Metabolism diseases

Backup of substrate: pyruvate, alanine, lactate

get lactic acidosis

Congenital or acquired (B1 def)

Sxs: neurologic defects
Tx: Increase ketogenic intake: Lysine and leucine; high fat

NADPH oxidase def

WBCs can utilize H2O2 from organisms and convert to ROIs
-more susceptible to catalase-positive species (S. aureus, Aspergillus) bc they neutralize H2O2, so WBCs can't fight infxn)

Decrease NADPH in RBCs --> can't detoxify free radicals & peroxides with glutathione

-Oxidizing agents --> Hemolytic anemia

Agents:
fava beans
sulfonamides
TB drugs
primaquine
Infection

X-linked; most common human enzyme def; blacks (malarial resistance)

Heinz bodies: oxidized Hb in RBCs

Bite cells: from phagocytic removal of Heinz bodies by macs

Fructokinase defect
-benign, asx (fructose does not enter cells)
-see fructose in blood and urine

Aldolase B def
Can't convert F1P --> DHAP & Glyceraldehyde

-F1P accumulates --> decrease in phosphate availability --> inhib glycogenolysis and GNG

sxs: hypoglycemia, jaundice, cirrhosis, vomiting

Tx: avoid fructose and sucrose (Glu + Fru)

Galactokinase def

Aldose reductase makes galactitol from galactose --> cataracts (failure to track objects or develop social smile)

Galactose-1-P Uridyltransferase def

Can't convert Galactose-1-P ---> Glucose-1-P

Accum substances, like galactitol

sxs: FTT, jaundice, hepatomegaly, cataracts, MR

Tx: no galactose or lactose (galac + glu)

excess NH4+, which depletes alpha-ketoglutarate --> inhibits TCA cycle

Ammonia intox: tremor, slurring, somnolence, vomiting, cerebral edema, blurry vision

Tx:
limit protein
Benzoate or phenylbutyrate: (bind a.a. and lead to excretion)
lactulose (in liver failure; broken down by bacteria --> acidic pH traps NH4+ ion in gut; excretion)

MC urea cycle disorder
X-linked (others are auto recessive)

-can't eliminate ammonia
-excess carbamoyl phosphate --> orotic acid

findings: orotic acid in blood and urine, decreased BUN, hyperammonemia (vs. orotic aciduria)

tx: benzoate, phenylbutyrate

def in Phe hydroxylase or THB (tetrahydrobiopterin)

-tyrosine becomes essential
-phenylketones in urine

sxs:
MR, growth retardation, seizures, fair skin (less melanin), eczema, mousy, musty body odor (bc aromatic a.a. --> PkU!)

Tx: no Phe intake (aspartame) and increase Tyrosine

-screened in newborns (after 2-3 days after maternal enzyme wanes)
-Phenylketones: phenylacetate, phenyllactate, phenylpyruvate

Infant has:
microcephaly, MR, GR, congenital heart defects

ochronosis
Homogentisic acid oxidase def (homogenously BLACK)

can't degrade Tyr to Fumarate

-auto recessive, benign

findings: dark connective tissue, sclera, urine; arthralgias (toxic to cartilage)

1. Tyrosinase def (can't make melanin from tyrosine)
2. Defective tyrosine transporters

*can be due to lack of neural crest migration

-variable inheritance bc locus heterogeneity (x-linked; auto recessive)

1. Cystathionine synthase def
-tx: no Met, increase Cys and B12/folate

2. Decreased affinity of cystathionine synthase for B6
tx: give more B6

3. Homocysteine methyltransferase def

*cysteine becomes essential
findings: "tight marfans"
MR, osteoporosis, tall, kyphosis, downward lens subluxation, atherosclerosis

defect of renal tubular AA transporter for
COLA:
cysteine
ornithine
lysine
arginine

in PCT of kidneys

-excess cystine (2 cysteines with disulfide bond) in urine --> kidney stones (hexagonal)

Tx: acetazolamide to alkalinize urine (decrease bicarb reabsorption)

def in alpha-ketoacid DH
*can't degrade branched AA:
I Love Vermont:
Ile, Leu, Val

-increased alpha-ketoacids in blood, esp Leu

sxs: severe CNS defects, MR, death

Tx: decrease protein intake; high dose TPP (thiamine) may help bc alpha-ketoacid DH complex requires 5 co-factors:
TPP
Lipoic acid
CoA
FAD
NAD

Hartnup Tryptup

defective neutral AA transporter in renal and intestinal cells
-causes tryptophan excretion in urine
-can't make niacin --> pellagra

Glucagon (liver) and EPI (liver and muscle) increase cAMP --> PKA --> phosphorylates (activates) glycogen phosphorylase kinase --> activates glycogen phosphorylase --> GLYCOGENOLYSIS

*Ca2+/calmodulin in muscle activates phosphorylase kinase so glycogenolysis is coordinated with muscle activity

Insulin --> receptor tyrosine kinase dimerizes --> activates protein phosphatase, which inactivates (dephosphorylates) glycogen phosphorylase kinase and glycogen phosphorylase --> inhibits glycogenolysis

Type I
Glucose-6-phosphatase def

-severe fasting hypoglycemia, increased glycogen in liver, blood lactate, HSM, enlarged kidneys, HLD, uric acid

Type II
lysosomal alpha-1,4-glucosidase def (acid maltase)

Cardiomegaly, respiratory failure --> early death

heart, liver, muscle

Type III
alpha 1,6 glucosidase def (debranching enzyme)


Milder form of Von Gierke's; normal blood lactate

gluconeogenesis is intact

Type V
Glycogen phosphorylase def

increased glycogen in muscle, but can't break it down --> painful muscle cramps, myoglobinuria with exercise

fAbry's
Alpha-galactosidase A def
Accum: ceramide trihexoside

X-linked

peripheral neuropathy of hands/feet, angiokeratomas, heart/kidney disease (need dialysis)

GaUcher's (MC)
"Gotcha tissue paper bones!"
beta-glUcocerebrosidase
accum: glucocerebroside

HSM, aseptic necrosis of femur, bone crises

Gaucher's cells: crumpled tissue paper macs

Pick your FOAMY boogers with your SPHINGer
Sphingomyelinase def
Accum: sphingomyelin

progressive neurodegeneration,
**HSM
cherry-red spot on macula, foam cells

Sack of Onions

Hexosaminidase A
Accum: GM2 ganglioside

progressive neurodegeneration
developmental delay
cherry-red spot on macula
onion skin lysosomes

**no HSM (vs. Niemann-Pick)

"Globoid Krab who can't see through his GLOBES"

Galactocerebrosidase def
Accum: Galactocerebroside

peripheral neuropathy, developmental delay,
optic atrophy
globoid cells
*affects myelin

"meta sulfa"

ArylSULFATASE A def
Accum: Cerebroside SULFATE

central and peripheral demyelination with ataxia, dementia

hurLer's

alpha-L-iduronidase def
accum: Heparan sulfate, dermatan sulfate

developmental delay, gargoylism, airway obstruction, corneal clouding, HSM

iduronate sulfatase def
Accum: heparan sulfate
dermatan sulfate

**X-Linked
Mild Hurler's + aggressive behavior, no corneal clouding