Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

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valve prolapse, which are observed in some cases, mimic a connective tissue disorder. Some physical abnormali- ties may be subtle or absent. The most distinctive fea- ture, which is present in 90% of prepubertal boys, is macroorchidism, or large testes. Because girls have two X chromosomes, they are more likely to have relatively normal cognitive development, or they may show a learning disability in a particular area, such as math- ematics. Women with the disorder may also experience premature ovarian failure or begin menopause earlier than women who are not affected by fragile X syndrome. The term fragile X stems from the cytogenic observa- tion of a constriction or fragile site on the long arm of the X chromosome. The fragile X syndrome results from a mutation in the FMR1 (fragile X mental retardation 1) gene that has been mapped to this fragile site. 2,3 The pro- tein product of the FMR1 gene, the fragile X mental retardation protein (FMRP), is a widely expressed ribo- nucleic acid (RNA)-binding protein. The protein trav- els from the cytoplasm to the nucleus, where it binds specific messenger RNAs (mRNAs) and then transports them from the nucleus to the synaptic ends of axons and dendrites, where the FMRP–mRNA complexes perform critical roles in regulating the translation of mRNA. 3 The inheritance of the FMR1 gene follows the pat- tern of X-linked traits, with the father passing the gene on to all his daughters but not his sons. However, unlike other X-linked recessive disorders, approximately 20% of males who have been shown to carry the fragile X mutation are clinically and cytogenetically normal. These “carrier males” can transmit the disease to their grandsons through their phenotypically normal daugh- ters. Another peculiarity is the presence of mental retar- dation in approximately 50% of carrier females. Both of these peculiarities have been related to the dynamic

(“happy puppet”) syndrome, which exhibits mental retardation along with paroxysms of laughter, ataxia, and seizures. In contrast, when the same deletion is inherited from the father, Prader-Willi syndrome results, and the child manifests intellectual impairment, uncon- trolled appetite, obesity, and diabetes. Figure 6-6 is a pedigree showing another inheritance pattern typical of genetic imprinting. In the example shown, gene expression is entirely “turned off” during spermatogenesis, so that any offspring who inherit the affected allele from the father will merely be carriers. Expression is “turned on” during oogenesis, however, so those who inherit the allele from the mother will express the disorder. Triplet Repeat Mutations: Fragile X Syndrome Fragile X syndrome is the prototype of disorders in which the mutation is characterized by a long repeat- ing sequence of three nucleotides. 1–3 Thus far, about 40  diseases associated with neurodegenerative changes, including Huntington disease and myotonic dystrophy, have been classified as triplet repeat mutations, in which the expansion of specific sets of three nucleotides within a gene disrupts its function. Fragile X syndrome , an abnormality in the X chro- mosome, is the common cause of inherited intellectual disability. 2,16–19 It is second only to Down syndrome as an identifiable cause of intellectual impairment. Because the syndrome is an X-linked disorder, it is more preva- lent in males (1 in 4000) than females (1 in 8000). 19 In addition to intellectual disability, the fragile X syn- drome is characterized by distinctive features including a large face, a large mandible, and large, everted ears. Hyperextensible joints, a high-arched palate, and mitral

Generation I

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C

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Generation II

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FIGURE 6-6. Pedigree of genetic imprinting. In generation I, male (A) has inherited a mutant allele from his affected mother (not shown); the gene is “turned off” during spermatogenesis, and therefore none of his offspring (generation II) will express the mutant allele, regardless of whether they are carriers. However, the gene will be “turned on” again during oogenesis in any of his daughters (B) who inherit the allele. All offspring (generation III) who inherit the mutant allele will be affected. All offspring of normal children (C) will produce normal offspring. Children of female (D) will all express the mutation if they inherit the allele.

Generation III

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Affected individuals

Have the mutant allele but are not affected

Do not have the mutant allele and are not affected