Final Review Sheet

From Iusmgenetics

Revision as of 17:21, 13 December 2011

Disease Profiles

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.

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.

Recessive Diseases

• Requires two mutant alleles to show the phenotype or disease state.

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.

• In Indiana we screen for:
  • Metabolic disorders:
    • Phenylketonuria
    • Galactosemia
    • Maple Syrup Urine Disease
    • Homocysteinuria
    • Biotinidase Deficiency
  • Endocrine disorders:
    • Hypothyroidism
    • Congenital Adrenal Hyperplasia
  • Hemoglobinopathies:
    • Sickle Cell Disease
  • Cystic Fibrosis
• Using several methods: enzyme assays, radiommunoassays, electrophoresis, tandem mass spectrometry

General Molecular / Biochemical Pathogenesis Principles

• Dominant diseases usually result from:
  • Gain of abnormal function
  • Haploinsufficiency
  • Dominant-negative effects (think multi-subunit proteins)
• 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.

Unusual Molecular Pathogenesis

Objectives

• Know the concepts:
  • Two hit phenomenon
  • Alterened gene structure / dose from unusual crossover
• Know the standard profile of each disease

Unstable repeat expansion

• Unstable repeat expansion refers to the phenomenon of nucleotide repeats accumulating in a certain region of the genome and causing disease.
  • can be at any location in the genome: non-coding regions, regulatory regions, introns, or exons.
    • When repeats result in coding regions, they are called poly amino acid tracts.
    • It is estimated that 20% of human proteins contain a poly amino acid tract.
  • usually triplets.
  • repeats are added with each mitosis / meiosis.
  • NB: instability can also result in decreases in repeats.
  • even the germline cells have instability
    • leads to anticipation: earlier onset of disease with each generation.
• The number of repeats usually correlates with severity of disease.
• interrupted repeats are less likely to expand
  • like in Fragile X syndrome, CGGs are interrupted by AGGs

• Poly amino acid tracts tend to manifest as neurologic disorders.
• Some poly amino acid tracts demonstrate anticipation.
• Poly amino acids tracts include:
  • Huntington disease
  • Spinocerebellar ataxia
  • Spinobulbar muscle atrophy
  • Macado-Joseph disease
  • Dentorubropallido dysplasia

Myotonic Dystrophy

Fragile-X Syndrome

Huntington Disease

Two Hit Phenomenon

• The concept of the two hit phenomenon is the idea that if a pt inherits one mutant allele, it only takes one "hit" at that locus to cause dieases; whereas if a pt has not inherited a mutant allele, two hits are required at the locus (which is highly unlikely) to cause disease.
  • The second hit can result from the mutation of the wild-type allele or the deletion of the wild-type allele.
• Loss of heterozygosity is related to the two hit phenomenon; LOH is the case when a pt has the same alleles at both copies of a loci.
  • LOH can result from uniparental disomy, abnormal crossover events, etc.

Polycystic Kidney Disease

Neurofibromatosis

Hemophilia A

Gene duplication

• Gene duplication can lead to disease.
• Gene duplication may be facilitated by homologous sequences and / or repeats flanking a loci causing misalignment during synthesis and an attempt at "repair" generating a new copy.

Charcot-Marie-Tooth Disease

Miscellaneous

• Familial hypercholesterolemia is a product of LDL receptor issues.
• Alpha globin deletions lead to alpha thalassemias.