (Orfadin®), 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC),
Monitoring for hepatocellular carcinoma (HCC)

Question 24

What is the MOA of Nitisinone?

Answer 24

Blocks parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), the second step in the tyrosine degradation pathway, prevents the accumulation of fumarylacetoacetate and its conversion to succinylacetone.

Question 25

what is Tyrosinemia type II

Answer 25

Results from 4-OH phenylpyruvic acid dehydrogenase deficiency

Question 26

what clinical presentation of Tyrosinemia type II

Answer 26

Causes much higher tyrosine elevations

Results in palmoplantar hyperkeratosis and keratitis

Question 27

Classic homocystinuria is due to _______

Answer 27

cystathionine beta synthase deficiency

Question 28

Untreated patients with homocystinuria present with ____

Answer 28

lens dislocation, scoliosis, pectus carinatum, mild developmental delays

Question 29

Elevated homocysteine leads to very high risk of _______

Answer 29

thrombotic events

Question 30

Even patients treated for homocystinuria get ________

Answer 30

osteoporosis, vascular risk

Question 31

The cardinal biochemical features of homocystinuria are:

Answer 31

markedly increased concentrations of plasma homocystine, total homocysteine, homocysteine-cysteine mixed disulfide, and methionine; increased concentration of urine homocystine; and reduced cystathionine β-synthase (CBS) enzyme activity

Question 32

____, the gene in which mutations result in homocystinuria caused by cystathionine β-synthase deficiency, is clinically available.

Answer 32

CBS

Question 33

what is the treatment of homocystinuria

Answer 33

protein-restricted and methionine-restricted diets; possibly betaine treatment; and/or folate and vitamin B12 supplementation

Question 34

A plasma ammonia concentration of _____ or higher associated with a normal anion gap and a normal plasma glucose concentration is an indication for the presence of a Urea Cycle Disorder

Answer 34

150 μmol/L

Question 35

what are the Sx’s of Acute Hyperammonemia

Answer 35

Encephalopathy, seizures, ataxia, visual loss, hallucinations, mania, Vomiting and loss of appetite
In neonates: temperature instability, hyperventilation

Question 36

what are the symptoms of chronic Hyperammonemia

Answer 36

Developmental delay
Nausea, failure to thrive, protein avoidance
Migraines
Anxiety, depression, disinhibition
Hepatomegaly, elevated liver enzyme

Question 37

The urea cycle is the sole source of endogenous production of _______

Answer 37

arginine, ornithine, and citrulline

Question 38

Which urea cycle enzymes overlap with the nitric oxide production pathway

Answer 38

ASS and ASL

Question 39

what are triggers for a hyperammonemic episode

Answer 39

Illness, fever, vomiting, fasting, surgery
Postpartum period, menarche
Intense exercise
Dietary protein load
Medications - valproate, peg asparaginase
UTI

Question 40

what is the most common urea cycle disorder

Answer 40

Ornithine transcarbamylase deficiency

Question 41

what causes Ornithine transcarbamylase deficiency

Answer 41

X-linked, deletions and point mutations in OTC
Gene is expressed only in the liver
There are many symptomatic females

Question 42

what are the Diagnostic metabolites of Ornithine transcarbamylase deficiency

Answer 42

Diagnostic metabolite is orotic acid; also with low citrulline, high glutamine

Question 43

true or false

Ornithine transcarbamylase deficiency is a newborn screening

Answer 43

False

Question 44

Ornithine transcarbamylase deficiency is often lethal in _______

Answer 44

the neonatal period for boys

Question 45

what is the Management of OTC

Answer 45

Very low protein diet (lowest of all IEMs)
Supplement citrulline or arginine
Ammonia scavenging medications
Close nutritional monitoring
Aggressive support during illness
Dialysis
Liver transplantation
? Gene therapy

Question 46

_______ is the most severe of the urea cycle disorders.

Answer 46

Carbamoylphosphate synthetase I deficiency (CPS1 deficiency)

Question 47

Affected individuals can also develop trichorrhexis nodosa, a node-like appearance of fragile hair that usually responds to arginine supplementation. this person has _______

Answer 47

Argininosuccinic aciduria (ASL deficiency)