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Background Hutchinson–Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription.
Methods We enrolled 15 children between 1 and 17 years of age, representing nearly half of the world's known patients with Hutchinson–Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006.
Results Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle–brachial indexes, and adventitial thickening.
Conclusions Establishing the detailed phenotype of Hutchinson–Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00094393
[ClinicalTrials.gov]
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Source Information
From the National Human Genome Research Institute (M.A.M., A.C.M.S., A.G., F.S.C., W.A.G., W.J.I.); Intramural Office of Rare Disease, Office of the Director, National Institutes of Health (M.A.M.); National Heart, Lung, and Blood Institute (V.S., E.G.N., R.O.C.); the Departments of Rehabilitation Medicine (M.B.P., B.S.), Nutrition (J.G.), and Nuclear Medicine (J.C.R.), Clinical Center, National Institutes of Health; National Institute on Deafness and Other Communication Disorders (C.C.B., C.Z., H.J.K.); National Eye Institute (B.P.B.); National Cancer Institute (M.L.T.); National Institute of Dental and Craniofacial Research (D.L.D., T.C.H.); and National Institute of Child Health and Human Development (J.A.Y.) — all in Bethesda, MD; Warren Alpert Medical School, Brown University, Providence, RI (L.B.G.); Children's National Medical Center (S.C., A.G.) and Georgetown University Medical Center (A.C.M.S.) — both in Washington, DC; Center for Chronic Illness and Disability, George Mason University, Fairfax, VA (L.H.G.); and Brigham and Women's Hospital, Boston (M.G.-H.).
Address reprint requests to Dr. Gahl at Bldg. 10, Rm. 10C-103, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1851, or at bgahl{at}helix.nih.gov.
Related Letters:
Hutchinson–Gilford Progeria Syndrome
Ershler W. B., Ferrucci L., Longo D. L., Ortiz A., Merideth M. A., Collins F. S., Gahl W. A.
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N Engl J Med 2008;
358:2409-2411, May 29, 2008.
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