BACKGROUND HutchinsonCGilford progeria syndrome is a rare, sporadic, autosomal dominating syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. other proteins, causing blebbing of the nucleus, disrupting mitosis,31 and altering gene manifestation. These abnormalities are not due to haploinsufficiency, since 446-86-6 manufacture mice completely lacking lamin A have normal nuclear morphologic characteristics and phenotypes.8 Rather, progerin acts inside a dominant negative fashion, since transfection of a mutant allele into normal cells induces nuclear blebbing.9 The result is HutchinsonCGilford progeria syndrome, one of 11 laminopathies caused by more than 180 known mutations. Our prospective investigation of HutchinsonCGilford progeria syndrome confirmed the growth impairment, alopecia, sclerotic pores and skin changes, bone-growth abnormalities, cardiovascular and central nervous system complications, abnormal dentition, occasional slight aminoaciduria, and decreased body fat associated with this disorder.1C3,12,32 We also confirmed the normal findings with 446-86-6 manufacture respect to hematologic ideals, serum chemical laboratory ideals, renal tubular and glomerular function, and humoral and cellular immune function. New findings included long term prothrombin times, elevated platelet counts and serum phosphorus levels, hyperopia, specific abnormalities of joint motion, a particular low-frequency conductive hearing loss, and oral engine abnormalities such as decreased lingual range of motion, labial weakness, and vertical nibbling. In addition, our individuals with HutchinsonCGilford progeria syndrome were remarkably active and mobile; despite reduced vascular compliance, in these children the mean range of the 6-minute walk test (approximately 1000 feet [304.8 m]) was associated 446-86-6 manufacture with high function, especially in view 446-86-6 manufacture of their musculoskeletal impairments. Growth in individuals with HutchinsonCGilford progeria syndrome is clearly irregular. In the individuals in our study, weight started to deviate from normal before height (Fig. 2A and 2B), and the average weight gain between 2 and 10 years of age (0.65 kg per year) was similar to that reported for children with HutchinsonCGilford progeria syndrome who have been analyzed both retrospectively (0.44 kg per year) and prospectively (0.52 kg per year).13 Muscle volume remained proportional to body mass, as indicated by normal production of creatinine per kilogram of body weight. Despite radiologic evidence of bone resorption, laboratory evidence suggests a normal rate of bone turnover. Although our determined z scores suggest osteoporosis or osteopenia, consideration must be given to short stature and small bones in children with HutchinsonCGilford progeria syndrome 446-86-6 manufacture as compared with age-matched control children.33 When adjusted for these factors, bone denseness may be higher than that determined with this study. Several possible causes of impaired growth were ruled out. Inadequate nutrition was not responsible, since energy intake was adequate for growth and serum prealbumin levels were normal. Growth hormone production appeared to be adequate, since IGF-I levels were normal. Insulin resistance was at worst mild; levels of both serum glucose and plasma free fatty acids decreased in response to endogenously produced insulin. Cardiovascular complications generally cause death in HutchinsonCGilford progeria syndrome. Medial smooth-muscle cells are lost, with secondary maladaptive vascular redesigning, intimal thickening, disrupted elastin materials, and deposition of extracellular matrix; sclerotic plaques that form in the aorta and coronary arteries are associated with stenosis.34,35 A transgenic mouse model recapitulates the vascular pathological features in humans and is useful in the investigation of potential therapies. The mouse model contains the human being mutant G608G gene as well as the normal match of genes. It shows progressive drop-out of vascular smooth-muscle cells, collagen and proteoglycan deposition with medial-wall fibrosis and thickening, and relative sparing of the endothelial-cell coating.36 Loss of medial cells is associated with a blunted vasodilator response. Our medical findings also show reduced vascular compliance, with elevated systolic and diastolic blood-pressure levels and an increased arterial augmentation rate. Peripheral vascular disease, with reduced ankleCbrachial indexes and vessel occlusion, occurred in two children (Fig. 3B and 3F). Endothelial function was reasonably maintained; brachial-artery reactivity was normal. PR22 One possible therapy for HutchinsonCGilford progeria syndrome would involve inhibition of farnesyl transferase activity to prevent the long term anchoring of progerin to the inner nuclear membrane. This treatment normalizes the nuclear morphologic features of fibroblasts in HutchinsonCGilford progeria syndrome30,37C39; in the transgenic mouse model,36 it maintains vascular smooth-muscle cells and decreases proteoglycan.