Diseases arising from chromosomal abnormalities, including changes in the number or structure of chromosomes. Several rare developmental abnormalities are attributable to chromosomal alterations.
Other genetic diseases, which involve single gene mutations but do not follow simple mendelian rules of inheritance. These single-gene disorders with nonclassic http://ebooksmedicine.net inheritance patterns include those resulting from triplet repeat mutations or from mutations in mitochondrial DNA, and those in which the transmission is influenced by an epigenetic phenomenon called genomic imprinting. Each of these four categories is discussed separately.
MENDELIANDISORDERS:DISEASESCAUSEDBYSINGLE-GENEDEFECTS
Single-gene defects (mutations) follow the well-known mendelian patterns of inheritance (
Tables 7.1 7.2 ). Although individually rare, together they account for approximately 1% of all adult admissions to hospitals and about 6% to 8% of all pediatric hospital admissions. Listed next are a few important tenets and caveats when considering mendelian disorders:
Mutations involving single genes follow one of three patterns of inheritance: autosomal dominant, autosomal recessive, or X-linked.
A single-gene mutation may have many phenotypic effects (pleiotropy) and, conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity). For example, Marfan syndrome, which results from a basic defect in connective tissue, is associated with widespread effects involving the skeleton, eyes, and cardiovascular system, all of which stem from a mutation in the gene encoding fibrillin, a component of connective tissues. On the other hand, several different types of mutations can cause retinitis pigmentosa, an inherited disorder associated with abnormal retinal pigmentation and consequent visual impairment.
Recognition of genetic heterogeneity not only is important in genetic counseling but also facilitates understanding of the pathogenesis of common disorders such as diabetes mellitus (Chapter 20).
• It is now increasingly recognized that the phenotypic manifestations of mutations affecting a known single
Table 7.1 Estimated Prevalence of Selected Mendelian Disorders Among Live-Born Infants
Huntingtondisease1in10,000
Sicklecellanemia1in500(U.S.AfricanAmericans)
Cysticfibrosis1in3200(U.S.Caucasians)
Tay-Sachsdisease1in3500(U.S.AshkenaziJewish;FrenchCanadians)
Phenylketonuria1in10,000
MPSs—alltypes1in25,000
Glycogenstoragediseases—all1in50,000types
Galactosemia1in60,000
Duchennemusculardystrophy1in3500(U.S.males)
Hemophilia1in5000(U.S.males) *Theprevalenceofheterozygoussicklecelltraitis1in12forU.S.AfricanAmericans.MPS, Mucopolysaccharidosis.
Table 7.2 Biochemical Basis and Inheritance Pattern for Selected Mendelian Disorders
MarfansyndromeFibrillinStructuralsupport:extracellularmatrix
CollagenStructuralsupport:extracellularmatrix
HereditaryspherocytosisSpectrin,ankyrin,orprotein4.1Structuralsupport:redbloodcellmembrane
Neurofibromatosis,type1Neurofibromin-1(NF-1)Growthregulation
Duchenne/BeckermusculardystrophyDystrophinStructuralsupport:cellmembrane *SomevariantsofEhler-Danlossyndromehaveanautosomalrecessiveinheritancepattern.