Aminoacidopathies, Organic Acidemias, and Defects of Urea Cycle Flashcards
Name the aminoacidopathies.
PKU (classic, cofactor deficiency, maternal) Non-PKU Hyperphenylalanemia Maple Syrup Urine Disease Homocystenuria Hyperhomocysteinemia Tyrosinemia
Name the organic acidemias discussed in class.
Methylmalonic Acidemia Propionic Acidemia Cobalamine Deficiencies (Cblc disease) Isovaleric Acidemia 3MCC
Name the urea cycle defects.
OTC Deficiency (X-linked) Argininosuccinate Lyase deficiency Arginemia
What is classic PKU?
phenylalanine dehydrogenase deficiency
when untreated, presents with severe, irreversible mental retardation, hypopigmentation (Phe –> Tyr –> melanin), seizures, behavioral problems
with treatment most have normal intellect but some develop ADHD, mood disorders, or executive function defects related to plasma phenylalanine levels
What is Cofactor deficiency PKU?
deficiency of tetrahydrobiopterin that presents with the same symptoms as classic PKU
How are PKUs (general) treated?
restriction of substrate (Phe free formula, some natural protein, non-protein foods) provide product (all formulas supplemented with tyrosin) provide cofactors (tetrahydrobiopterin) substitute enzyme (clinical trials with alternate enzyme) block transport (large neutral amino acids to compete at blood brain barrier) goal is to maintain Phe level between 2-6
What is Maternal PKU?
when a mother has untreated PKU –> elevated Phe levels which are teratogenic (causes microcephally, ID, congenital heart disease, low birth weight)
severity of effects correlated with [Phe]
necessary to keep [Phe] between 2 and 5 prior to conception and throughout pregnancy because organogenesis is early in gestation (if not well managed women may not detect the pregnancy in time for treating to matter –> babies normally highly affected)
What gene is associated with PKU?
PAH gene
>500 mutations
panethnic
What is Non-PKU Hyperphenylalanemia?
less severe form of PKU that does not require treatment because some PAH has residual function normally resulting in Phe <20mg/dl
What is the difference between Hyperphenylalaninemia and Variant PKU?
<6mg/dl Phe due to residual PAH activity = hyperphenylalanemia (no known adverse effects; do not treat)
620mg/dl Phe due to residual PAH activity = variant PKU (treat with phenylalanine restricted diet)
What is Maple Syrup Urine Disease?
on NBS but low incidence
deficiency of BCKAD (branching amino acid cannot be properly digested –> high levels of leucine and branched fatty acids)
presents with altered mental state, poor feeding, and lethargy progressing to coma
in older children, ataxia and slurred speech, waxing/waning mental status changes
severe neurological damage or death due to cerebral edema
How is Maple Syrup Urine Disease treated?
initial and acute decompensations treated with intensive care (monitoring of neurological status, fluids status, and sometimes hemodialysis)
long term maintenance with dietary restrictions of BCAA (BCAA deficient formulas and protein restricted diet), provide cofactors (thiamine trial), liver transplant is curative
Explain the genetics of MSUD.
mutation in the E1alpha/E1beta subunit of the multimeric enzyme (mutations in other subunits cause different conditions)
AR
panethnic
incidence increased in menonites (E1alpha) and AJ (E1beta) populations
What is homocystenuria?
found on NBS
deficiency of CBS (required for connective tissue proper development) leading to accumulation of homocystein and methionine
presents as marfanoid habitus (tall, long arm span), dislocated optic lenses, osteoporosis, ID (distinct from Marfans), thromboembolic events
good prognosis if well managed (if homocystein level >100 there is high liklihood of thrombolytic event)
How is homocystenuria treated?
restrict substrate (dietary restriction of methionine) provide cofactors (vitamin B12 and B6) provide alternative routes of elimination (betaine/cystadade)
What is Tyrosinemia Type I?
Hepatorenal/classical
fumaryl acetoacetate hydrolase deficiency
characterized by liver failure, hepatocellular carcinoma, renal Fanconi’s, porphyria-like attacks
due to fumarylacetoacitate and succinylacetone accumulations
What is Tyrosinemia Type 2?
Occulocutaneous
tyrosine aminotransferase deficiency
less severe than Type 1 (no accumulation of metabolites because disruption is higher in pathway)
results in lesions on corneas, palms, and soles of feet as well as hyperkeratosis
tyrosine accumulations result in crystals in eyes and under skin (painful)
How are tyrosinemias treated?
low Phe and tyrosine in diet
some natural protein
protein free foods
Type 1 use NTBC (inhibitor of HPD which blocks higher in the pathway to prevent the accumulation of toxic metabolites –> artificial Type 2)
How do organic acidemias (in general) typically present?
emesis failure to thrive developmental delay metabolic acidosis (normal blood pH= 7.4 so anything other than that is acidotic and needs attention) hyperammonemia
What is methylmalonic acidemia?
deficiency of methylmalonyl CoA mutase (or adenosylcobalamin cofactor deficiency or defects in cobalamin synthesis and transport)
“benign” form with lower level of elevation or transient form persisting up to a year after birth (detected on NBS)
some patients are vitamin B12 responsive (because it is a cofactor of the reaction)- which can be determined genetically because they are distinct
What complications are associated with methylmalonic acidemia?
renal disease (MMA attacks kidneys)
gout and hyperuricemia (can present)
pancreatitis (common)
metabolic “stroke” with subsequent involuntary movements (may occur)
optic atrophy or retinitis may be late complications
prolonged QT waves
can mimic mitochondrial disease in long term untreated patients
What is propionic acidemia?
propionyl CoA carboxylase deficiency (or due to deficiency of biotin cofactor)
What complications are associated with propionic acidemia?
no biotin response (pts with isolated PA) recurrent pancreatitis (common cause of death) prolonged QT (with or without cardiomyopathy due to secondary respiratory chain defects) optic atrophy (due to secondary respiratory chain defects) and retinitis metabolic stroke (may occur; acute or progressive extrapyramidal syndrome)
How do you acutely manage MMA/PA?
NPO- cut protein dose
reversal of catabolism (main goal)
correction (bicarb replacement)
detoxification (levocarnitine and hemodialysis for the refractory acidosis)
What are the long term treatments available for MMA?
restrict substrate (low protein, restruct substrate of amino acid, antibiotics to lower gut bacteria’s production of propionic acid)
provide cofactors (hydroxy B12 if applicable)
alternate routes of elimination (carnitine)
other (bicitra for acid-base stabilization)
What are the long term treatments available for PA?
restrict substrate (low protein, restrict substrate of amino acids, antibiotics to decrease gut bacteria’s production of propionic acid)
provide cofactors (biotin)
alternative routes of elimination (carnitine)
other (biactra for acid-base stabilization)
What are the features of Cbl C disease?
methylmalonic acidemia homocystinuria mental retardation seizures nystagmus cardiac abnormalities abnormal dentition
What is isovaleric acidemia?
AR deficiency of isovaleryl CoA dehydrogenase resulting in an inability to fully metabolize leucine accumulation of isovaleric acid, isovalerylglycine, isovalerylcarnitine, 3-hydroxyisovaleric good prognosis (normal neuro outcomes) most notable symptom is foot odor acute form (presents in neonatal period with emesis, lethargy, metabolic acidosis, hyperammonemia, ketonuria, odor, and pancytopenia) or chronic intermittent form (1st decompensation follows stressor) or asymptomatic form
What options are available for treatment of isovaleric acidemia?
restrict substrate (low protein and leucine)
alternate routes of elimination (carnitine and glycine)
other (bicitra for acid-base stabilization)
What is 3MCC?
3-methylcrotonyl CoA carboxylase deficiency
leucine catabolic pathway
most commonly seen acidemia
most are asymptomatic but those who do have symptoms present with emesis, hypoglycemia, and ketosis
How do you treat 3-MCC?
protein restriction
biotin
carnitine
What is the general presentation of Urea Cycle Disorders?
young age of onset (typically >24 hours of age)
lethargy, poor feeding, emesis, seizures, bleeding, hyperventilation, coma
death with no treatment
later onset defects (caused by less severe mutations/ better enzyme activity) present with ID, recurrent emesis, failure to thrive, recurrent coma, and history of protein aversion
What alternative diagnosis can be considered when a newborn presents with symptoms of a urea cycle disorder?
sepsis (most common cause of these symptoms)
use ammonia levels to distinguish
How are Urea Cycle Disorders treated (generally)?
restrict substrate (essential aa formulas) provide product (arginine and citruline supplementation) replace enzyme (liver transplant- especially in patients with difficulty in compliance) provide alternative routes of elimination (ammonia scavengers like sodium phenylbutyrate and sodium phenylacetate plus sodium benzoate) treat secondary effects (increased intracranial pressure, DIC, etc.)
Describe the inheritance of OTC deficiency.
x-linked
female carriers tend to have mild symptoms (due to X inactivation) but can have severe symptoms during stressors (eg. pregnancy, surgery)
What are symptoms or arginosuccinate lyase deficiency?
typical coarse hair
cirrhotic changes
What is the characteristic feature of Argininemia?
lower limb spasticity (most patients)
