3 Inheretied Metabolic Disorders Flashcards
metabolism vs metabolic pathway
metabolism: the sum of all chemical reactions in the body
metabolic pathway: several stages involved in conversion of one metabolite to another
Garrod’s hypothesis
coined inborn metabolic disorders->
genetic defect is related to enzyme deficiency
alkaptinuria - not properly metabolize phenylalanine, deficiency in homogenesic acid - pile up in joints - when urine exposed to air it turns black due to oxidization of homogenetic acid oxidase
most common inheritance pattern for IEM
autosomal recessive
some X-linked (mothers are carriers)
mitochondiral diseases detected
categories of IEM
Biomolecule: Protein Carb Lipid Nucelic acid
Organelle:
lysosome
mitochondria
peroxisomes
most common clinical features of IEM
poor feeding vomiting apnea irritability jaundice abnormal tone seizure developmental delay, mental retardation urine odor, dysmorphism, hiccoughs
every child with unxeplained symptoms shoyld be suspected of having a metabolic disorder
disorders of amino acid metabolism
phenylketonuria (phenylalanine)
homocystenuria ( methionine)
maple syrup urine disease (lueicine, isolueube, valine)
tyrosinemia (tyrosine)
phenylketonuria
errors in AA metabolism
mutaton in phenylalainine hydroxylase (PAH) gene
Loss of PAH activity -> increase phenylalanine in blood and brain -> brain damage
clinical features: developmental delay, low IQ, autism, hypopigmentation must odor urine
carbohydrate metabolism disorders
inability to metabolie specific sugars, abberrant glycogen/glucose storage
manifest with: hypoglycemia, hepatosplenomeagly, lactic acidosis/ketosis
EX: GSD, galactosemia, fructose intolerance
glycogen storage diseases GAD
abnormal inhereited glycogen metabolism in liver, muscle and brain
lead to buildup of glycogen in tissues categorized numerically (0-X)
enzymes deficent in von Gierke and Pompe disease
GSD I - von Gierke - glucose 6 phosphatase
GSD II - Pompe - lysosomal a-glucosidase
pathway of glucose production in liver
glycogen
glucose 1 p
glucose 6 p -> glu 6 phophatase in ER of liver-> cleave Glu 6 to create glucose
glucose
pathway of glycogen production in liver
glucose
GLUT 2
Glucose 6P
Glucose 1P
Glycogen
GSD I von Gierke
cause: defective glucose 6 phosphatase
inherited pathway: autosomal recessive
clinical presentation: present at 3 or 4 months
hypoglycemia: tremor, irritability, hyperventilation, cerebral edema, poor growth, short stature, recurrent infections, fever diarrhea, perioral and anal ulcers
1 hyperlipidemia -> increase NADPH -> promote FA synthesis
2 hyperuricemia -> increase pentose phosphatase pathway -> increase ribose 5 phos -> increase purine and prymidine synthesis -> catabolism -> increase uric acid
- osteroporsis lactic acidosis effects bone mineralization
- ketosis- gluconeogenesis not working -> FA -> acetyl coA-> ketone bodies
3 different mutations that can occur with von Gierke disease
- gene coding for liver glucose 6 phosphatase -> cannot cleave glucose 6 in ER
- gene coding for ER subsrtate
- product transport proteins of glucose 6 phosphatase system -> increase NADPH -> increase ribose 5 phosph -> increse purine/prymidine -> increase FA syntheiss
mechanism that causes lysosomal storage disorder
defective lysosomal acid hydrolysis of endogenous macromolecules -> accumulation of glycoproteins, glycolipids, glycosaminoglycans within lysosomes in various tissues
slow progressive disease
EX: Tay Sachs, Niemann pick, Gauchers
Tay Sachs
lysosomal storage disease
autosomal recessive
prevelant in askenaski jews and french canadians (1 :3,000 normally 1: 300,000)
Cause: decrease Hex-A enzyme activity -> increase GM2-ganglioside -> mental and motor retaration
clincial features: loss of hearing, seizures, “sartile response”, “cherry red macula”
no cure-> 2 yrs -> vegetative state -> death by 5 years
purpose of urea cycle
dispose of nitorogen waste and biosynethsis of argenine
function of OTC
essential in converting ammonia -> citrulline
OTC deficiency
ACUTE AND SEVERE!!!
cause: error in second reaction of ammonia detoxification -> OTC deficient cannot convert ammonia _> citrulline
clinical features:
hyperammonia - sucling reflex, lethargic, irritable first signs
affected males -> early severe neonatal encephalopathy
alkalosis - increased pH
NORMAL plasma glucose, lactate, urine organic acids
purpose of FA oxidization
process of mobilizing stored fat to meet increased energy needs
interruption in any portion of this process will result in significant reductions in energy production
EX: MCAD, glutaric aciduria, canavan disease
MCAD
Cause: inefficiency to break down MCAD
mutation in ACAMD gene-> lead to deficiency in MCAD enzyme -> medium-chain FAs are not broken down properly -> fats not converted to energy
fats can deposit in brain and liver
age of onset: young with periods >12 hours of fasting qith intermittent infectious diseases
Clincial features: hypoketotic hypoglycemia
reye like illness - acute vomitting, lethary, seizures, coma, death
diagnosis and management of IEM
- suspicion
- evaluation
- treatment
treatment options for IEM
dietary restriction supplement deficent product stimulate alternative pathway supplment vitamin co factor organ transplantation enzyme replacement therapy gene therapy
Gluconeogenesis in prolonged fasting:
- During exertion (not enough O2) pyruvate -> lactate -> enters Cori cycle in liver -> glucose
- fasting continues: falling insulin levels permit catabolism of muscle protein and triglycerides from adipose tissue
free FA from triglycerides-> ketone and acetyl coA-> acetyl coA generate energy through Krebs cycle
Ketones used by extrahepatic tissues as a source of energy -> excessive ketones = ketoacidosis
- Breakdown of protein results in AAs and ammonia -> ammonia is converted -> urea through the urea cycle and excreted by kidneys
AAs used to synthesize new glucose in liver cells by gluconeogenesis
