Disease
Cystinuria
Type A
Mutation
Cationic AA & Cystine
transporter
Mutation in heavy chain
Mutation in light chain
Type B
Type AB
Mutations in both chains
Hartnup
Disorder
Neutral AA transporter
(poor tryptophan uptake)
Kidney Form
Transporter does not
associate with collectrin—
not expressed on apical
surface of kidneys –AAs
not reabsorbed
Small Intestine
Form
ACE 2 necessary for
expression of transporter
in SI
Symptoms
-excrete large amounts of cystine in urine
-flat hexagonal crystals in urine
- + in cyanin-nitroprusside test (purple)
- cystine not reabsorbed in kidney (kidney stones)
-excrete large amounts of cystine, lysine, arginine,
and ornithine
-homoz-excrete large amounts of cystine, lysine, arginine,
and ornithine
-heteroz-slightly affected
-occasionally get cystine kidney stones
-compound heterozygote--full blown cystinuria
Similar to pellagra
-rash w/ photosensitivity
-psychosis
-cerebellar ataxia
-elevated AAs in urine
-Faulty tryptophan uptake
**precursor to nicotinamide (rash/photosensitivity)
**precursor to serotonin (psychosis)
-many patients are asymptomatic
**protein deficient diet can make it worse
Treatment
-adequate hydration-keeps urine
dilute
-keep urine slightly alkaline-↑cystine solubility
**oral Kcitrate, Na citrate, & Na
Bicarb
-reduction of cysteine &
methinonin—reduce animal protein
-drugs—penicilliamine and αmercaptopropionylglycine
**reacts w/ cysteine and make a
more soluble disulfide bond
-dietary niacin
*replaces deficient nicotinamide
Lysinurgic
Protein
Intolerance
Maple Syrup
Urine Disease
LAT 1
Branched Chain Amino
Acid DHD
E1-ketoacid decarboxylase
(type 1A or 1B) (thiamine
dependent)
E2-dihydrolipoyl
acyltransferase (type II)
-defective uptake of lysine, arginine, and ornithine in small
intestines and kidneys
-↑ urinary excretion of lysine, arginine, and ornithine
-↓ levels of plasma lysine and arginine
- derangement in urea cycle in liver (due to low ornithine)
*elevation of plasma ammonia
*neurological problems
*aversion to protein rich foods—vomiting/diarrhea
-growth retardation, enlargement of spleen, muscular
hypotonia, and osteoporosis
-renal and pulmonary complications
**infants symptom free as long as breast fed**
-enchephalopathy 4-7 days after birth
-branched chain AAs elevated in blood
**valine, isoleucine, and leucine**
-alloleucine present (diagnostic)
-lethargy/no interest in feeding
-weight loss
-progressive neurological deterioration
-alternate hypo- and hypertonia
-burnt sugar or maple odor in urine
-some degree of mental impairment
E3-dihydrolipoaminde
dehydrogenase (t 3)
Isovaleric
Acidemia
Isovaleryl CoA
Dehydrogenase (IVA)
(coenzyme: Flavin)
catalyzes isovaleryl Coa
β-methylcotonoyl CoA
-accumulation of isovaleric acid and 3-hydroxyvaleric acid
in plasma and urine
First type
-symptoms seen w/in 2 wks of birth
-vomiting, dehydration, listlessness, acidosis
Second Type
-chronic and intermittent
-restrict protein intake (make sure
px still receive essential AAs)
-promote N excretion (Na benzoate
and phenylbuturate)
-oral citrulline (precursor to
ornithine--up take through other
neutral AA transporter)
-must remove toxic metabolites
-continuous blood exchange
transfusion or dialysis
-thiamine may improve tolerance in
some patients (type 1A and 1B)
-pxs generally healthy between
episodes of metabolic imbalance
-degree of impairment depends on
amount of time leucine levels were
high
-dietary protein restriction—limit
intake of leucine, but supplement
with mixture of AAs
-oral glycine and IV carnitine during
metabolic crisis: reacts w/ IA to
form IA-carnitine and IA-glycine
***non toxic***
-early diagnosis and treatment
Isovaleric
Acidemia
(continued)
Methylmalonic
Acidemia
(MMA) &
Propionic
Acidemia (PA)
Methylmalonyl CoA
mutase
-catalyzes methylmalonyl
CoA Succinyl CoA
-adenosylcobalmin is
cofactor
Propionyl-CoA carboxylase
-catalyzes propionyl CoA
methylmalonyl CoA
-Biotin as cofactor
Nonketonic
glycine cleavage system
hyperglycinemia
-vomiting, lethargy (progressing to coma)
-elevated anion gap
-metabolic acidosis
-ketonuria
-unwashed body odor
-exacerbated in first 12mos by stress, infection, and high
protein meals
-gastrointestinal signs; poor suckling, vomiting, weight loss,
abdominal distention
-neurological manifestations; abnormal posture &
movement, generalized hypotonia, lethargy, seizures
-metabolic acidosis
-increased anion gap (due to increased organic acids)
-ketonuria
-anemia
-hyperuricemia (↑ uric acid)
-leukopenia
-hyperammoniemia
-brain: accumulation of metabolites inhibit TCA and
mitochondrial respiration; necrosis; spongioisis, cyst
formation
-kidney: in MMA—chronic renal failure
-heart: in PA—cardiomyopathy (rapidly fatal); appears to
be related to poor uptake of carnitine
-↑ in glycine
-glycine receptors in inhibitory neurons (skeletal musc)
-NMDA receptor has glycine binding site (↑ Ca influx)
-decreased supply of N5N10CH2THF
-derangement of 1 C metabolism interferes w/
remethylation of methionine
-lethargy & vomiting
-convulsions & loss of primitive reflexes
-myoclonic seizures
-apnea
minimizes effects on development
of brain
**better long term diagnosis than
any other organic aciduria**
-outlook is very bad
-limit dietary protein
-avoid long fasts
-kidney/liver transplant
-reduce activity of NMDA glutamate
receptor (diazepam: competes with
glycine for allosteric site; ketamine
and dextropmethorphan: NMDA
receptor antagonists
-promote excretion of glycine w/ Na
benzoate (forms Hippurate)
-control seizures (phenobarbital)
Urea Cycle Disorder
Hyperammonemia type 1
Hyperammonemia Type 2
Reaction affected
NH3+HCO3- carbamoyl PO4
Ornithinecitrulline
Enzyme deficient
Carbamoyl Phosphate Synthetase I
(CPI)
Treatment
Arginine (stimulates CPI)
N-Acetylglutamate synthase
Carbamoy glutamate (activates
CPI)
↑carb/↓protein diet
Ornithine transcarbamylase
Benzoic acid or phenylacetic acid
to treat ammonia intoxication
Arginine (enhances citrulline
excretion)
Arginosuccinate
synthetase deficiency
Citrulline+aspartate
arginosuccinate
Arginosuccinate synthetase
Arginosuccinate lyase
deficiency
Arginase Deficiency
Arginosuccinate arginine +
fumarate
Arginine orthinine + urea
Arginosuccinate lyase
arginine
Arginase
Diet of essential AAs (no arginine)
Low protein diet to reduce plasma
ammonium
Treatments for all of the urea cycle diseases include:
-low protein/high carb diet: reduces ammonia production
-levulose: bacteria in gut metabolize levulose to acidic compoundmore ammonium—excreted in feces
-antibiotics: suppress ammonia producing bacteria in gut
-Sodium Benzoate/sodium phenylbutyrate: form covalent products with glycine (hippurate) and glutamine(phenylacetyl glutamate)—
promote nitrogen excretion if feces