Molecular and Biochemical Genetics

From Iusmgenetics

(Difference between revisions)
(→Newborn Screening)
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*In Indiana we screen for:
*In Indiana we screen for:
**Metabolic disorders:
**Metabolic disorders:
-
***Phenylketonuria
+
***[[Phenylketonuria]]
-
***Galactosemia
+
***[[Galactosemia]]
-
***Maple Syrup Urine Disease
+
***[[Maple Syrup Urine Disease]]
-
***Homocysteinuria
+
***[[Homocysteinuria]]
-
***Biotinidase Deficiency
+
***[[Biotinidase Deficiency]]
**Endocrine disorders:
**Endocrine disorders:
***Hypothyroidism
***Hypothyroidism
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**Hemoglobinopathies:
**Hemoglobinopathies:
***Sickle Cell Disease
***Sickle Cell Disease
-
**Cystic fibrosis
+
**[[Cystic Fibrosis]]
*Using several methods: enzyme assays, radiommunoassays, electrophoresis, tandem bass spectrometry
*Using several methods: enzyme assays, radiommunoassays, electrophoresis, tandem bass spectrometry

Revision as of 14:12, 28 November 2011

Contents

Molecular and Biochemical Genetics

Objectives

  • Important terms:
    • "Incomplete" dominance or "semi-dominant": homozygous individuals have a worse manifestation than heterozygous individuals (achondroplasia).
    • "Distinct disorder": consistent clinical and radiological findings.


  • Important concepts:
    • Types of mutations:
      • Missense: changed amino acid
      • Nonsense: introduced stop codon
      • Neutral / silent: no amino acid change
      • Polymorphisms are a population term; it means 1% of the pop has it; it does not infer whether it causes disease or not
      • RNA splicing: gain or loss of splice site
      • Regulation mutation: affects gene regulation
      • Indels: gain or loss of one or more bases; leads to frameshift if not a multiple of 3
      • Repeat expansion: repeated segment (usually 3 bases) expands as nucleotide copy / repair mechanisms get hung up
    • Haploinsufficiency:
    • Dominant-negatie effect:


  • For individual diseases, know: clinical features, mode of inheritance, genes involved / gene defect, pathogenesis, treatment (sometimes)

Review your fundamentals

Dominant Diseases

  • Dominant disease are defined as those manifested when only one allele is mutated.
    • Recall that some diseases can be both dominant and negative because of allelic heterogeneity and locus heterogeneity.
  • There are multiple ways we describe a single allele (not both copies) can cause disease:
    • Qualitative effects: the protein product gains a function.
    • Quantitative effects: the protein product is broken.
    • Combination of qualitative and quantitative.
    • Others
  • It is important to understand the disease pathogenesis in order to think wisely about treatment.

Achondroplasia

Osteogenesis imperfecta

Ehlers Danlos Syndrome

Marfan syndrome

Familial Hypercholesterolemia

Recessive Diseases

  • Requires two mutant alleles to show the phenotype or disease state.
  • Recall that a proband with a recessive disease usually has parents who are both carriers.
    • However, there are exceptions: uniparental disomy, skewed lyonization.
  • Recessive disorders usually result from a missing component of a pathway.
    • Phenotype usually results from the accumulation of a precursor / metabolite.

Homocysteinuria

Cystic Fibrosis

Hemochromatosis

Alpha-1-Anti-Trypsin deficiency

Phenylketonuria

Tay-Sachs Disease

Galactosemia

Maple Syrup Urine Disease

Biotinidase Deficiency

X-linked Diseases

Rett Syndrome

Lesch-Nyhan syndrome

Inherited Muscular Dystrophies

Newborn Screening

  • The following criteria for newborn screening assure that our screening has analytic validity, clinical validity, and clinical utility:
    • The disorder must be well defined.
    • The disorder must be fairly high in population frequency (to justify the cost of newborn screening by the cost saved in care for the true-positives).
    • The disorder must be poorly clinically detected early in life (assymptomatic) (otherwise it is more cost effective to let physicians identify the disease at newborn checkups).
    • The disorder must be significant in morbidity / mortality if left untreated (otherwise we might start treating things that have little consequence).
    • The disorder must be treatable such that there is an improved condition (lest we start adding anxiety to insult).
    • The test must be rapid, inexpensive, specific AND sensitive over an entire population.
    • The test must be acceptable and cost-effective.
    • The test must be appropriately administered.


  • Newborn screening is required by law on all infants
    • A second test is required if the first screen is done prior to 48 hours


Pitfalls of Screening

  • False positives cause unecessary stress / anxiety and investigation / treatment.
  • False negatives cause false security.
  • Recalling the requirement that a screened disease must be "treatable" in some effective way, we see that prolonging the knowledge of a disease may be a form of harm if the disease cannot be treated.
  • Procedures prompted by screening can be uncomfortable and unnecessary.

General Molecular / Biochemical Pathogenesis Principles

  • Dominant diseases usually result from:
    • Gain of abnormal function
    • Haploinsufficiency
    • Dominant-negative effects (think multi-subunit proteins)
    • Combinations of these reasons
  • Recall that dominant disease can be "incomplete" and thus have more severe phenotypes when presented as homozygous conditions.
  • Recessive diseases usually result from:
    • Loss of normal function
  • Heterozygotes of recessive diseases (carriers) usually have enough wild-type gene product to function properly
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