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)
