Metabolic Disorders Flashcards
(156 cards)
1
Q
First Metabolic Disorder
A
Archibald Garrod (1902) Alkaptonuia
2
Q
Normal Pathway
A
A –> B –> C –> D
3
Q
Disturbed Pathway
A
A –> B –> C –> E
C is accumulation of substrate
E is formation of unusual metabolites.
D is deficiency of product.
4
Q
6 categories of metabolic disorders
A
AA metabolism Organic Acid Metabolism Carb Metabolism Heme biosynthesis Nucleotide Metabolism (didn't talk about this) Organelle Disorders
5
Q
Genetic Heterogeneity
A
Diff Underlying Causes but Present the Same-Could be genetic or environmental
6
Q
Clinical Heterogeneity
A
Similar Cause but Diff Presentation
- Same gene could be different mutations
- Could have genetic modifiers
- Could be due to diff environment
7
Q
How are metabolic disorders usually diagnosed
A
Usually on most severe phenotypes
- Then, as start to get more familiar, get milder cases
- Some diseases also get asymptomatic testing.
8
Q
How do metabolic disorders arise
A
Start w/ DNA change
Could be point mutations - silent won’t have an effect, missense if change in conserved AA and typically nonsense mutation that leads to null protein
Or could be due to insertion/deletion.
9
Q
Bias of Ascertainment
A
People are more likely to be investigated for disease if have an abnormality so don’t see full spectrum
10
Q
What kind of disorder is PKU
A
AA disorder
11
Q
What enzyme is deficient in PKU and what pathway is affected?
A
Phenylalanine Hydroxylase
- Phe can’t be converted to Tyrosine
- Results in hyperphenylalaninemia -high phenylalanine in the blood
12
Q
PKU:
Substrate Accumulated?
Product Deficiency?
Unusual Metabolites Formed?
A
- Phe
- Tyr
- Phenylketones
13
Q
PKU inheritance
Incidence + Carrier?
A
Autosomal Recessive
1:15,000 - carrier is 1:60
14
Q
Outcome of PKU late Diagnosis
A
smell, decreased pigmentation (pale), mental retardation (IQ 35)
15
Q
To show symptoms of PKU, need Phe dietary intake (T/F)
A
True
16
Q
Why is there decreased pigmentation?
A
B/c Tyrosine is needed for melanin production
17
Q
Acute Phe Toxicity Reversible when Less than
A
1300
18
Q
Chronic Toxicity to Brain from PKU
A
results in dysmyelination and permanent damage
19
Q
Phenylalanine Hydroxylase Mutations
A
Many, over 1000
Many people with PKU are compound heterozygotes-means have 2 diff mutations
20
Q
How to measure phenylalanine hydroxylase enzyme activity
Review-
A
Can do a biopsy
If null = expect 0% activity
Typical PKU < 1%
Non-PKU hyperphenylalanimeia (HPA) > 5%
Can also look at expression studies
- Can be null allele
- Vmax allele (reduced activity )
- Km, kinetic allele(affinity for substrate or cofactor)
- Unstable allele= increased turnover
21
Q
Exceptions to Studying Enzyme Activity
A
Y204C-in vitro was normal but it was actually splicing mutation
V399V - silent prediction but also severe phenotype
-Creates new splice site which leads to a null phenotype
22
Q
Correlations b/w Genotype and Phenotype for PKU
A
- Overall correlation of genotype and biochemical phenotype
- Overall Correlation of biochemical phenotype and IQ
- On individual basis: can have similar plasma Phe but diff brain She-Could be due to other genes
23
Q
What other genes could contribute to differences in brain Phe even though same blood plasma
A
LAT1 - transporter protein - AA need transporter protein. High Phenylalanine could block others from going on and these could be precursors for NT
24
Q
Polymorphisms that Affect PKU severity
A
Large Neutral AA transporter NT biosynthesis Myeline Biosynthesis Monoamine Oxidase B And any regulation regions for any of these genes
25
Clinical Heterogeneity for PKU
Mild mutations do not completely destroy enzyme activity - leads to milder disease
Other genes can affect phenylalanine exposure
If delayed/sub-optimal treatment - need dietary Phe to develop brain damage
26
Genetic Heterogeneity for PKU
Other protein/enzyme deficiencies:
1. Enzyme deficiency in the same pathway
2. Part of same multimeric enzyme complex
3. A cofactor needed to activate eenzyme
27
Hyperphenylaniemia can be caused by
```
PAH Mutations (98%)
And BH4 Mutations (2%)
```
28
Malignant PKU
Due to BH4 (Tetrahydrobiopterin)
| -Deficiency in cofactor synthesis or recycling
29
How do biopterin defects arise
```
GTPCH def (1), PTPS def (2), SR def (3) or DHPR (4)
(involved in making BH4)
```
30
What else is affected by BH4 deficiency?
Tyrosine --> L-DOPA --> Dopamine
Tryptophan --> 5-OH-Tryptophan --> Serotonin
So basically important NT synthesis affected.
31
GSD1
Glycogen Storage Disorder -
| Deficient in GSD1 - which converts Glucose-6-P to Glucose
32
GSD1A Problems
Early Fasting Hypoglycemia (ketotic) - can cause seizures
Hepatomegaly - enlarged and then gets fatty - due to triglyceride accumulation
Gluconeogenesis Blocked:
- B/c GSD1 is shared enzyme
- Results in lactic acidosis + hyperuricemia
- Hypertriglycerides + pancreatitis
- Dont respond to glucagon - due to increased lactate
- Can also get platelet dysfunction - nosebleeds
- Renal disease (gout)
- Liver Cancer high risk and renal failure
33
A, B, D, E for GSD1A
```
A = Glycogen
B = Glc-6P accumulates
D = lactates, purines (uric acid) and FAs (triglycerides) - unusual products
E = glucose deficient
```
34
GSD1A Clinical Heterogeneity
Milder mutations that don't destroy enzyme activity
| Prolonged exposure of brain to hypoglycemia = results in brain damage
35
GSD1b
```
-Genetic Heterogeneity
Transporter (cytosol into ER)
-Liver big and hypoglycaemia
-Neutropenia - so get frequent infections
-Mucous Membranes get ulcers
```
36
GSDIII
Genetic Heterogeneity
- Debrancher Enzyme
- Aymptomatic Hepatomegaly
- Spleen enlargement (mild)
- Muscles affected
Sometimes presents like GSD1 -
Hypoglycemia, hyperlipidemia, failure to thrive
- BUT glucneogenesis intact
-Lactic acidosis less
-Less hyperuricemia
-Some moderate transaminase elevations
-Glucagon response - up to 4 hours after meal
37
GSD V1
- Genetic Heterogeneity
- Phosphorylase
- LIke GSD III
- Less common
- No myopathy
38
GSD 1X
Genetic Heterogeneity
- Phosphorylase B Kinase
- Several genes, X-linked is most often
- ALso similar to GSD III but more common than GSD V1
- Minimal/no response to glucagon, cirrhosis rare
- Rarely get myopathy (in non X-linked forms)
39
Classical Galactosemia
Caused by GALT deficiency
40
Galactosemia Characterization - when consume galactose
- Failure to Thrive (not growing well), vomiting
- Jaundice (hepatomegaly and progresses to liver synthetic function failure (clotting factor proteins become deficient leading to bleeding problems)
- Fonconi Syndrome-renal tubular dysfunction (leaking from the tubules)
- Septicemia
41
What is a major reason for clinical heterogeneity for Galactosemia
Exposure to galactose
42
What needs to happen for the galactosemia to be acute
exposure to galactose
43
What goes galactosemia progress to?
Liver failure (bile stasis, portal fibrosis, cirrhosis)
Cataracts
Developmental Delay
44
A, B, C, D, E in Galactosemia
```
A = Lactose
B = Galactose
C = Gal-1P Accumulation
D = glucose deficiency
E = galactitol + galactonate (form from galactose accumulation)
```
45
How do galactitol and galactonate form
Galactose gets reduced to galactitol (polyol pathway)
| -Gets oxidized to galactonate
46
What happens to galactitol, galactonate, and galactose-11 phosphate
Galactitol = excreted by kidney - it damages eyes and other organs
Galactonate = accumulates in tissues and so does G1P
47
Pathophysiology of Acute Toxicity Syndromes + LT complications
UNCERTAIN
48
Cataract formation - Galactosemia
Due to galactitol
-Irreversible
-Galactitol doesnt affect kidney or liver
49
Clinical Heterogeneity of GALT
Milder mutations that don't destroy enzyme activity - galactose effects only true when baby is small
Suboptimal treatment: need lactose/galactose exposure for acute disease
-If liver exposed to prolonged toxic metabolites can cause liver failure
50
Epimerase Deficiency
2 Types:
1. Benign - only in blood cells
2. Generalized Deficiency - Like GALT deficiency (genetic heterogeneity)
Epimerase converts b/w UDP-gal and UDP-glc
51
MCAD deficiency
- Fatty acid beta-oxidation disorder
| - Beta oxidation is blocked - but this process is needed when trying to maintain blood sugar when fasting
52
How are triglycerides broken down?
- Short and medium fatty acids enter mitochondria directly
- Long chain transported by carnitine
- Inside mitochondrial matrix - FA will undergo beta-oxidation - to form acetyl-CoA
- Acetyl-CoA form ketone bodies that are transported to tissues for energy
53
MCAD Role
Fatty acid chain shortened by 4 enzyme reactions - will be shortened by 2 carbons
- Shortened FA undergoes further beta-oxidation until reduced to acetyl-coA
- MCAD does the 4 enzyme reactions for medium length carbon chains b/c each of the 4 reactions are done by enzymes specific to carbon chain length.
54
A,B,C,D, E for MCAD Deficiency
```
A = fatty acids
B = acyl carnitines
C = Acyl CoA (accumulate this)
D = deficient in ketones so see hypoglycemia
E = dicarboxylic acids and acylglycines (formation of unusual metabolites)
```
55
MCAD Inheritance
Autosomal Recessive
- Incidence (1:10,000 to 20,000)
- One mutation which is most prevalent (especially in Caucasians)
- Carrier rate is 1 in 50
56
MCAD Clinical Presentation
Hypoglycemia (low blood sugar) + low ketones when fasting
Low blood sugar leads to low Brain Sugar Levels (confusion, coma, and death)
-leads to sleepiness, seizures, and deaths
Sudden Infant Death Syndrome - due to unexplained cardiac arrest
High mortality rates (20 to 25%) in first 3 years of life-if survive could have brain damage due to hypoglycemia
57
MCAD Clinical Heterogeneity
Mild mutations that don't completely destroy enzyme activity
-Environmental differences:
May not show all symptoms even with severe phenotype
-ex. if one child vomiting - would have more severe hypoglycemia compared to child who didnt
58
Genetic Heterogeneity for MCAD
Another enzyme deficiency that could be:
1. In same biochemical pathway (another beta-oxidation pathway)
2. Same multimeric enzyme complex
3. Needed to activate the enzyme
59
MADD
MCAD genetic Heterogeneity
- Multiple Acyl-CoA Dehydrogenase Deficiency or Glutaric Aciduria (GA Type 2)
- Cant deal w/ FADH2
- SO dehydrogenase enzymes are deficient in activity
- MCAD function is decreased - leads to hypoketotic hypoglycaemia
60
Causes of MADD
3 gene defects:
1. a-ETF
2. B-ETF
3. ETF-QO
And environmental causes
61
MADD Genetic Heterogeneity
Jamaican Vomiting Illness (Ackee)
| -Can poison electron chains if eat when not ripe
62
Tay-Sachs Disease
Stops degradation of GM2 ganglioside (component of cell membranes)
Undegraded Material accumulates in lysosome - causing cell and organ dysfunction
Results in progressive brain damage and then death = b/c accumulating in neurons
63
Tay-Sachs Type of Disease
One of more than 50 "Lysosomal Storage Disorder"
-Type of GM2 Gangliosidosis
64
Tay-Sachs Disease
Autosomal Recessive
Rare (1: 400,000)
High Prevalence in Select Populations -Ashkenazi Jewish ( 1: 4000)
65
A, B, C, D, E
```
GM1 is A,
B doesnt apply here
C is GM2 - this accumulates and this IS THE PROBLEM!!!!!
D is GM3 (deficient in this product)
E-doesnt apply
```
66
Tay Sachs Clinical
Tay - affects eyes - seen in 1881
Sachs - affects neurons - seen in 1896
neurodegenerative
Onset is early, death by age 4
Motor weakness (cant move limbs against gravity) , exaggerated startle response
Regression of development-prominent feature
Less responsive to environment - blinds, and seizures as well
67
Eye Problem=TS
see yellow part surrounding foveal rim = abnormal
| -b/c lots of Gm2 gangliosides being stored there
68
Tay-Sachs Pathophysiology
Gangliosides are important membrane components -important for cellular interaction
High levels of these in gray matter of the brain
Will accumulate in lysosome
Leads to cellular stress response
69
TS Enzyme Deficiency
Hex A enzyme Defect
- HexA has 2 diff subunits - Alpha and Beta
- Alpha Subunit Coded for by HEXA gene
- Beta subunit coded by HEXB gene
- HexA enzyme defect due to HEXA mutation
70
Sandhoff Disease
HexB deficiency
- Made from 2 beta subunits
- If HEXB gene mutation - leads to deficiency in HexA enzyme but also HexB
71
Tay Sachs Clinical Heterogeneity
Residual enzyme activity determines severity
Infantile Acute
-2 null mutations so no HEX A activity
-< 1% normal activity
Late Infantile, Juvenile
-1 null mutation + 1 mutation w/ residual activity (compound heterozygote)
-1 -2% normal activity
Adult/Chronic
- May have 2 mutations w/ residual activity
-2 to 5% normal activity
72
Tay-Sachs Mutations
```
Acute Encephalopathic:
-Most mutations - no mRNA or unstable mRNA so enzyme is destroyed and metabolite accumulates quickly
-Intracellular retention
-Failure of subunit assembly
Sub-acute encephalopathic:
-Splicing w/ some normal mRNA
-AA substitutions
```
Chronic Encephalopathic:
-Partial Activity Retained
73
What happens when there are two different mutations for TS (person is compound heterozygote)
Phenotype will correlate better w/ less severe mutation
74
Genetic Heterogeneity with TS
Enzyme deficiency could be in 1. Same biochemical pathway
2. Part of the same multimeric enzyme complex
3. Necessary for enzyme activity
75
Other GM2-gangiosidoses: HEXB Mutations
| genetic heterogeneity
HEXB Mutations
- HexA and HexB enzyme defects
- HexB has wider substrate specificity
- Leads to Sandhoff disease-similar to Tay-Sachs but also involves other organs
- Variable severity
76
Other GM2-Gangliosidoses
| GM2 activator defects
GM2 activator protein complexes with GM2 for presentation to HexA enzyme
Like a cofactor
W/o GM2 activator - Hex A activity to GM2 ganglioside is decreased
Like Tay-Sachs (infantile form)
77
Acute Intermittent Porphyria
Heme biosynthesis defect
Porphobilinogen deaminase deficiency also (Hydroxylmethylbilane synthase deficiency)
May not always be considered metabolic
78
Enzyme deficient in AIP
PBG
| Porphobilinogen Deaminase Deficiency
79
AIP Inheritance
Autosomal Dominant
| Incomplete penetrance - so people can have gene but not all show the disease
80
AIP Symptoms
- Females usually more affected than males but in terms of genes it is the same
- Acute abdominal pain (vomiting, constipation)
- Peripheral Neuropathy-weak and numb
- Central nervous system affected - can get psychosis, seizures
- Cardiovascular system affected- can result in hypertension, tachycardia - can die from seizures
81
what does PBG deaminase do
Coverts PBG to Hydromethybilane
82
A, B, C, D, E for AIP
```
A-not applicable
B-Ala
C-PBG accumulates
D - heme deficient
E-not applicable
```
Problem iheme deficient - needed for enzymes for p450 and hemoglobin
PBG accumulates and then ALA accumulates as well
83
AIP clinical heterogeneity
90% asymptomatic
-Females more affected than males - due to hormones and menstruation which puts demand on hemoglobin synthesis
Medications and alcohol can trigger attacks - Drugs that activate p450 enzyme biosynthesis (which requires heme)
Some drugs inhibit PBG deaminase (ie could be used for seizure) which could kill them
84
Genetic Heterogeneity for AIP
Enzymes in same biochemical pathway (heme biosynthesis enzyme)
ALA dehydrates deificency
Hereditary coproporphryia
Variegate Porphyria - porphyrin affects skin - leads to skin lesions
Or enzyme causes inhibition of heme biosynthesis
85
Symptoms for
1. PKU
2. Tay-Sachs
3. MCAD
4. GSD1a
5. Galactosemia
6. AIP
1. Slow dev + mental retardation
2. Dev regression + slow death
3. Hypoglycemia - sudden death
4. Hypoglycemia and big liver - brain damage, acidosis, and maybe death
5. Acute liver disease, acidosis, sepsis, liver failure, cataracts
6. Acute abdomen, neurological maybe death
86
Screening
Looking for disease in specific pop- asymptomatic patients: carrier, prenatal, newborn + pre-symptomatic
87
3 Ways to Diagnose and Screen
1. Metabolite testing
2. Enzyme activity testing
3. DNA testing
88
AIP Screen
Look at PBG
When left in urine - will turn darker colour due to oxidation
-Forms porphobilin
89
In what diseases does glucose decrease
GSD1a, MCAD and GALT
90
Common Chemical Analyses
```
Spectrophotometry
Electrochemistry
Enzyme Assay (enzyme as reagent to measure chemical)
Immunoassay (antibody as reagent to measure chemical/protein)
```
91
GALT Diagnosis
Can measure Gal and Gal-1P in RBCs
92
PKU diagnosis
Phe raised and Tyrosine lowered
93
Chromatography + Electrophoresis
- Separate mixtures of compounds into individual components
- Charge or physical characteristics
- Pass through a column w/ a mobile phase and stationary phase - mobile compounds attracted to mobile phase
- Then gets converted into chromatogram
94
Internal Standard
Compare to compounds measured for variability
95
How else can you diagnose PKU
you can measure phenylketones in the urine
96
How to diagnose MCAD
Measure dicarboxylic acids and acylglycines in the urine
97
Mass Spec
Separate ions based on mass and charge
| Ions are in gas phase
98
Mass Spec Fingerprint
Compounds can have equal masses
| Can separate into their own components by blasting them to form a fingerprint
99
Advantages of MS
Selective detector - can monitor individual ions
- Can separate 2 more co-running peaks
- Also increase sensitivity
- Can use stable isotopes as internal standards that are chemically identical
100
Criteria for disease to be good for Newborn Screening
Test must be available (low FN - so sensitive) and (low FP - specific)
- Benefits of screening must outweigh risks + costs
- Need a definite diagnosis
- Screening should allow some medical intervention
- Need both short-term and long -term follow-up
101
What diseases meet criteria for screening?
PKU, MCAD, and Galactosemia
-PKU b/c treatable
-MCAD can prevent symptoms
-
102
What diseases don't meet criteria for screening
Tay-Sachs -not treatable
- GSD1a - doesnt have a good test
- AIP - 99% of people who have condition dont show symptoms
103
Heel Test
blood - filter paper stabilizes sample
104
Tandem Mass Spec
Faster b/c no need for chromatography
- High throughput
- Look for compounds based on ions generated
105
TMS Screening
```
Can measure AA, fatty acids, organic acids (acyl carnitines)
-so good for PKU and MCAD - but any organic acid disorder -same class of compound forms
```
106
Why are super raree disorders have high incidence when measuring TMS
screening for both AA and AC at the same time
107
Enzyme Analysis
Substrate needs to be high so that substrate is not rate limiting step
108
Enzyme Analysis is good for what diseases
GALT, AI
| - b/c can measure directly from RBC
109
Enzyme Analysis is not good for what diseases:
PKU, MCAD, GSD1a-b/c enzyme is in liver
110
Enzyme analysis for TS
Hex A and B - very similar activity
- 4MUG = HexA and B will hydrolyze
- 4 MUGS= HexB won't hydrolyze
- GM2 activator not needed for either substrate
- When hydrolyze - will get fluorescent substance so can measure
111
HexA and B activity in no heat
- Both have activity
112
HexA and B activity in heat
HexA - not heat stable = no enzyme activity
| HexB = heat stable - so only B will show
113
If youre normal for HexA and B what do you expect in the no heat and heat EA assay
No heat = total enzyme Activity
| Heat = Just B
114
If youre TS for HexA and B what do you expect in the no heat and heat EA assay
No heat - Total T lower b/c HexA gone
| Heat - Same total T
115
If youre Sandhoff for HexA and B what do you expect in the no heat and heat EA assay
No heat - total T is lowest-both HexA and B low
| Heat = approx the same
116
4MUGS - normal
HexA activity and B none
117
4MUGS - TS
Hex A lower
118
4MUGS-Sandhoff
HexA lower
119
Can you tell disorders apart with 4MUGS enzyme assay
NO
120
How to measure GM2 activator deficiency
Use Natural substrate - GM2
121
Cons of EA
Need accessible tissue
Overlapping enzyme activity
Might need to take into account activators/cofactors
Dont pick up more subtle activity
Sample integrity - issue with GALT - summer: kills more activity = more positives, while in winter less positives
122
Carrier Screening TS w/ enzyme assay
Use serum, cells in blood, cultured cells, tears
-Carriers have 50% of normal level
-
123
Carrier Screening for TS - problems
(FALSE NEGATIVES) B1 mutations: normal activity on synthetic substrate but decreased activity on GM2 ganglioside
False positive - decreased activity on synthetic substrate but normal on GM2 ganglioside-pseudodeficiency
False Positive- P - isoenzyme
- Heat stable HexA in serum during pregnancy behaves like HexB in 4 mug assay
- % Hex A is low in non-carrier
124
DNA analysis
heterogeneity affects -
Phenotypic= dont recognize correct condition
Genetic multiple genes can cause the phenotype
Targeted approach: look for specific mutations
Untargeted: scan for any mutations
125
Targeted mutation approach P and C
Easy to screen for specific mutations
| Dont see what you dont look for
126
Untargeted Mutation Approach P and C
Good change of finding mutation
-Can be more time consuming
Can be more difficult to interpret data especially if unknown gene
127
Targeted Approach how it wroks
Usually have a restriction enzyme that cuts DNA diff depending on whether it has mutation or not
128
Untargeted
Use Sanger Sequencing
129
DNA testing for TS
1278ins4 (75-80%)
IVS12 +1G to C= 15%
For Jews
For non Jewish = G2695 (5%)
And 35% have pseudodeficient allele
130
General Treatment Principles
1. Surpluses
- reduce substrate build-up
- remove toxic compounds
2. Deficiencies
- supply deficient products
- secondary deficiencies
3. Fix the block
- Residual enzyme activity
- Replace missing enzyme (ERT, gene therapy)
131
What needs to be targeted for each of the disease for treatment
PKU- Phe
TS: Gm2
MCAD: hypoglycemia dangerous
GSD1a: hypoglycemia dangerous, some toxic metabolites
Galactosemia - Galactose metabolites toxic, UDP sugar levels abnormal
AIP-PBG and ALA toxic
132
How to deal w/ substrate build-up
Dietary approach is main
Newer approach is drugs - to inhibit pathway before block
- To block toxic substrates from reaching target organs
133
Phe buildup in PKU
from protein and aspartame
| - diet
134
Prevent Phe buildip
Have a low PHE protein diet
Make up rest of nutritional needs w/ medical foods
-Medical foods-infant formula - compound you want to control
-Could either remove all protein - substitute in individual AA
-Or remove all protein and give protein w/ low PHE
- low protein - vegan for meat + dairy
- Wheat flour - gluten free foods- flour replaced w/ starch
135
Phe Diet is
EXPENSIVE DAWG - 4-10X more although - at least 13X less protein
136
GALT treatment (surplus)
Lactose/galactose-free diet for acute toxicity
- LT complications doesnt really help:
1. poor growth
2. Speech abnormality
3. Mental retardation
4. Neurologic Syndromes
5. Primary Ovarian Failure in FEMALES
137
GSD1A treatment (surplus)
Supplement glucose to prevent glycogen breakdown
138
AIP treatment (surplus)
Supply heme to prevent first step so that ALA doesnt accumulate
Also avoid drugs that activate P450 enzyme biosynthesis
139
Tay Sachs treatment (surplus)
Inhibit pathway before metabolic block
- Use miglustat
- will inhibit glucosylceramide synthesis-which is first step in forming Gm2 ganglioside
140
Miglustat for Gaucher
-B/c direct substrate for enzyme
141
GSD1a deficiency
Supply
142
PKU Phe in Brain
Give high large AA -so dont block transporter as much so get normal transmitters
143
Hyperphenylalaninemia BH4
Can supply bopterin and unblock but for NT related disorders = need to give dopamine and tryptophan
144
MCAD deficiency treatment
ketones and carnitine
145
Secondary deficiencies
Due to treatment
| ex. Protein deficient diet in PKU leads to missing vitamins
146
Enhancing Enzyme Activity by
Cofactors, coenzymes, chpaerones
| -But need residual activity and midler disease -not for null mutations
147
BH4 Responsive PKU
PAH defect
| Activity may be improved w/ BH4
148
How to test if PKU is responsive to BH4
20mg/kg of BH4 w/ diet same
If >30% DECREASE in Phe, responder
Usually most reponisve are those with mild hyperphenylalaninemia
149
Miglustat as a Chaperone
Stabilize misfolded enzymes and increase activity
150
Providing the enzyme
Bone marrow -
Hard to find person
High mortality
Transfusion Therapy
-Transiet
iron overload
-Infection to due to repeated transfusions
151
ERT
Natural and Now Recombinaant
- Nat cons -soruce availability, cost of producing, and risk of infection
- Recombinant-production cost and contamination
152
ERT requirements
```
CDNA
-understadning fo pathophysiology
Should have an effect at low %
-Not tightly regulated
-Should be uptaken into tissue through IV
```
153
CRIMPOsitive vs Negative
Negative-null mutations so form antibodies
Positive - Some protein formed and tolerance
154
Gene Therapy
3 main types
1. Deliver defective gene product
2. Modify mRNA to increase or decrease product
3. USe CRISPR
155
Requirements for Gene Therpay
cDNA
understanding pathophysioogu
Not tightly regulated
Have an effect at low %
156
Why was geen therapy delayed
b/c gave kids cancer
