Biochemistry + metabolic syndromes Flashcards
6 symptoms that prompt consideration of a metabolic disorder
Catastrophic neonatal presentation
Biochemical disturbances
Liver disease or dysfunction
Neurologic features (delay, ataxia, stroke)
Myopathy or cardiomyopathy (heart, skeletal)
Signs of a storage disease
cause of rapid breathing (tachypnea) in neonate
This info is inaccurate, skip. (Bc acidosis = compensatory alkalosis.)
could be due to trying to lower acidity of blood by exhaling carbon dioxide due to LACTIC ACIDOSIS
could also be due to high ammonia levels.
HCO3 - bicarbonate level - becomes low: when?
due to metabolic acidosis.
in organic acidemia - too much acid - body attempt to buffer it by producing more buffer to neutralize acid - HCO3 - as result, HCO3 level drops = metabolic acidosis.
To compensate for acid, body breathes more to release CO2, which makes blood more basic. (respiratory alkalosis) –> LOW CO2. Low pH.
Organic acidemias = LOW pH [acidic]
Urea cycle disorders = HIGH pH
pH tells you what happened first. If pH is low, then it started with metabolic acidosis. If pH high, more likely due to ammonia. Ammonia makes person breathe more rapidly. This decreases CO2. Makes blood more alkaline. pH is thus increased.
Urea cycle disorders
and
Organic Acidemias
… can present with:
CHRONIC SYMPTOMS aversion to protein Poor feeding, anorexia Vomiting \+/- Hypotonia \+/- Develop delays
CRISIS SYMPTOMS:
vomiting/seizures
ALKALOSIS if organic acidemia (compensatory)
ACIDOSIS if Urea/Ammonia
…if more distal defect in cycle, can present with liver enlargement/dysfunction, or dev delays, without crises
metabolic acidosis
hyperammonemia (high ammonia)
hypoglycemia
episodes of biochemical decompensation (”metabolic crises”)
organic acid is what’s left after de-amination of
amino acids (removal of N group –> to urea cycle)
developmental delay, hypotonia, ocassional seizures if sick - which test to order?
plasma/urine amino acids to test for urea cycle disorder, esp during “crises”
Organic Acidemia - Biotinidase deficiency
hypotonia, seizures
eczema, alopecia
hearing loss, retinal disease
which conditions require testing of urine organic acids?
organic acidemias,
fatty acid oxidation defects,
mitochondrial disorders
during periods of decompensation (crises) - otherwise may be uninformative.
renal fanconi syndrome
severe metabolic liver disease,
kidney disease
kidneys not working properly
can’t retain bicarb, glucose, amino acids, phosphate
pH low/acidic
(low phosphate causes rickets)
fatty acid oxidation defect - blood findings?
low glucose (incidental) LOW KETONES
ketones –> should be high if glucose is low, to compensat,e but low ketones could mean a defect in fatty acid oxidation.
tyrosinemia associated with symptoms of ____, another genetic condition
porphyria - usually young/adult women
—> neurologic crises
can be seen in Tyrosinemia Type 1 due to succinyl acetae
acute fatty liver could mean……
METABOLIC CRISIS
how: kid doesn't want to eat because sick fat goes to liver to be broken down but fat can't be broken down due to defect thus, liver becomes fatty
due to: “Reye syndrome-like disease” fatty acid oxidation defects mitochondrial disease
homocysteinuria
SKELETAL Unusually tall Long limbs/ arachnodactyly Pectus excavatum/ carinatum Osteoporosis Scoliosis Pes cavus
NEURO
delay/MR
psychiatric
seizures
EYE
myopia, lens dislocation
BLOOD
tendency to clot
Homocysteinuria VS Marfan - 3 differences
Homocyst. vs Marfan
stiff joints / loose joints
clotter / aortic dissection
dev delay/MR / no mental issues
Menke
Metabolic disease of copper
hypopigmentation
kinky hair
hypotonia, delays
death
Pompe
Glycogen build-up; recessive
acid alpha-glucosidase (also known as acid maltase) -GAA gene –> glycogen builds up in lysosomes
hypotonia
HCM or cardiomegaly
hepatomegaly
Myozyme
1 in 40,000
Lesch-Nyan
build-up of uric acid
Developmental delays, learning disorder Insensitivity to pain; self-injurious behavior Renal stones (uric acid) Hyperuricemia
XLR; 1 in 380,000
Zellweger
Prenatal onset Dysmorphic Hypotonia Seizures Liver disease Death within months
peroxisome
autosomal recessive
many genes can cause it
heart and muscle mainly use __ fat, so __ fatty oxidation disorders affect the heart and muscle, primarily.
heart and muscle use LONG CHAIN FATS…
so cardiomyopathy and myopathy mostly present in longer chain fatty acid disorders because the long chain fats aren’t cleaved and barely any ketones are generated.
low ketone production found in which disorders?
Long-chain fatty acid oxidation
Medium-chain fatty acid oxidation
Carnitine transport (of fatty acids into mitochondria)
ketosis associated with which disorders?
short chain fatty acid oxidation (cleave lots of ketones from a long-chain fatty acid, to medium-chain, but issue at short chain).
low free carnitine is indicative of -
Total carnitine = free carnitine + esterified carnitine.
Free carnitine = 70-90% of total carnitine.
To evaluate carnitine transport defects, fatty acid oxidation defects, organic acidemias, mitochondrial disease.
If healthy/asymptomatic, low free (and high esterified) carnitine levels may indicate an unusual compound binding to free carnitine.
diagnostic tests for fatty acid oxidation disorders, organic acidemias
organic acids
free carnitine/esterified carnitine. if + then:
ACYLCARNITINE
ACYLGLYCINE – stuff that binds to stuff
certain metabolites bind to carnitine/glycine; can be diagnostic. check blood, esp when sick.
Ragged Red Fibers
MELAS
NERP (?)
if lethargy, test:
ammonia
(urea cycle defects certain amino acid disorders organic acidemias fatty acid oxidation defects mitochondrial disorders)
Recurrent acute decompensation - what to order?
Blood gases
Electrolytes, bicarbonate
Glucose
Ammonia
Liver functions
Lactate
Urinalysis
----------------------------------------
if suspicion is high:
Blood amino acids
Blood acylcarnitines
Urine organic acids
Urine acylglycinesNTBC is tx for which metabolic condition?
Tyrosinemia type 1 – prevents conversion of a substance metabolically upstream of tyrosine
meconium ileus
pretty much diagnostic of CF
Class 1, 2, 3 mutations - severity?
Class 4, 5 mutatoins - severity?
DF508 - which class?
df508 = class 2
class 1,2,3 = severe class 4,5 = less severe
class 1 = null
congenital bilateral absence of vas deferens / male infertility
screen for uncommon CF mutations
males usually have normal sweat test and lung function, but maybe asthma. large proportion of people with this abnormality have CF mutations.
what modifies CF severity?
Intron 8 polypyrimidine tract (T) dictates splicing efficiency of CFTR
5T – least efficient
7T
9T – most efficient
in df508, skew toward 9T (100%) vs wt (11%)
CF - which chronic/complex disease is increased in individuals with CF?
diabetes, 50% risk after age 20
lung function in CF primarily correlates with
nutritional status. CF is primarily a nutritional disease
If person has severe CF mutation + 5T / wt allele, are they affected? what about 9T?
9T + severe = unaffected (“efficient gene splicing)
5T + severe = CAVD (vas def) in males (“inefficient splicing”)
Effect of Intron 8 on Mild CFTR mutations (such as R117H)
Genotype mild mutation/severe mutation
Mild mutation with 9T –> CBAVD
Mild mutation with 5T –> Pancreatic Sufficient CF
CF incidence
- caucasians
- african americans
- Hispanics
- caucasians / 1 in 3,000 // carrier 1/30
- african americans / 1 in 17,000 // carrier 1/65
- Hispanics / 1 in 10,000 // carrier 1/50 (!)
asians lower.
