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Biochemical Genetics


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Central metabolism
involves production of energy; breakdown of things like proteins, FAs, and CH2Os with thei final step being the production of ATP
Patterns of inheritance of inborn errors of metabolism
-Usually autosomal recessive
-may also be X-linked
-mitochondrial disorders included in this category--maternally inherited
Overall incidence of inborn errors of metabolism
1 in 4,000 births
Causes of toxicity when metabolic pathway is disrupted by diminished/absent enzyme activity
1. accumulation of substrates may be toxic
2. loss of products
3. accumulation of secondary products
Other proteins that enzyme activity depends on
1. proteins that transport substrates across membranes
2. enzymes that process/recycle cofactors/coenzymes
Steps in enzyme processing that can go wrong
1. processing in Golgi and ER
2. transport to distal site
3. protein assembly
Examples of acute onset disorders
1. intoxication disorders
2. disorders of AA metabolism
3. organic acid metabolism
4. FA oxidation
Progressive onset disorders
=inability to break down cellular components or compounds which are normally recycled by the cell or reutilized in other cells in other ways
-vacuoles fill up with undegraded material, interfering with cell function and eventually killing the cell
Common S/S of acute onset disorders
acidosis, hyperammonemia (D/T inhibition of the urea cycle D/T acidosis), hypoglycemia, seizures, coma, death
Common S/S of progressive disorders
Develop more slowly usually, often present in childhood (usu. later than acute onset D/Os), coarse features, organomegaly, joint contractures
Clinical heterogeneity
refers to phenotypic variation in a given disorder
Genotype/phenotype correlation
particular mutation in a gene rarely will always correlate with a given phenotype D/T environmental considerations and modifier genes
Locus heterogeneity
Mutations of different genes can cause similar phenotypes
Allelic heterogeneity
Different alleles at the same locus can cause similar phenotypes
Standards of diagnosis of inborn errors of metabolism
1. clinical evidence
2. metabolite pattern
3. enzyme deficiency
4. disease-causing mutation
*gold standard is to demonstrate all four
Treatment that restores enzyme activity
1. reactivate with supplemental vitamins: works if problem is reduced affinity for cofactor
2. Enzyme replacement therapy: very expensive and recombinant enzymes don't cross BBB
3. organ transplant
4. gene therapy
Treatment that removes toxicity/accumulating compounds
1. Substrate reduction therapy: e.g., restrict Phe in diet for PAH deficiency
2. Provide alternative pathways for removal of toxic compounds: e.g., phenylacetate binds NH4+, then is excreted in urine.
Examples of supplying/substituting missing products
1. FA oxidation disorder OR glycogen storage disorder: supply starch
2. urea cycle disorder: supply Arg
Examples of progressive onset disorders
1. lysosomal storage disorders
2. disorders of metal metabolism
Examples of amino acidopathies
1. phenylketonuria (PAH deficiency)
2. maple syrup urine dz
3. tyrosinemia
4. homocystinuria
How can illness exacerbate amino acidopathy?
illness may cause patient to become catabolic, leading to breakdown of endogenous protein (e.g., from skeletal muscle); similar effect as eating protein
What are the most common organic acidemias?
1. methylmalonic acidemia
2. propionic acidemia
3. isovaleric acidemia
Mechanistic difference b/t AAemia and organic acidemia
AAopathy is usually D/T proximal enzyme defect--e.g., one or two steps down from the actuall AA. Organic acidemia usually a distal enzyme defect--further down in the pathway after AA has been transaminated.
PAH deficiency vs. BH4 processing defect
PAH deficiency causes isolated elevation in Phe (and low Tyr); treat with low Phe diet. BH4 is required for other enzymes--Trp hydroxylase and NO synthase--so BH4 defect causes widespread problems; may respond to high-dose BH4 supplementation.
Maternal PKU
If pregnant mother does not control PKU, her high levels of Phe can cross placenta and cause microcephaly, impaired CNS development/mental retardation.
Tissues affected in lysosomal storage dz: depends on what?
Site of involvement (=site of accumulation of material) varies according to where the SUBSTRATE is normally encountered, NOT on where the enzyme is--b/c the enzyme is usually ubiquitously distributed in normal individual.
Clinical features of lysosomal storage disorders
1. Present in infancy-early childhood (or later); usu. later than acute onset D/Os
2. Loss of milestones: normal development plateaus, stops progression
3. Accumulation in various tissues: coarse facies, corneal clouding, macular cherry red spots
4. Organomegaly
5. Hernias
6. Skeletal abnormalities
Overall incidence of lysosomal storage diseases
1 in 20,000 births
Pathology of Hurler syndrome
Alpha-L-iduronidase enzyme deficiency, causing accumulation of mucopolysaccharide (GAGs) in the cell, most notably dermatan sulfate.
refers to the phenomenon observed in mitochondria of having multiple (3-7) copies of its genome (circular DNA)
Enzyme deficiency in galactosemia
galactose-1-P-uridyltransferase (GALT); replaces 1-P with UDP to make UDP-galactose
What causes cataracts to form in galactosemia?
Secondary pathway: aldose reductase reduces galactose to galactitol-->causes cataracts
S/S of galactosemia
vomiting, diarrhea, jaundice, hypotonia, bleeding, seizures, liver disease/cirrhosis, kidney disease, mental retardation, and bacterial sepsis.
Treatment of galactosemia
Removal of dietary lactose/galactose.
Prognosis of treated galactosemia
Treatment largely eliminates acute toxicity, but long-term consequences still occur: variable cognitive impairment, speech impairment, ataxia, premature ovarian failure.
Functions of peroxisomes
1. oxidation of long-chain FAs
2. production of ether lipids (e.g., plasmalogens) essential for CNS function
X-linked adrenoleukodystrophy
a. What is it?
b. Female carriers?
c. Variability?
a. most common peroxisomal D/O
b. female carriers may become symptomatic when stressed
c. variable, progressive neurodegenerative dz; at least 4 different forms of the dz:
-Most severe form: childhood onset, rapid progression, inflammatory demyelination. Mild form: adult onset, spastic paraparesis.
Pathology of X-linked adrenoleukodystrophy
ABCD1 transport protein mutation. WT protein transports VLCFAs into peroxisome to be degraded.
Treatment of X-linked adrenoleukodystrophy
1. BMT
2. Sx may be ameliorated by early Tx with Lorenzo's oil

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