Traits generally involve mutations in genes that code for enzymes (e.g., phenylalanine hydroxylase–deficient in PKU) and are associated with serious illness and shortened life span
PKU, Phenylketonuria.
Most disorders involving the X chromosome are recessive. With only one copy of the X chromosome, males are more likely to manifest these diseases than females. Each son born to a female carrier of an X-linked recessive trait has a 50% chance of inheriting the trait, but none of this woman’s daughters would be affected (each daughter has a 50% chance of being a carrier). An affected father transmits the mutation to all of his daughters, who are carriers, but not to his sons; having received their father’s Y chromosome, they would not be affected (thus there is no male-to-male transmission) (Tables 47-6, 47-7 and Fig. 47-4).
SEE CHAPTER 182.
SEE CHAPTER 151.
Figure 47-3 Pedigree of family showing autosomal recessive inheritance.
Only a few X-linked dominant disorders have been described. Both males and females are affected by this group of disorders, but females have less severe symptoms due to X-chromosome inactivation. This is the case for X-linked vitamin D–resistant rickets (hypophosphatemic rickets), a disorder in which the kidney’s ability to reabsorb phosphate is impaired. Phosphate levels and resulting rickets are not as severe in females as in males.
However, many X-linked dominant disorders are lethal inmales. Affected mothers can have affected or normal daughters but only normal sons. Affected sons die in utero. This isthe case in incontinentia pigmenti, which has a characteristic swirling skin pattern of hyperpigmentation that develops aftera perinatal skin rash with blistering. Affected females also have variable involvement of the central nervous system, hair, nails,
Fragile X syndrome (FRAXA; 1:4000 males The gene is located at Xq27.3 numerous other names) The condition is attributable to a CGG triplet expansion that is associated with localized methylation (inactivation) of distal genes. Females may have some expression. Instability of the site may lead to tissue mosaicism; lymphocyte genotype and phenotype may not correlate
Incidence of the trait is higher in males than in females
Trait is passed from carrier females, who may show mild expression of the gene, to half of their sons, who are more severely affected
Each son of a carrier female has a one in two chance of being affected
Trait is transmitted from affected males to all of their daughters; it is never transmitted father to son
Because the trait can be passed through multiple carrier females, it may skip generations teeth, and eyes. In Rett syndrome, caused by mutations in the MECP2 gene, females are normal at birth, but later in the firstyear of life develop microcephaly and developmental regressionand plateau. About 50% of patients develop seizures. Girls oftenare diagnosed with autism and, by 2 years of age, adopt a hand-washing posture that causes them to lose all purposeful hand movements.
Often termed polygenic inheritance, multifactorially inheriteddisorders result from the interplay of genetic and environmental
Figure 47-4 Pedigree showing X-linked recessive inheritance.
factors. In addition to 20% of congenital malformations, including cleft lip and palate and spina bifida, most common disordersof childhood and adult life, such as asthma, atherosclerosis, diabetes, and cancer, result from an interaction between genes andthe environment. These disorders do not follow simple mendelian modes of inheritance; rather, affected individuals tend to cluster in families. The disorders occur more often in firstand second-degree relatives than would be expected by chance, and they are more likely to be concordant (although not 100%) inmonozygotic twins than in dizygotic twins.
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