Amino Acid Metabolism Disorders Flashcards
Cysinuria
decreased tubular reabsorpiton of Cystine (along with ornithing, arginine, lysine)
inherited deficiency of cystine transporter
cystine excreted in urine and percipitates in renal tubules (cystines stones in renal tract)
hexagonal cystine crystals
- typically asymptomatic
- very painful if breaks off
(do not ocnfuse with birefringent crystals of sodum urate in synovial fluid of gout patients)
Hartnup disease
inherited defect in neutral amino acids (i.e. tryptophan)
decreased dietary absorption of tryptophan
increased excretion of tryptophan
- NAD+ deficiency (pellagra)
- low protein diet (lacking niacin supplementation)
4 D’s of Pellagra
- Diarrhea
- Dermatitis
- Dementia
- Death
Phenylketonuria (PKU I)
Autosomal recessive
Deficiency of either:
- Phenylalanine hydroxylase (PAH)
- Tetrahydrobiopterin (BH4)
increased Phe levels (alternate pathway for degredation- phenylpyruvic acid)
-excreted in urine (mousey odor)
tyrosine becomes essential
detected during 1st week of life (neonatal screening)
- Guthrie Test
- Mass Spec.
- tested twice due to false negative from maternal clearence
Untreated
- delayed neurological milestones
- low IQ
- seizures if blood Phe is high
decreased pigmentation of skin & hair
(tyrosine > melanin inhibitied by elevated Phe)
low Phe diet (responds well)
low protein diet (avoid aspartame-artificial sweetener)
dietary restricition must be started immedietly
Sapropterin (syntehtic BH4)
- mild/moderate PKU-1
- patients have mutant enzyme (low affinity for co-factor)
- first non dietary treatment of PKU
Maternal PKU syndrome
women with PKU must maintain low Phe levels before conception and during pregancy
high maternal Phe leads to fetal defects
- microcephaly
- lack of mental dev.
- congential heart defects
elevated Phe has teratogenic properties
PKU II (malignant PKU)
deficiency of either
- dihydrobiopterin synthesis
- dihydrobiopterin reductase (BH2/BH4)
elevated PHE and its metabolites
- severe CNS symptoms
- decreased nucleotide synthesis (serotonin, dopamine, catecholamines)
worse prognonsis than PKU-1
dietary Phe restriiton
dietary biopterin and precursors of NT (difficult because of blood brain barrier)
Alkaptonuria
deficiency- homogentistic acid oxidase deficiency
decreased levels of maleylacetoacetate, fumarate, acetoacetate
benign inborn error of phenylalanine-tyrosine catabolism
homogentistic acid deposits (accumulate in cartilage and CT)
- ochronosis (discoloration of cartilage and CT)
i. e. blue/black auricle of ear
homogentistic acid excreted in urine (brown discoloration on standing)
dietary restriciton of phe and tyrosine may reduce deposits
Tyrosinemia Type I
deficient- fumaryl acetoacetate hydrolase
inborn error of Phe-Tyr catabolism
severe usually fatal
-liver and renal failure
cabbage like odor of urine (elevated metabolites)
dietary restricion of Phe and Tyr (two essential AA’s)
- proves difficult
- Tyr needed for NT synthesis
Maple Syrup Urine Disease (MSUD)
deficiency- branched chain a-keto acid dehydrogenase (TPP coenzyme; i.e. vitamin deficiency)
increase in branched chain amino acids
- neurological manifestations
- ketosis
- maple syrup odor of urine
- decreased Acyl CoA
symptoms begin in neonates 4-7 days
- poor feeding, vomitting, lethargy
- alternating muscular hypotonia and hypertonia
- seizures
- encephalopathy
dietary restriciton of BCAA
(leucine, isoleucine, valine)
difficult to treat (lifelong restriciton) all three BCAA’s are essential
dietary supplementation of TPP (B1) if enzyme has low coenzyme affinity
Methylmalonic Aciduria
deficiency- Methylmalonyl CoA mutase deficiency
elevated levels of methylmalonic acid in circulation
- metabolic acidosis
- seizures, encephalopathy
some impobe with vitamine B12 supplementaiton
(caused by methylmalonyl CoA mutase enzyme to have reduced affinity for B12)
Homocystinuria
deficienty- cystathione B-synthase (PLP cofactor)
(transulfuration pathway)
high plasma and urine levels of homocysteine
- binds to CT and disrupts structure
- interferes w collagen
- dislocation of lens
- skeletal abnormalities
- premature arterial disease
some respond to B6 supplementation if cofactor affinity issue
