Clark A Means to an End The Biological Basis of Aging and Death (Oxford, 2002)

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.5.1).HG progerics only rarely exceed four feet inheight during their brief lives.All body hair, including the eyebrowsand eyelashes, either fails to develop or is lost; any hair that remains onthe head is white and usually described as "downy" or "fuzz-like."There are also skeletal and structural abnormalities.These may be rel-atively minor, such as the receding chin, large cranium, beak-like noseand protruding eyes seen in almost all HG progerics.These featuresare caused by the slow growth of facial bones, including the teeth, andwasting of facial flesh; the comparatively normal size of the rest of theskull results in what have been described as small, bird-like faces.Figure 5.1.Thirteen-year-old male child with Hutchison-Gilford progeria.(Drawnby Celine Park)81A MEANS TO AN ENDVoices are usually thin and high-pitched.Other physical problems aremore serious and debilitating: the long bones are lacking in proper cal-cification, and as a result are thinner and shorter than normal.The col-lar bones often fail to develop properly, causing the shoulder and chestareas to appear narrow.The fingers and toes are usually very short, dueto degeneration and resorption of the distal bones.In most cases thereis marked degeneration of the hip structure, resulting in a "bow-legged" condition.Elbow and knee joints are of normal size, but tendto fill with fibrotic scar tissue, giving them a swollen appearance andmaking limb movement difficult.Overall, the apparent physical simi-larity of HG progerics is rather startling; it is often said of them thatthey look more like one another than like other members of their ownfamilies.Some of the most striking changes take place in the skin.The sub-cutaneous layers, with their fat and nutritive cells, degenerate; theremaining superficial layers of the skin become thin, rather dry, andsomewhat transparent.(As noted by both Hutchinson and Gilford,these changes often do not extend to the pubic region.) Thus one ofthe characteristic features of progeric children, in addition to theirbaldness, is the visual prominence of numerous veins, particularly inthe scalp.The skin itself becomes wrinkled and lacking in tone,exhibits "liver spot" discolorations, and heals poorly.These changesinvolve all regions of the body, and mimic quite closely changes in theskin normally seen in very old adults.Children with HGPS have an average lifespan of twelve to thirteenyears; survival beyond twenty years is rare.They never develop sexu-ally.Voices do not deepen in males; females do not develop breasts;neither sex develops hair associated with sexual maturation.(Theabsence of nipples remarked by Hutchinson is seen in about half ofaffected individuals.) In cases examined at autopsy, the germ cells(sperm and ova) are also clearly incapable of reproductive function, andno individual with HGPS has ever produced children.They are of nor-mal intelligence throughout life, and their personalities are alsoremarkably normal in light of their condition, of which they areentirely aware.HG progerics appear to proceed directly from child-hood to old age, without ever passing through adolescence or youngadulthood.It is for this reason that HGPS has been proposed to rep-resent both a precocious (early onset) and accelerated manifestation of82HUMAN GENETIC DISEASES THAT MIMIC THE AGING PROCESSat least some portions of the normal human aging process.Andindeed, nearly all progerics die at the end of their brief lives of the samecauses as the truly aged: most from heart attacks or strokes, a few fromcongestive heart failure, and occasionally one or two from respiratorycollapse.Virtually all show extensive atherosclerosis ("hardening of thearteries") at autopsy.On the other hand, as Martin and many othershave pointed out, there are many features seen in normal aging that areabsent in HGPS.The metabolism of HG progerics, and in particularthe function of the numerous proteins required to operate the body'svarious metabolic systems, seem quite normal for their true calendarage, and do not reflect the changes seen in the metabolism of theelderly.Their vision and hearing are excellent.Moreover, they experi-ence none of the senile dementia common in older adults, and theyhave normal neurological function throughout life.Cancer, so com-mon in the true elderly, is absent in HGPS.Clearly there is something terribly wrong in these children.Butwhat? What could possibly explain this bizarre and tragic compressionof a human life into a handful of years? The marked uniformity ofsymptoms expressed in progerics suggests a common underlying dis-ease mechanism.But what kind of a disease could account for what wesee unfolding in these children? And what, if anything, can it tell usabout the normal aging process?One powerful piece of evidence that the aging process as manifestedin these patients is connected to senescence as studied in other systemscomes from analysis of their fibroblasts growing in vitro.In a studypublished in 1971, it was shown that skin-derived fibroblasts fromHGPS children, when cultured in vitro, grew much more slowly thansuch fibroblasts taken from other children in the same family, and evenmore slowly than fibroblasts taken from their parents.In fact, dou-blings were scarcely detectable.Not only does the skin look old, itscomponent cells behave as if they were old.By the criterion of replica-tive senescence, the HGPS children appeared to be even older thantheir parents.By virtually any definition, HGPS is a disease, and it is a diseaseunlikely to be caused by external agents.By exclusion, we can con-fidently expect that it is ultimately explicable in terms of a geneticderangement, a mutation in one or more genes affecting one or morecritical proteins.The question then becomes, how does this genetic83A MEANS TO AN ENDdefect arise? Is it a sporadic mutational event occurring in the lifetimeof the afflicted individual, or is it inherited? Is it a dominant mutation,or is it recessive? Is it autosomal, or is it sex-linked? Questions likethese are normally answered by following the disease in succeedinggenerations of families.Because there are so few HGPS individualsalive at any given time, and because they do not produce children whocould inherit the disease, these questions are more difficult to resolve,but there are a number of things we can say about its genetic pattern.Since it affects both males and females equally, it is clearly autosomaland not sex-linked.Its extreme rarity could be consistent with a spo-radic autosomal dominant mutation arising in a mature germ cell ofone parent.This is rendered unlikely by the fact that there are severalwell-documented cases of more than one child in a single family withHGPS.We would then have to imagine that this rare mutationoccurred spontaneously more than once in the parents of such fami-lies [ Pobierz całość w formacie PDF ]

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