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BIOCHEM 3H03 > Metabolic Disorders > Flashcards

Metabolic Disorders Flashcards

1
Q

First Metabolic Disorder

A 
Archibald Garrod (1902)
Alkaptonuia
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2
Q

Normal Pathway

A

A –> B –> C –> D

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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.

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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
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5
Q

Genetic Heterogeneity

A

Diff Underlying Causes but Present the Same-Could be genetic or environmental

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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
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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.
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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.

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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

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10
Q

What kind of disorder is PKU

A

AA disorder

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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
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12
Q

PKU:
Substrate Accumulated?
Product Deficiency?
Unusual Metabolites Formed?

A
  1. Phe
  2. Tyr
  3. Phenylketones
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13
Q

PKU inheritance

Incidence + Carrier?

A

Autosomal Recessive

1:15,000 - carrier is 1:60

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14
Q

Outcome of PKU late Diagnosis

A

smell, decreased pigmentation (pale), mental retardation (IQ 35)

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15
Q

To show symptoms of PKU, need Phe dietary intake (T/F)

A

True

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16
Q

Why is there decreased pigmentation?

A

B/c Tyrosine is needed for melanin production

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17
Q

Acute Phe Toxicity Reversible when Less than

A

1300

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18
Q

Chronic Toxicity to Brain from PKU

A

results in dysmyelination and permanent damage

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19
Q

Phenylalanine Hydroxylase Mutations

A

Many, over 1000

Many people with PKU are compound heterozygotes-means have 2 diff mutations

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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
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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

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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
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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

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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
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25
Q

Clinical Heterogeneity for PKU

A

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

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26
Q

Genetic Heterogeneity for PKU

A

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
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27
Q

Hyperphenylaniemia can be caused by

A 
PAH Mutations (98%) 
And BH4 Mutations (2%)
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28
Q

Malignant PKU

A

Due to BH4 (Tetrahydrobiopterin)

-Deficiency in cofactor synthesis or recycling

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29
Q

How do biopterin defects arise

A 
GTPCH def (1), PTPS def (2), SR def (3) or DHPR (4) 
(involved in making BH4)
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30
Q

What else is affected by BH4 deficiency?

A

Tyrosine –> L-DOPA –> Dopamine
Tryptophan –> 5-OH-Tryptophan –> Serotonin

So basically important NT synthesis affected.

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31
Q

GSD1

A

Glycogen Storage Disorder -

Deficient in GSD1 - which converts Glucose-6-P to Glucose

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32
Q

GSD1A Problems

A

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
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33
Q

A, B, D, E for GSD1A

A 
A = Glycogen 
B = Glc-6P  accumulates
D = lactates, purines (uric acid) and FAs (triglycerides) - unusual products 
E = glucose deficient
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34
Q

GSD1A Clinical Heterogeneity

A

Milder mutations that don’t destroy enzyme activity

Prolonged exposure of brain to hypoglycemia = results in brain damage

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35
Q

GSD1b

A 
-Genetic Heterogeneity
Transporter (cytosol into ER) 
-Liver big and hypoglycaemia 
-Neutropenia - so get frequent infections 
-Mucous Membranes get ulcers
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36
Q

GSDIII

A

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

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37
Q

GSD V1

A
  • Genetic Heterogeneity
  • Phosphorylase
  • LIke GSD III
  • Less common
  • No myopathy
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38
Q

GSD 1X

A

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)
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39
Q

Classical Galactosemia

A

Caused by GALT deficiency

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40
Q

Galactosemia Characterization - when consume galactose

A
  • 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
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41
Q

What is a major reason for clinical heterogeneity for Galactosemia

A

Exposure to galactose

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42
Q

What needs to happen for the galactosemia to be acute

A

exposure to galactose

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43
Q

What goes galactosemia progress to?

A

Liver failure (bile stasis, portal fibrosis, cirrhosis)
Cataracts
Developmental Delay

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44
Q

A, B, C, D, E in Galactosemia

A 
A = Lactose 
B = Galactose 
C = Gal-1P Accumulation 
D = glucose deficiency 
E = galactitol + galactonate (form from galactose accumulation)
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45
Q

How do galactitol and galactonate form

A

Galactose gets reduced to galactitol (polyol pathway)

-Gets oxidized to galactonate

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46
Q

What happens to galactitol, galactonate, and galactose-11 phosphate

A

Galactitol = excreted by kidney - it damages eyes and other organs

Galactonate = accumulates in tissues and so does G1P

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47
Q

Pathophysiology of Acute Toxicity Syndromes + LT complications

A

UNCERTAIN

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48
Q

Cataract formation - Galactosemia

A

Due to galactitol
-Irreversible

-Galactitol doesnt affect kidney or liver

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49
Q

Clinical Heterogeneity of GALT

A

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

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50
Q

Epimerase Deficiency

A

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

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51
Q

MCAD deficiency

A
  • Fatty acid beta-oxidation disorder

- Beta oxidation is blocked - but this process is needed when trying to maintain blood sugar when fasting

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52
Q

How are triglycerides broken down?

A
  • 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
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53
Q

MCAD Role

A

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.
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54
Q

A,B,C,D, E for MCAD Deficiency

A 
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)
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55
Q

MCAD Inheritance

A

Autosomal Recessive

  • Incidence (1:10,000 to 20,000)
  • One mutation which is most prevalent (especially in Caucasians)
  • Carrier rate is 1 in 50
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56
Q

MCAD Clinical Presentation

A

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

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57
Q

MCAD Clinical Heterogeneity

A

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

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58
Q

Genetic Heterogeneity for MCAD

A

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
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59
Q

MADD

A

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
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60
Q

Causes of MADD

A

3 gene defects:

  1. a-ETF
  2. B-ETF
  3. ETF-QO

And environmental causes

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61
Q

MADD Genetic Heterogeneity

A

Jamaican Vomiting Illness (Ackee)

-Can poison electron chains if eat when not ripe

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62
Q

Tay-Sachs Disease

A

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

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63
Q

Tay-Sachs Type of Disease

A

One of more than 50 “Lysosomal Storage Disorder”

-Type of GM2 Gangliosidosis

64
Q

Tay-Sachs Disease

A

Autosomal Recessive
Rare (1: 400,000)
High Prevalence in Select Populations -Ashkenazi Jewish ( 1: 4000)

65
Q

A, B, C, D, E

A 
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
Q

Tay Sachs Clinical

A

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
Q

Eye Problem=TS

A

see yellow part surrounding foveal rim = abnormal

-b/c lots of Gm2 gangliosides being stored there

68
Q

Tay-Sachs Pathophysiology

A

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
Q

TS Enzyme Deficiency

A

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
Q

Sandhoff Disease

A

HexB deficiency

  • Made from 2 beta subunits
  • If HEXB gene mutation - leads to deficiency in HexA enzyme but also HexB
71
Q

Tay Sachs Clinical Heterogeneity

A

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
Q

Tay-Sachs Mutations

A 
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
Q

What happens when there are two different mutations for TS (person is compound heterozygote)

A

Phenotype will correlate better w/ less severe mutation

74
Q

Genetic Heterogeneity with TS

A

Enzyme deficiency could be in 1. Same biochemical pathway

  1. Part of the same multimeric enzyme complex
  2. Necessary for enzyme activity
75
Q

Other GM2-gangiosidoses: HEXB Mutations

genetic heterogeneity

A

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
Q

Other GM2-Gangliosidoses

GM2 activator defects

A

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
Q

Acute Intermittent Porphyria

A

Heme biosynthesis defect
Porphobilinogen deaminase deficiency also (Hydroxylmethylbilane synthase deficiency)

May not always be considered metabolic

78
Q

Enzyme deficient in AIP

A

PBG

Porphobilinogen Deaminase Deficiency

79
Q

AIP Inheritance

A

Autosomal Dominant

Incomplete penetrance - so people can have gene but not all show the disease

80
Q

AIP Symptoms

A
  • 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
Q

what does PBG deaminase do

A

Coverts PBG to Hydromethybilane

82
Q

A, B, C, D, E for AIP

A 
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
Q

AIP clinical heterogeneity

A

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
Q

Genetic Heterogeneity for AIP

A

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
Q

Symptoms for

  1. PKU
  2. Tay-Sachs
  3. MCAD
  4. GSD1a
  5. Galactosemia
  6. AIP
A
  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
Q

Screening

A

Looking for disease in specific pop- asymptomatic patients: carrier, prenatal, newborn + pre-symptomatic

87
Q

3 Ways to Diagnose and Screen

A
  1. Metabolite testing
  2. Enzyme activity testing
  3. DNA testing
88
Q

AIP Screen

A

Look at PBG
When left in urine - will turn darker colour due to oxidation
-Forms porphobilin

89
Q

In what diseases does glucose decrease

A

GSD1a, MCAD and GALT

90
Q

Common Chemical Analyses

A 
Spectrophotometry 
Electrochemistry 
Enzyme Assay (enzyme as reagent to measure chemical)
Immunoassay (antibody as reagent to measure chemical/protein)
91
Q

GALT Diagnosis

A

Can measure Gal and Gal-1P in RBCs

92
Q

PKU diagnosis

A

Phe raised and Tyrosine lowered

93
Q

Chromatography + Electrophoresis

A
  • 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
Q

Internal Standard

A

Compare to compounds measured for variability

95
Q

How else can you diagnose PKU

A

you can measure phenylketones in the urine

96
Q

How to diagnose MCAD

A

Measure dicarboxylic acids and acylglycines in the urine

97
Q

Mass Spec

A

Separate ions based on mass and charge

Ions are in gas phase

98
Q

Mass Spec Fingerprint

A

Compounds can have equal masses

Can separate into their own components by blasting them to form a fingerprint

99
Q

Advantages of MS

A

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
Q

Criteria for disease to be good for Newborn Screening

A

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
Q

What diseases meet criteria for screening?

A

PKU, MCAD, and Galactosemia
-PKU b/c treatable
-MCAD can prevent symptoms
-

102
Q

What diseases don’t meet criteria for screening

A

Tay-Sachs -not treatable

  • GSD1a - doesnt have a good test
  • AIP - 99% of people who have condition dont show symptoms
103
Q

Heel Test

A

blood - filter paper stabilizes sample

104
Q

Tandem Mass Spec

A

Faster b/c no need for chromatography

  • High throughput
  • Look for compounds based on ions generated
105
Q

TMS Screening

A 
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
Q

Why are super raree disorders have high incidence when measuring TMS

A

screening for both AA and AC at the same time

107
Q

Enzyme Analysis

A

Substrate needs to be high so that substrate is not rate limiting step

108
Q

Enzyme Analysis is good for what diseases

A

GALT, AI

- b/c can measure directly from RBC

109
Q

Enzyme Analysis is not good for what diseases:

A

PKU, MCAD, GSD1a-b/c enzyme is in liver

110
Q

Enzyme analysis for TS

A

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
Q

HexA and B activity in no heat

A
  • Both have activity
112
Q

HexA and B activity in heat

A

HexA - not heat stable = no enzyme activity

HexB = heat stable - so only B will show

113
Q

If youre normal for HexA and B what do you expect in the no heat and heat EA assay

A

No heat = total enzyme Activity

Heat = Just B

114
Q

If youre TS for HexA and B what do you expect in the no heat and heat EA assay

A

No heat - Total T lower b/c HexA gone

Heat - Same total T

115
Q

If youre Sandhoff for HexA and B what do you expect in the no heat and heat EA assay

A

No heat - total T is lowest-both HexA and B low

Heat = approx the same

116
Q

4MUGS - normal

A

HexA activity and B none

117
Q

4MUGS - TS

A

Hex A lower

118
Q

4MUGS-Sandhoff

A

HexA lower

119
Q

Can you tell disorders apart with 4MUGS enzyme assay

A

NO

120
Q

How to measure GM2 activator deficiency

A

Use Natural substrate - GM2

121
Q

Cons of EA

A

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
Q

Carrier Screening TS w/ enzyme assay

A

Use serum, cells in blood, cultured cells, tears
-Carriers have 50% of normal level
-

123
Q

Carrier Screening for TS - problems

A

(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
Q

DNA analysis

A

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
Q

Targeted mutation approach P and C

A

Easy to screen for specific mutations

Dont see what you dont look for

126
Q

Untargeted Mutation Approach P and C

A

Good change of finding mutation
-Can be more time consuming
Can be more difficult to interpret data especially if unknown gene

127
Q

Targeted Approach how it wroks

A

Usually have a restriction enzyme that cuts DNA diff depending on whether it has mutation or not

128
Q

Untargeted

A

Use Sanger Sequencing

129
Q

DNA testing for TS

A

1278ins4 (75-80%)
IVS12 +1G to C= 15%
For Jews

For non Jewish = G2695 (5%)
And 35% have pseudodeficient allele

130
Q

General Treatment Principles

A
  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
Q

What needs to be targeted for each of the disease for treatment

A

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
Q

How to deal w/ substrate build-up

A

Dietary approach is main
Newer approach is drugs - to inhibit pathway before block
- To block toxic substrates from reaching target organs

133
Q

Phe buildup in PKU

A

from protein and aspartame

- diet

134
Q

Prevent Phe buildip

A

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
Q

Phe Diet is

A

EXPENSIVE DAWG - 4-10X more although - at least 13X less protein

136
Q

GALT treatment (surplus)

A

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
Q

GSD1A treatment (surplus)

A

Supplement glucose to prevent glycogen breakdown

138
Q

AIP treatment (surplus)

A

Supply heme to prevent first step so that ALA doesnt accumulate

Also avoid drugs that activate P450 enzyme biosynthesis

139
Q

Tay Sachs treatment (surplus)

A

Inhibit pathway before metabolic block

  • Use miglustat
  • will inhibit glucosylceramide synthesis-which is first step in forming Gm2 ganglioside
140
Q

Miglustat for Gaucher

A

-B/c direct substrate for enzyme

141
Q

GSD1a deficiency

A

Supply

142
Q

PKU Phe in Brain

A

Give high large AA -so dont block transporter as much so get normal transmitters

143
Q

Hyperphenylalaninemia BH4

A

Can supply bopterin and unblock but for NT related disorders = need to give dopamine and tryptophan

144
Q

MCAD deficiency treatment

A

ketones and carnitine

145
Q

Secondary deficiencies

A

Due to treatment

ex. Protein deficient diet in PKU leads to missing vitamins

146
Q

Enhancing Enzyme Activity by

A

Cofactors, coenzymes, chpaerones

-But need residual activity and midler disease -not for null mutations

147
Q

BH4 Responsive PKU

A

PAH defect

Activity may be improved w/ BH4

148
Q

How to test if PKU is responsive to BH4

A

20mg/kg of BH4 w/ diet same
If >30% DECREASE in Phe, responder

Usually most reponisve are those with mild hyperphenylalaninemia

149
Q

Miglustat as a Chaperone

A

Stabilize misfolded enzymes and increase activity

150
Q

Providing the enzyme

A

Bone marrow -
Hard to find person
High mortality

Transfusion Therapy
-Transiet
iron overload
-Infection to due to repeated transfusions

151
Q

ERT

A

Natural and Now Recombinaant

  • Nat cons -soruce availability, cost of producing, and risk of infection
  • Recombinant-production cost and contamination
152
Q

ERT requirements

A 
CDNA
-understadning fo pathophysiology 
Should have an effect at low %
-Not tightly regulated
-Should be uptaken into tissue through IV
153
Q

CRIMPOsitive vs Negative

A

Negative-null mutations so form antibodies

Positive - Some protein formed and tolerance

154
Q

Gene Therapy

A

3 main types

  1. Deliver defective gene product
  2. Modify mRNA to increase or decrease product
  3. USe CRISPR
155
Q

Requirements for Gene Therpay

A

cDNA
understanding pathophysioogu
Not tightly regulated
Have an effect at low %

156
Q

Why was geen therapy delayed

A

b/c gave kids cancer

BIOCHEM 3H03 (5 decks)

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