Biochemical Genetics

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Central metabolism

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involves production of energy; breakdown of things like proteins, FAs, and CH2Os with thei final step being the production of ATP

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Patterns of inheritance of inborn errors of metabolism

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-Usually autosomal recessive
-may also be X-linked
-mitochondrial disorders included in this category--maternally inherited

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Overall incidence of inborn errors of metabolism

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1 in 4,000 births

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Causes of toxicity when metabolic pathway is disrupted by diminished/absent enzyme activity

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1. accumulation of substrates may be toxic
2. loss of products
3. accumulation of secondary products

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Other proteins that enzyme activity depends on

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1. proteins that transport substrates across membranes
2. enzymes that process/recycle cofactors/coenzymes

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Steps in enzyme processing that can go wrong

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1. processing in Golgi and ER
2. transport to distal site
3. protein assembly

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Examples of acute onset disorders

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1. intoxication disorders
2. disorders of AA metabolism
3. organic acid metabolism
4. FA oxidation

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Progressive onset disorders

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=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

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Common S/S of acute onset disorders

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acidosis, hyperammonemia (D/T inhibition of the urea cycle D/T acidosis), hypoglycemia, seizures, coma, death

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Common S/S of progressive disorders

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Develop more slowly usually, often present in childhood (usu. later than acute onset D/Os), coarse features, organomegaly, joint contractures

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Clinical heterogeneity

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refers to phenotypic variation in a given disorder

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Genotype/phenotype correlation

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particular mutation in a gene rarely will always correlate with a given phenotype D/T environmental considerations and modifier genes

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Locus heterogeneity

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Mutations of different genes can cause similar phenotypes

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Allelic heterogeneity

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Different alleles at the same locus can cause similar phenotypes

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Standards of diagnosis of inborn errors of metabolism

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1. clinical evidence
2. metabolite pattern
3. enzyme deficiency
4. disease-causing mutation
*gold standard is to demonstrate all four

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Treatment that restores enzyme activity

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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

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Treatment that removes toxicity/accumulating compounds

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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.

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Examples of supplying/substituting missing products

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1. FA oxidation disorder OR glycogen storage disorder: supply starch
2. urea cycle disorder: supply Arg

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Examples of progressive onset disorders

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1. lysosomal storage disorders
2. disorders of metal metabolism

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Examples of amino acidopathies

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1. phenylketonuria (PAH deficiency)
2. maple syrup urine dz
3. tyrosinemia
4. homocystinuria

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How can illness exacerbate amino acidopathy?

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illness may cause patient to become catabolic, leading to breakdown of endogenous protein (e.g., from skeletal muscle); similar effect as eating protein

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What are the most common organic acidemias?

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1. methylmalonic acidemia
2. propionic acidemia
3. isovaleric acidemia

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Mechanistic difference b/t AAemia and organic acidemia

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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.

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PAH deficiency vs. BH4 processing defect

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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.

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Maternal PKU

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If pregnant mother does not control PKU, her high levels of Phe can cross placenta and cause microcephaly, impaired CNS development/mental retardation.

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Tissues affected in lysosomal storage dz: depends on what?

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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.

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Clinical features of lysosomal storage disorders

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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

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Overall incidence of lysosomal storage diseases

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1 in 20,000 births

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Pathology of Hurler syndrome

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Alpha-L-iduronidase enzyme deficiency, causing accumulation of mucopolysaccharide (GAGs) in the cell, most notably dermatan sulfate.

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Polyplasmy

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refers to the phenomenon observed in mitochondria of having multiple (3-7) copies of its genome (circular DNA)

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Enzyme deficiency in galactosemia

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galactose-1-P-uridyltransferase (GALT); replaces 1-P with UDP to make UDP-galactose

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What causes cataracts to form in galactosemia?

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Secondary pathway: aldose reductase reduces galactose to galactitol-->causes cataracts

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S/S of galactosemia

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vomiting, diarrhea, jaundice, hypotonia, bleeding, seizures, liver disease/cirrhosis, kidney disease, mental retardation, and bacterial sepsis.

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Treatment of galactosemia

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Removal of dietary lactose/galactose.

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Prognosis of treated galactosemia

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Treatment largely eliminates acute toxicity, but long-term consequences still occur: variable cognitive impairment, speech impairment, ataxia, premature ovarian failure.

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Functions of peroxisomes

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1. oxidation of long-chain FAs
2. production of ether lipids (e.g., plasmalogens) essential for CNS function

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X-linked adrenoleukodystrophy
a. What is it?
b. Female carriers?
c. Variability?

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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.

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Pathology of X-linked adrenoleukodystrophy

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ABCD1 transport protein mutation. WT protein transports VLCFAs into peroxisome to be degraded.

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Treatment of X-linked adrenoleukodystrophy

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1. BMT
2. Sx may be ameliorated by early Tx with Lorenzo's oil