Dzs of AA transport affect both
Intestinal and renal epithelial transport
Hartnup dz
Impaired transport of neutral AAs and deficiency of some essential AAs (like tryptophan) may occur
Cystinnuria
Dibasic AAs (cysteine, ornithine, arginine, lysine) are affected but no nutritional deficit despite fact that lysine is essential
Hartnup defect
Intestinal and renal tubular reabsorption defect of neutral AAs
Tryptophan deficiency leads to nicotinic acid and serotonine deficiency
Hartnup clinical finding, diagnosis, and therapy
Photodermatitis, cerebellar ataxia…sometimes asymptomatic
High levels of neutral AAs in urine and low levels in plasma
Nicotinamide 40-300 mg/day…sun protection
Trp deficiency of hartnup leads to
Dementia, dermatitis, and diarrhea
Similar to nicotinic acid def dz and pellegra
Trp is precurosr to nicotinic acid
Indicanuria mechanism
Converted to indole in gut, reabsorbed into blood, excreted in urine causing bluish urine or blue diaper syndrome
Indole is oxidized to form indigo blue
Cystinuria
Forms cystine stones
Most common AA metabolic dz
Cystine characteristics
Product of 2 cysteines
Not soluble and forms crystal at high concentrations
People with cystinuria lack
Transporter in proximal tubule of kidney that absorbs cystine from urine stream and puts it back in blood…cystine levels are much higher in urine of these people and leads to crystals
Cystinuria subunits
SLC7A9 and SLC3A1…mutation in either one can lead to cystinuria
Tx of cystinuria
Water
Penicillamine which reduces cystine to cysteines which are more soluble
Extracorporeal shock wave lithotripsy (basically an X-ray) can be used to break up stones
PKU presentation, clincal findings, defect, and genetics
Mental retardation and fair skin
Phenylalanine hydroxylase (liver and kidney)
Increased amounts of ketoacids such as phenylpyruvic acid
Auto rec
Classical PKU
Mutation in phenylalanine hydroxylase
Rarer form of PKU
Defect in dihydripterin reductase whih makes a cofactor (tetrahydrobiopterin) needed by phenylalanine hydroxylase
Dihydropterin reductase rxn
Takes dihydropterin to tetrahydrobiopterin so that phenylalanine hydroxylase can convert phenylalanine to tyrosine
Phenylpyruvic acid effect
Hurts brain development
Why do PKU patients have lighter skin
Phe never converted to Tyr so decreased melanin, proteins, dopamine
How is PKU assayed?
Mass spec to look for Phe levels in blood
PKU tx
Reduce Phe in diet…avoid aspartame
Trysinemia types 1 and 2
Defects in enzymes that break down tyrosine
2 - tyrosine aminotransferase that converts tyrosine to 4HPP
1 - FAA hydrolase that converts FAA to fumarate and acetoacetate
Tyrosinemia type 1 defect and clinical findings
Enzyme defect is fumarylacetoacetate hydroxylase
Acute infantile form - severe liver failure, vomiting, bleeds, spesis, hypoglycemia, renal tubulopathy (Fanconi Syndrome)
Chronic form - Hepatomegaly, cirrhosis, grwoth retardation, rickets, hematoma, tubulopathy, neuropathy and ab pain (due to porphyrines)
Tyr type 1 other names
Hepato-renal tyrosinemia
Tyrosinosis
Hereditary infantile tyrosinemia
Tyr type 1 inheritance…metabolic effect…where is enzyme expressed?
Auto rec
Buildup of fumaryl acetoacetate and succinyl acetone…decrease in fumarate and acetoacetate
Enzyme expressed more in liver and prox renal tubular epithelial cells
Tyr type 1 tx
Nitisinone (NTBC) - blocks second step in tyrosine degradation pathway (4-OH phenylpyruvate dioxygenase) and prevents accumulation of FAA and conversion to succinylacetone…prescribe ASAP
Tyrosine and Phe restricted diet
Liver trasnplant
Tyr type 2 defect, findings, diagnosis, therapy
Cytosolic tyrosine aminotransferase
Painful corneal lesios (lacrimation, photophobia, scars), mild mental retardation
High Tyr and Phe levels
Tyrosine and Phe restricted diet
MSUD symptoms and infant signs
Poor appetite, irrtability, maple smelling urine, mental retardation, seizures, death if untreated
Lose sucking reflex and become limp with episdoes of rigidity
What AA increased in MSUD
Valine, Ile, and Leu (branched chain AAs)
Enzyme defect of MSUD
Branched chain ketoacid dehydrogenase…4 different subunits
People with MSUD have defective
BCKD protein complex that normally breaks down leucine, valine, Ile
MSUD tx
Restrict diet (only reduce) Some can also take thiamine (cofactor of branched chain ketoacid dehydrogenase)
Homocystinuria/Beta-synthase deficiency mutation
Crystathione beta synthase is defective and cannot take homocysteine to crystathionine
CBS gene
Beta-synthase def mech
Accumulation of homocysteine which is excreted in urine…can interact with cysteines of proteins…can cause lens dislocation
Normal cysteine synthesis
Comes from methionine and utilizes crystathionine beta-synthase
Homocystinuria symptoms
Lens dislocation Osteoporosis Vascular events Death Mental retardation
Homocystinuria tx
Try pyridoxine (vitamin B6 cofactor of CBS) in all...increases CBS activity Methionine restricted and cysteine supplemented