Amino Acid Metabolism and Urea Cycle Defects Flashcards
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.
Guthrie microbial
what is the treatment of Classic PKU:
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.
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
BH4 cofactor,
120 µmol/L (2 mg/dL)
Untreated children with persistent severe hyperphenylalaninemia (i.e., PKU) show impaired brain development. Signs and symptoms include: _______
microcephaly, epilepsy, severe intellectual disability, and behavior problems. Hypopigmentation,
Eczema, Hypomyelination on brain MR
Phe concentrations of _____ are generally regarded as safe.
120-360 µmol/L (2-6 mg/dL) or 40-240 µmol/L (1-4 mg/dL)
Ultimate IQ of a patient with PKU is directly related to ______
the age of initiation of therapy and the Phe levels achieved in childhood
Some PKU patients have residual enzyme activity that can be further increased with supplementation of the _____
BH4 cofactor
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 .
120 and 360 µmol/L (2-6 mg/dL)
Infants born to mothers with uncontrolled PKU have _______
growth restriction, microcephaly, intellectual disability and heart malformations
Maple Syrup Urine Disease Results from deficiency of the __________
branched chain ketoacid dehydrogenase complex
Maple syrup urine disease (MSUD) in untreated neonates is characterized by what features at 12-24 hours after birth;
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
what may occur by age 7-10 days in Maple syrup urine disease (MSUD) in untreated neonates
coma and central respiratory failure
In untreated Maple syrup urine disease (MSUD) what clinical manifestations can be seen by age 4-5 days.
deepening encephalopathy manifesting as lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as “fencing” and “bicycling”
In untreated Maple syrup urine disease (MSUD) what is the phenotype by age 2-3 days;
ketonuria, irritability, and poor feeding
The three genes associated with MSUD are ______
BCKDHA (E1a subunit gene, MSUD type 1A),
BCKDHB (E1b subunit gene, MSUD type 1B),
DBT (E2 subunit gene, MSUD type 2)
Treatment of MSUD includes
dietary leucine restriction, high-calorie BCAA-free formulas, judicial supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring
Adolescents and adults with MSUD are at increased risk for __________ . Orthotopic liver transplantation is an effective therapy for classic MSUD.
ADHD, depression, and anxiety disorders and can be treated successfully with standard psychostimulant and antidepressent medications
how is MSUD diagnosed
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
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 _______
severe liver involvement ,
growth failure and rickets.
Untreated children with tyrosinemia type 1 may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include _________
change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation.
Diagnostic metabolite in tyrosinemia type 1 is ______
succinylacetone in urine
Tyrosinemia type I results from deficiency of the enzyme _______
fumarylacetoacetate hydrolase (FAH),
what is the treatment of tyrosinemia?
Nitisinone (Orfadin®), 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC),
Monitoring for hepatocellular carcinoma (HCC)
What is the MOA of Nitisinone?
Blocks parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), the second step in the tyrosine degradation pathway, prevents the accumulation of fumarylacetoacetate and its conversion to succinylacetone.
what is Tyrosinemia type II
Results from 4-OH phenylpyruvic acid dehydrogenase deficiency
what clinical presentation of Tyrosinemia type II
Causes much higher tyrosine elevations
Results in palmoplantar hyperkeratosis and keratitis
Classic homocystinuria is due to _______
cystathionine beta synthase deficiency
Untreated patients with homocystinuria present with ____
lens dislocation, scoliosis, pectus carinatum, mild developmental delays
Elevated homocysteine leads to very high risk of _______
thrombotic events
Even patients treated for homocystinuria get ________
osteoporosis, vascular risk
The cardinal biochemical features of homocystinuria are:
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
____, the gene in which mutations result in homocystinuria caused by cystathionine β-synthase deficiency, is clinically available.
CBS
what is the treatment of homocystinuria
protein-restricted and methionine-restricted diets; possibly betaine treatment; and/or folate and vitamin B12 supplementation
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
150 μmol/L
what are the Sx’s of Acute Hyperammonemia
Encephalopathy, seizures, ataxia, visual loss, hallucinations, mania, Vomiting and loss of appetite
In neonates: temperature instability, hyperventilation
what are the symptoms of chronic Hyperammonemia
Developmental delay Nausea, failure to thrive, protein avoidance Migraines Anxiety, depression, disinhibition Hepatomegaly, elevated liver enzyme
The urea cycle is the sole source of endogenous production of _______
arginine, ornithine, and citrulline
Which urea cycle enzymes overlap with the nitric oxide production pathway
ASS and ASL
what are triggers for a hyperammonemic episode
Illness, fever, vomiting, fasting, surgery
Postpartum period, menarche
Intense exercise
Dietary protein load
Medications - valproate, peg asparaginase
UTI
what is the most common urea cycle disorder
Ornithine transcarbamylase deficiency
what causes Ornithine transcarbamylase deficiency
X-linked, deletions and point mutations in OTC
Gene is expressed only in the liver
There are many symptomatic females
what are the Diagnostic metabolites of Ornithine transcarbamylase deficiency
Diagnostic metabolite is orotic acid; also with low citrulline, high glutamine
true or false
Ornithine transcarbamylase deficiency is a newborn screening
False
Ornithine transcarbamylase deficiency is often lethal in _______
the neonatal period for boys
what is the Management of OTC
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
_______ is the most severe of the urea cycle disorders.
Carbamoylphosphate synthetase I deficiency (CPS1 deficiency)
Affected individuals can also develop trichorrhexis nodosa, a node-like appearance of fragile hair that usually responds to arginine supplementation. this person has _______
Argininosuccinic aciduria (ASL deficiency)
