Disorders of autosomal recessive inheritance are manifested in the homozygous state. They occur when both of the alleles at a given gene locus are mutants. Therefore, such disorders are characterized by the following features: (1) The trait does not usually affect the parents, who are carriers of one diseased allele, but multiple siblings may show the disease; (2) siblings have one chance in four of being affected (i.e., the recurrence risk is 25% for each birth); and (3) if the mutant gene occurs with a low frequency in the population, there is a strong likelihood that the affected patient (the proband) is the product of a consanguineous marriage. They make up the largest group of mendelian disorders.
In contrast with the features of autosomal dominant diseases, the following features generally apply to most autosomal recessive disorders:
The expression of the defect tends to be more uniform than in autosomal dominant disorders.
Complete penetrance is common.
Onset is frequently early in life.
Although new mutations for recessive disorders do occur, they are rarely detected clinically. Because the affected person is an asymptomatic heterozygote, several generations may pass before the descendants of such a person mate with other heterozygotes and produce affected offspring.
In many cases, enzymes are affected by the mutation. In heterozygotes, equal amounts of normal and defective enzyme are synthesized. Usually the natural “margin of safety” ensures that cells with half of their complement of the enzyme function normally.
The Y chromosome is home to the testes-determining gene SRY, which directs male sexual differentiation, but apart from very rare instances of Y-linked familial deafness, no Y chromosome–linked mendelian disorders have ever been reported. Thus, for the most part, sex-linked disorders are X linked. Most X-linked disorders are X-linked recessive and are characterized by the following features:
Heterozygous female carriers transmit them only to sons, who of course are hemizygous for the X chromosome.
Heterozygous females rarely express the full phenotypic change, because they have the paired normal allele. Although one of the X chromosomes in females is inactivated (see further text), this process of inactivation is random, which typically allows sufficient numbers of cells with the normal expressed allele to emerge.
http://ebooksmedicine.net • An affected male does not transmit the disorder to sons, but all daughters are carriers. Sons of heterozygous women have one chance in two of receiving the mutant gene.
Autosomaldominantdisordersarecharacterizedbyexpressioninheterozygousstate;theyaffectmalesandfemalesequally,andbothsexescantransmitthedisorder.
Autosomaldominantdisordersofteninvovledysfunctionalreceptorsandstructuralproteins.
Autosomalrecessivediseasesoccurwhenbothcopiesofagenearemutatedandfrequentlyinvolveenzymes.Malesandfemalesareaffectedequally.
X-linkeddisordersaretransmittedbyheterozygousfemalestotheirsons,whomanifestthedisease.FemalecarriersusuallyareunaffectedbecauseofrandominactivationofoneXchromosome.
Marfan syndrome is an autosomal dominant disorder of connective tissues, manifested principally by changes in the skeleton, eyes, and cardiovascular system. It is caused by an inherited defect in an extracellular glycoprotein called fibrillin-1. This glycoprotein, secreted by fibroblasts, is the major component of microfibrils found in the extracellular matrix. Microfibrils serve as scaffolding for the deposition of tropoelastin, an integral component of elastic fibers. Although microfibrils are widely distributed in the body, they are particularly abundant in the aorta, ligaments, and the ciliary zonules that support the ocular lens, precisely the tissues that are prominently affected in Marfan syndrome.