Biochem High Yield Disorders Flashcards
1
Q
What is the inheritance pattern of pyruvate dehydrogenase complex deficiency?
A
X-linked
2
Q
What does pyruvate dehydrogenase complex deficiency cause?
A
Cannot convert to pyruvate to AcetylCoA. Causes a buildup of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT).
3
Q
What are the sx of pyruvate dehydrogenase deficiency?
A
Neurologic defects, lactic acidosis, incr serum
alanine starting in infancy.
4
Q
What is the treatment for pyruvate dehydrogenase deficiency?
A
Incr intake of ketogenic nutrients - high fat content, or high lysine/leucine.
5
Q
Why is rotenone poisonous?
A
Inhibits Complex I of OxPhos. Decr proton gradient
6
Q
Why is antimycin A poisonous?
A
Inhibits Complex III of OxPhos. Decr proton gradient
7
Q
Why is cyanide/CO poisonous?
A
Inhibits Complex IV of OxPhos. Decr proton gradient
8
Q
What is oligomycin poisonous?
A
Directly inhibits mito ATP synthase, incr proton gradient, no ATP produced bc electron transport stopped.
9
Q
Why are uncoupling agents poisonous?
A
Incr permeability of membrane, causes drop in proton gradient and incr in O2 consumption. ATP synthesis stops but et continues. Produces heat.
10
Q
What are three uncoupling agents?
A
2,4-Dinitrophenol, aspirin, thermogenin in brown fat.
11
Q
Deficiency + inheritance pattern in G6PD deficiency?
A
X linked. Glucose-6-phosphate dehydrogenase. Responsible for regeneration of NADPH.
12
Q
What is the secret advantage to G6PD?
A
Increased malarial resistance
13
Q
What is the product of G6PD?
A
NADPH and 6-phosphogluconate –> ribulose-5-P.
14
Q
What are the fates of ribulose 5-P?
A
Ribose-5-P (—> PRPP, nucleotide synthesis)
Glyceraldehyde-3-Phosphate (back to glycolysis)–>TGs
Fructose-6-P –> glycolysis
15
Q
Enzymes in free radical defense via G6PD?
A
Glutathione perioxidase, glutathione reductase, G6PD.
16
Q
Deficiency + inheritance pattern in essential fructosuria?
A
autosomal recessive defect in fructokinase.
17
Q
Symptoms of essential fructosuria? Where does the fructose go?
A
Benign, asymptomatic. Fructose can be phosphorylated by hexokinase, or can leave the cell.
Fructose appears in blood and urine.
18
Q
Deficiency + inheritance pattern in fructose intolerance?
A
autosomal recessive defect in aldolase B. Fructose-1-phosphate accumulates.
19
Q
What happens in the cell as a result of fructose intolerance?
A
Fructose-1-phosphate accumulates, causing decrease in available phosphate, which results in inhibition of glycogenolysis.
20
Q
What are the sx of fructose intolerance and when do patients present?
A
Pts present after consumption of fruit, juice, or honey.
Hypoglycemia, jaundice, cirrhosis, vomiting.
21
Q
What will lab findings of fructose intolerance be?
A
Urine dip negative - tests glucose only. Can test for reducing sugar.
22
Q
Treatment of fructose intolerance?
A
No intake of fructose and sucrose (glucose + fructose).
23
Q
Deficiency + inheritance pattern in galactokinase deficiency?
A
Autosomal recessive deficiency of galactokinase, which phosphorylates Galactose.
24
Q
What may accumulate if galactose is present in diet?
A
Galactitol (aldose reductase).
25
What are the sx of galactokinase deficiency?
Infantile cataracts. May present as failure to track objects of develop a social smile. Otherwise relatively mild.
26
What are lab findings of galactokinase deficiency?
Galactose appears in blood and urine.
27
Deficiency + inheritance pattern in classic galactosemia?
Autosomal recessive absence of galactose-1-phosphate-uridyltransferase. Conversion of galactose-1-P to glucose-1-P via UDP-Gal/Glu
28
What are symptoms of classic galactosemia?
Soon after birth, failure to thrive, jaundice, hepatomegaly, infantile cataracts, intellectual disability.
E-coli sepsis in neonates!
29
What is the treatment of classic galactosemia?
Exclude galactose and lactose (galactose + glucose) from diet.
30
What is the deficient enzyme in lactase deficiency?
Lactase
31
What are the types of lactase deficiency?
1. Primary (age-dependent decline due to absence of lactase-persistent allele; seen in asian/african/native americans).
2. Secondary: loss of brush border due to gastroenteritis, autoimmune dz, etc.
3. Congenital lactase deficiency: rare.
32
What are the sx of lactase deficiency?
Bloating, cramps, flatulence, osmotic diarrhea.
33
What are the lab findings of lactase deficiency?
Stool w/ low pH. Breath has high hydrogen content w/ lactose tolerance test. Intestinal bx shows normal mucosa in hereditary types.
34
Treatment of lactase deficiency?
No dairy, or add lactase pills to diet.
35
What does aldose reductase do?
Converts glucose to sorbitol (and galactose to galactitol).
36
How is sorbitol handled by tissues?
Converted to fructose by sorbitol dehydrogenase
37
Which tissues don't have sorbitol dehydrogenase?
schwann cells, retina, kidney. Lens mostly. Diabetes causes havoc 2/2 sorbitol accumulation bc of chronic hyperglycemia.
38
Purpose of urea cycle?
Eliminate nitrogen generated by breakdown of amino acids.
39
Order of Urea cycle?
Ordinarily, Careless Crappers Are Also Frivolous About Urination.
Ornithine, Carbamoyl Phosphate, Citrulline, Aspartate, Arginosuccinate, Fumarate, Arginine.
40
What can cause hyperammonemia?
Liver Disease
| Hereditary defects in urea cycle
41
What does hyperammonemia deplete and lead to?
Leads to depletion of alpha-ketoglutarate due to excess NH4+, leading to inhibition of TCA.
42
What is alpha-ketoglutarate used in?
1) TCA
2) Picks up ammonia from aspartate to become glutamate, asparate becomes oxaloacetate --> Malate. SHUTTLE! AST is enzyme.
43
Sx of hyperammonemia?
tremor (asterixis), slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
44
Treatment of hyperammonemia?
1) limit protein in diet
2) lactulose acidifies the GI tract and traps NH4+ for excretion
3) Rifaximin decreases colonic ammoniagenic bacteria
4) Benzoate/phenylbutyrate bing amino acid and lead to excretion, can decrease ammonia levels.
45
What cause of hyperammonemia has an identical presentation to deficiency of carbamoyl phosphate synthetase I?
N-acetylglutamate is a required cofactor for CAP synthetase I, which brings ammonia into the urea cycle. Absence --> hyperammonemia.
46
What is the presentation of N-acetylglutamate deficiency?
In infants as poorly regulated respiration and body temperature, poor feeding, developmental delay, intellectual disability.
47
What is the most common urea cycle disorder and its inheritance pattern?
Ornithine transcarbamylase deficiency, X-linked recessive.
48
What does OTC do?
Ornithine + CAP --> citruline via OTC. Cannot eliminate ammonia, CAP excess converted to orotic acid (pyrimidine synthesis pathway).
49
What is the presentation of OTC deficiency?
Usually presents in first few days of life, may present later. sx of hyperammonemia.
50
Lab findings w/ OTC deficiency?
Increased orotic acid in blood and urine, decreased BUN,. Diff from orotic aciduria bc no megaloblastic anemia (caused by insufficient pyrimidine).
51
What is the deficiency and inheritance pattern in PKU?
Phenylalanine hydroxylase. Autosomal recessive.
52
What is the deficiency in malignant PKU?
Tetrahydrobiopterin cofactor.
53
What are the lab findings with PKU?
Incr phenylalanine, and excess phenylketones in urine. Phenylacetate, phenylactate, and phenylpyruvate.
54
What is the presentation of PKU?
Sx: Intellectual disability, growth retardation, seizures, fair skin, eczema, musty body odor. Newborn screening 2-3 days after birth (normal at birth bc of maternal enzyme).
55
Treatment of PKU?
decr phenylalanine, incr tyrosine, BH4 supplementation. No aspartame!
56
What are the findings of maternal PKU with improper dietary therapy?
Infant with microcephaly, intellectual disability, growth retardation, congenital heart defects.
57
What is the inheritance pattern and defect in maple syrup urine disease?
Autosomal recessive defect in degradation of BRANCHED amino acids by alpha-ketoacid-dehydrogenase.
58
What cofactors does alpha-ketoacid-dehydrogenase require?
Same as pyruvate dehydrogenase. B1, B2, B3, B5, lipoic acid. Most common issue -- deficient thiamine. B1.
59
Which are the branched amino acids?
I Love Vermont (isoleucine, Leucine, Valine).
60
What is the presentation of maple syrup urine disease?
urine smells like burnt sugar/maple syrup. Severe CNS defects, intellectual disability, death.
61
Treatment of MSUD?
Restriction of isoleucine, Leucine, Valine, thiamine supplementation.
62
What is propionic acidemia?
Congenital deficiency of propionyl CoA carboxylase, converts propionyl CoA to methylmalonyl CoA (joins TCA as succinyl CoA).
63
What is propionyl CoA derived from?
Val, Ile, Met, Thr, and odd numbered fatties.
64
What is Histidinemia?
AR disorder. Deficiency of histidinase. Will see three titrable protons. Speech defects, retardation, emotional disturbances.
65
Which aminos have three titrable protons?
Arg Hist Lys
Asp Acid, Glut Acid
Cysteine, Tyrosine
66
What is the deficiency and inheritance pattern in alkaptonuria?
Homogentisate oxidase in degradative pathway of tyrosine to fumarate.
67
What are the findings of alkaptonuria?
Usually benign. Pigment-forming homogentisic acid accumulates in tissue cause: dark connective tissue, brown pigmented sclerae, urine turns BLACK on prolonged exposure to air. May have debilitating arthralgias. (toxic to cartilage).
68
What defects can lead to homocystinuria?
1) Cystathionine synthase deficiency
2) Dec affiinity of cystathione synthase for B6 (TX: Inc B6 and cysteine in diet)
3) Homocysteine methyltransferase/methionone synthase deficiency (tx: inc methionone in diet).
69
What is the treatment for homocystinuria caused by cystathione synthase deficiency?
Dec met, inc cystine, b12, and folate in diet.
70
What is the treatment for homocystinuria caused by decr affiinity of cystathione synthase for B6?
Incr B6 in diet A LOT, Incr cysteine
71
What is the treatment for homocystinuria caused by Homocysteine methyltransferase/methionone synthase deficiency?
Increase methionine in diet.
72
What are the sx of homocystinuria?
Excess homocysteine in urine, intellectual disability, osteoporosis, marfanoid habitus, kyphosis, lens subluxation (DOWN AND IN), thrombosis, and atherosclerosis (stroke/MI).
73
What is the defect and inheritance pattern of cystinuria?
Auto recess hereditary defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of (COLA) cysteine, ornithine, lysine, and arginine.
Pretty common - 1/7000.
74
What is the presentation of cystinuria? What test confirms?
Recurrent precipitation of hexagonal cystine (2 cysteines connected by disulfide bond). Urinary cyanide-nitroprusside test is diagnostic.
75
What is the treatment of cystinuria?
Alkalinize urine (potassium citrate, acetazolamide) and chelating agents (penicillamine). Hydrate.
76
What are the four glycogen storage diseases? Inhreitance pattern?
```
Very Poor Carb Metabolism: (all AR). All result in accumulation of glycogen within cells.
Von Gierke (I)
Pompe (II)
Cori (III)
McArdle (IV)
```
77
What is the deficient enzyme in Von Gierke?
Glucose-6-phosphatase. (ER enzyme, Gets G6P back to glucose).
78
What is the presentation of Von Gierke?
Severe fasting hypoglycemia.
| Elevated liver glycogen, elevated serum lactate, elevated triglyc, elevated uric acid, and hepatomegaly.
79
What is the treatment of Von Gierke?
Frequent oral glucose/cornstarch, avoid fructose and galactose.
80
What is the deficient enzyme in Pompe (II)?
Lysosomal-a,1,4-glucosidase (acid maltase).
81
What is the presentation of Pompe (II)?
Pompe trashes the Pump. Cardiomegaly, HCM, exercise intolerance, and systemic findings leading to early death. (heart, liver and muscle are affected).
82
What is the deficient enzyme in Cori disease?
Debranching enzyme (alpha,1,6,glucosidase).
83
What is the presentation of Cori disease?
Milder form of Type I with normal blood lactate levels. Gluconeogensis intact.
84
What is the deficient enzyme in McArdle disease?
Skeletal muscle glycogen phosphorylase (myophorphorylase)
85
What is the presentation of McArdle disease?
cArdle hurts Muscle. Elevated glycogen in muscle, cannot break down --> painful muscle cramps, myoglobinuria with strenuous exercise, and arrythmia from electrolyte abnormalities.
86
What is the treatment for McArdle disease?
Vitamin B6 (cofactor).
87
What is the deficient enzyme in Fabry disease?
α-galactosidase A
88
What is the accumulated substance in Fabry disease?
ceramide trihexoside
89
What is the presentation of Fabry disease?
Peripheral neuropathy of hands/feet,
angiokeratomas, cardiovascular/renal
disease.
90
What is the most common lysosomal storage disease?
Gaucher's disease
91
What is the deficient enzyme in Gaucher's?
Glucocerebrosidase
| β-glucosidase
92
What is the accumulated substance in Gaucher's?
Glucocerebroside
93
What is the presentation of Gaucher's?
Hepatosplenomegaly, pancytopenia,
osteoporosis, aseptic necrosis of
femur, bone crises.
94
What histological finding is associated with Gaucher's?
Gaucher cells: (lipid-laden macrophages resembling
| crumpled tissue paper).
95
What is the treatment for Gaucher's?
Recombinant glucocerebridase.
96
What is the defect in Niemann Pick disease?
Sphingomyelinase
97
What is the accumulated substance in Niemann Pick?
Sphingomyelin
98
What is the presentation of Niemann Pick?
Cherry red spot on macula, Progressive neurodegeneration,
| hepatosplenomegaly.
99
What is the histological finding associated with Niemann Pick?
lipid laden macrophages --> foam cells.
100
What is the defect in Tay-Sachs?
Hexosaminidase A
101
What is the accumulated substance in Tay-Sachs?
GM2 ganglioside.
102
What is the presentation of Tay-Sachs?
Progressive neurodegeneration,
developmental delay, “cherry-red”
spot on macula. NO hepatosplenomegaly (vs Nieman Pick)
103
What is the histological finding associated with Tay-Sachs?
Lysosomes w/ onion skin.
104
What is the defect in Krabbe disease?
Galactocerebrosidase
105
What is the accumulated substance in Krabbe?
Galactocerebroside, psychosine
106
What is the presentation of Krabbe disease?
Peripheral neuropathy, developmental
| delay, optic atrophy, globoid cells.
107
What is the defect in metachromic leukodystrophy?
Arylsulfatase A
108
What is the accumulated substance in metachromic leukodystrophy?
cerebroside sulfate
109
What is the presentation of metachromic leukodystrophy?
Central and peripheral demyelination
| with ataxia, dementia.
110
What is the defect in Hurler syndrome?
α-l-iduronidase
111
What is the accumulated substrate in Hurler syndrome?
Heparan sulfate,
| dermatan sulfate
112
What is hte presentation of Hurler syndrome?
Developmental delay, gargoylism,
airway obstruction, corneal clouding,
hepatosplenomegaly.
113
What is the deficiency of Hunter syndrome?
Iduronate sulfatase
114
What is the accumulated substrate in Hunter syndrome?
Heparan sulfate,
| dermatan sulfate
115
How does the presentation of Hunters vary from Hurler's?
Hunters is milder. No corneal clouding (hunters can see), more aggression.
116
Which lysosomal storage disease are X-linked R?
Hunters and Fabry.
117
What are the disorders to know in fatty acid oxidation?
Medium chain acyl-CoA dehydrogenase deficiency.
| Systemic primary carnitine deficiency
118
What accumulates in medium chain acyl-CoA dehydrogenase deficiency?
8-10carbon fatty acid acyl carnitines in blood.
119
What is the presentation of medium chain acyl-CoA dehydrogenase deficiency?
May present in infancy or early childhood w/ vomiting, lethargy, seizures, coma, and liver dysfunction. Hypoketotic Hypoglycemia*. Look for inappropriately low ketones after fasting. Minor illness can lead to sudden death.
120
What is the treatment of medium chain acyl-CoA dehydrogenase deficiency?
Avoid fasting.
121
Systemic primary carnitine deficiency is?
Inerheted defect in tx of LCFAs into mito. Toxic accumulation. Causes weakness, hypotonia, hypoketotic hypoglycemia.
122
What is the defect in Type I familial dyslipidemia?
Hyperchylomicronemia. AR defect in Lipoprotein Lipase or apoC-II decreases endothelial uptake of chylos.
123
What is increased in the blood in Type I familial dyslipidemia?
Chylomicrons, TG, Cholesterol
124
What is the presentation of Type I familial dyslipidemia?
Causes pancreatitis, hepatosplenomegaly,
and eruptive/pruritic xanthomas (no risk for
atherosclerosis). Creamy layer in supernatant.
125
What is the presentation of Type IIa familial dyslipidemia?
Hypercholesterolemia. Autosomal dominant defect or absence of LDL receptors.
126
What is increased in the blood in Type IIa familial dyslipidemia?
LDL, cholesterol
Heterozygotes (1:500): have cholesterol ~300.
Homozygotes (very rare): cholesterol ~700.
127
What is the presentation of Type IIa familial dyslipidemia?
Accelerated atherosclerosis (may have MI before age 20), Achilles tendon xanthomas, corneal arcus.
128
What is the defect in Type IV familial dyslipidemia?
Hypertriglyceridemia. AD defect - hepatic overproduction of VLDL.
129
What is increased in the blood in Type IV familial dyslipidemia?
VLDL, TG.
| TGemia >1000 can cause acute pancreatitis.
130
What does 1g of protein or carbohydrate = in kcal?
4 kcal.
131
What does 1 g fat = in kcal?
9 kcal.
132
What does 1 g alcohol = in kcal?
7 kcal.
133
In the fed state, what processes are occurring?
Glycolysis and aerobic respiration.
134
What drives processes in the fed state?
Insulin --> stimulates store of lipids, proteins, and glycogen. (protein-phophatase 1 dephosphorylates glycogen synth, which activates it, and dephosphorylates F1,6biphosphatase, which deactivates it.
135
In between meals, what processes are occurring?
Hepatic glycogenolysis (major).
Hepatic gluconeogenesis
Adipose release of FFA (minor).
136
What drives processes in the fasting state?
Glucagon and epi stimulate use of fuel reserves.
137
How long until glycogen stores are depleted in starvation?
1 day.
138
How are blood glucose levels maintained in starvation 1-3 days?
- Hepatic glycogenolysis, Adipose release of FFA.
- Muscle and Liver shift fuel use from glucose to FFA to preserve glucose for brains.
- Hepatic gluconeogensis from peripheral tissue lactate and alanine, and from adipose tissue glycerol and proprionyl-CoA (from odd chains).
139
After 3 days of starvation, what becomes the main source of energy?
Adipose stores (ketone bodies become the main source of energy for the brain).
After adipose depleted, vital protein degradation accelerates, leading to organ failure and death.
Amt of excess stores determines survival.
140
What is the defect in abetalipoproteinemia?
Auto Recess loss of function mutation in MTP gene - codes for chaperone protein needed in proper folding of apoB (48 and 100) proteins. Pts will have lipid accumulation in enterocytes - foamy/clear cytoplasm.
