Método de las áreas tributarias para calcular cargas en elementos estructurales

In this section I will concentrate on one particular condition, Hutchinson- Gilford progeria syndrome (HGPS), as this is generally considered the best model and we have had the opportunity to study two affected patients. Other conditions also quoted as examples of accelerated ageing or listed in Table 2.

3.6.1 Clinical features of HGPS

Progeria is a term sometimes applied to several diseases in which the individual appears prematurely aged. HGPS is a much more clearly defined condition with a very distinct clinical phenotype. First outlined in 1886 and the early years of this century (Hutchinson, 1886; Gilford, 1904) some 75 cases have since been described in the literature (60 of whom are reviewed by DeBusk, 1972). This over-represents its true incidence which is in fact extremely low. The United States reports only 1 case per 8 million births (DeBusk, 1972). The very consistent clinical phenotype suggests a genetic causation. There have been reports of affected siblings and cousins from unaffected consanguineous parents (DeBusk, 1972; Khalifa, 1989) suggesting autosomal recessive inheritance, but with such small numbers inheritance patterns are difficult to substantiate.

The clinical features of HGPS as reviewed by several authors are summarized here (DeBusk, 1972; Mills and Weiss, 1990; Brown, 1992). At birth most appear normal but present within the first year of life with failure to thrive or skin/hair abnormalities. Both height and weight deficits become rapidly apparent, the latter most marked with an invariable striking lack of subcutaneous fat. There are consistent cranio-facial abnormalities giving a "plucked-bird" appearance with micrognathia, mid-facial cyanosis, a

"sculptured" nose, prominent scalp veins and alopecia. Dentition is abnormal and delayed, and complete sexual maturation does not occur. Skeletal abnormalities such as short dystrophic clavicles, a pyriform thorax and coxa valga, are common. The skin typically appears "aged" being thin and dry with little hair, prominent veins and many loose wrinkled areas even at five years old. Other regions may seem scleroderma like with tethering and a smooth shiny appearance. Later irregular pigmented areas appear and there may be dystrophic nail changes. Arthritis and thinning bones are common but differ radiologically and pathologically from the osteoarthritis and osteoporosis accompanying old age. Intellect and cognitive function are normal, though may be later affected by cerebrovascular disease. Vascular complications are the commonest cause of death as there is widespread premature atherosclerosis. Cardiac vessels are most severely affected often causing angina by the age of 10, and myocardial infarctions/cardiac failure in the teens. The mean age at death is 13.4 years with a range of 7 to 27 years.

No demonstrable abnormalities of endocrine function have been found other than insulin resistance (Villee et al. 1969), which may also be a feature of

normal ageing. None of the reported HGPS cases have demonstrated other aspects of old age such as senile cataracts, presbyacusis, arcus senilis, osteoarthritis or the development of senile plaques/neurofibrillary tangles in the CNS.

Disease/ syndrome "Ageing" clinical features Other major clinical features "lacking" features

HGPS alopecia; skin changes; muscle and

CT atrophy; atherosclerosis; arthritis; osteoporosis; insulin resistance

dysmorphic facies; abnormal dentition; congenital skeletal abnormalities

cataracts; CNS changes; neoplasms

Werner's syndrome hair greying; cataracts; skin changes; muscle and CT atrophy;

atherosclerosis; osteoporosis; neoplasms;

growth retardation;

hypogonadism; diabetes; skin ulceration;

soft tissue calcification

CNS changes;

prostatic hypertrophy; hypertension

Cockayne's syndrome skin, muscle and connective tissue changes;

cataracts; deafness

growth retardation; mental deficiency; photosensitivity; hypogonadism;

Neoplasms; CNS changes; CVS disease

Down's syndrome dementia;

neoplasms; cataracts

mental and growth retardation; hypogonadism; congenital

vascular malformations

ageing skin/muscle changes; acquired CVS disease

Ataxia telangiectasia neoplasms;

increased spontaneous chromosomal abnormalities

congenital vascular

abnormalities; impaired immune function; cerebellar ataxia;

ageing skin/muscle/CT changes; CNS changes; Acquired CVS disease

Disorders cited as models of accelerated ageing in man, illustrating the merits and limitations of using such models in the study of normal ageing. HGPS = Hutchinson-Gilford progeria syndrome; CT = connective tissue; CVS = cardiovascular system; CNS = central nervous system. References: (Goldstein, 1971; Mills and Weiss, 1990; Martin, 1988).

3.6.2 HGPS as a model of accelerated ageing

Assessment of a disease as a model of normal ageing requires that we distinguish features of "normal" ageing from disease processes, which as I have previously discussed is not easy. None of the proposed models in Table 2 express a full cross-section of the ageing phenomenon. Those who have considered the candidates in detail conclude that HGPS is the best model we have, though recognising it s limitations (Mills and Weiss, 1990; Brown, 1992). HGPS perhaps has more clinical homology than the others, and superficially has a more reliable onset and progression than for instance Werner's syndrome or ataxic telangiectasia. Moreover it has been observed that HGPS is manifested primarily in cells of mesodermal origin (Brown et al. 1985), providing

a potential means whereby a single gene defect might exert a profound phenotypic ageing effect. Whilst no-one would suggests that HGPS truly represents an accelerated version of normal ageing, the study of such patients might reveal pointers to processes which both have in common and aid our understanding not only of this rare condition, but also of normal ageing.