17 Inborn errors of metabolism Flashcards
Why are genes for metabolic disorders usually mild?
proteins usually excess. Usually one gene needed
What are the biochemical characteristics of classical galactosemia?
Most common carb defect, galactose-1-phosphate uridyl trans affected, no galactose to glucose xvert, shunts to galactitol and galactonate
What are the symptoms of galactosemia?
Hepatic insufficiency, cataracts, development delay, mental retardation
What are prevention and Tx for galactosemia?
Blood enzyme screening and dietary restriction
What are the biochemical characteristics of hereditary fructose intolerance?
Defect in fru-1,6 bisphosphate leads to fructose intolerance and gas
What are the characteristics of Von Gierke Disease?
Glycogen storage disorder, defect glu6phos, glycogen is not metabolized/glu released from liver, hepatomegaly/hypoglycemia during starvation
What are the characteristics of phenylketonuria?
Defect in phenylalanine hydroxylase, no phenylalanine metabolism, accumulations disrupts brain =/= myelination, protein synth = retardation
What are the Tx and pregnancy factors for PKU?
Dietary limitations and high levels of phenylalanine can affect fetus
What are the characteristics of maple syrup urine disease?
Cannot metabolize BCAA, accumulation leads to neurodegeneration and death in one month
What is a special prevalence point in Maple syrup urine disease?
Usually rare but 1/7 for menonites
What are the characteristics of MCAD deficiency?
defect in MCAD, fatty acid defect, hypoglycemia after fasting, accumulates fatty acid intermediates = low ketone/glycogen = cerebral edema/death
What is Tx and prevention for MCAD deficiency?
Always have a supply of glucose, avoid fasting at all costs
What population is MCAD likely?
Northwest europeans
What is the most likely mutation in MCAD deficiency?
90% is single missense from A to G resulting in lysine to glutamate
What are the characteristics of congenital adrenal hyperplasia?
blocked corticosteroid synth in which excess androgenic precursors lead to virilization of females in-utero and salt-wasting(dehydration, lethargy)
What are the characteristics of Zellweger syndrome?
Peroxisome biogenesis disorder, neonatal hypotonia with distinctive face and death in infancy
What is the biochemical result of zellweger syndrome?
Does not allow the digestion of Very Long Chain Fatty acids and protein importing into the matrix
What is the general molecular overview of lysosomal storage disorders?
Accumulation of nondegraded mucopolysaccharaides, sphingolipids, glycoproteins and glycolipids, most are enzyme defects that can inhibit transport or targeting
What are the characteristics of mucopolysaccharidoses?
GAG degrade defect, sufate drugs inhibited, ten enzyme defects = six disorders, all autosomal recessive, but hunters = x linked recessive
What are the similarities and differences of MPS?
chronic/multisystem = Hearing/vision/joint and cardiovascular problems may result. Mental retardation only in hurler, hunter and sanfilippo.
How can hurler and scheie be differentiated?
Only clinically
What are the three sphingolipidoses and their enzyme defects?
Gaucher - beta glucosidase, tay-sachs - beta hexosaminidase A, Niemann-Pick - sphingomyelinase
What is a population consideration for gaucher?
Rare except in ashkenazi jews
What are the characteristics of I-cell disease?
Phosphotransferase defect prevents mannose-6-p binding to proteins with lysosome targets = accumulated inclusions
What are the four enzymes that can be affected in the urea cycle?
Carbamoyl phosphate synthetase (CPS). Ornithine transcarbamoylase (OTC). Arginosuccinate synthetase (ASA). Argininosuccinate (AS).
What is the most common urea cycle defect and what type is it?
OTC deficiency an X-linked recessive gene
What are the genetic and phenotypic characteristics of OTC deficiency?
10 exon can be mutated, females = symptomatic carriers, incr orotate/nitrogen (hyperammonemia)
How is energy production phenotypes complex?
OXPHOS system as well as being able to use different substrates = many proteins and different requirements in different tissues = high complexity
How can transport system phenotypes be simple?
Many transport systems but tissues may need similar substrates = same transporter in different tissues
What are the characteristics of Cystinuria?
Common, 2 types, inability to transport cystine and dibasic amino acids causes accumulation = amino acid loss in urine, kidney stones
What is cystine and what other amino acids are lost in cystinuria?
Cystine is 2 cysteines with a disulfide bond making it least soluble of all aa. Dibasic amino acids also include lysine, arginine and ornithine
How can cystinuria kidney stones be Tx?
High pH and penicillamine will solubilize cystine
What are the two genes mutated in cystinuria?
Type I - SLC3A1. Type II and III - SLC7A9
What is another cystine associated genetic disorder?
Cystinosis in which transporter for lysosomes with cystine is defective. Leads to Fanconi syndrome
What are the characteristics of wilson disease and what type of disorder is it?
Defect copper excretion.incr Cu in liver/ brain. dysarthria, arthropathy, cardiomyopathy, kidney/ liver damage. Kayser-Fleischer eye ring. metal ion xport disorder
What are the genetic components of wilsons disease?
ATP7B gene. Expressed highly in liver/kidney. Many mutations known, 40% northern Europeans have only single missense
What are the characteristics of Hereditary Hemochromatosis?
Excessive intestinal iron absorption. Accumulates in liver, heart, pancreas joints. Dx = liver biopsy w/ hemosiderin stain.
What is the epidemiology of Hemochromatosis?
northern europeans 1/8 carrier. 1/200-400 affected. incomplete penetrance. symptoms 40yo male 40 female
What are the genetic factors associated with hemochromatosis?
Mutation of C282Y of HFE gene. cysteine to tyrosine at beta 2 microglobulin domain. high prevalance = selective advantage?
How is hemochromatosis Tx?
Reduce iron = phlebotomy (bleeding)
