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A Closer Look at Progeria Syndrome

Study of this rare disorder provides insight into the mechanisms of aging.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes rapid, premature aging and early death from cardiovascular disease and stroke (median age at death, 13 years). HGPS is almost always caused by a de novo point mutation in the lamin A gene (LMNA) that produces a truncated mutant protein called progerin. Progerin disrupts the nuclear membrane, alters transcription, and appears to accumulate in cells with normal aging.

These authors prospectively studied 15 children aged 1 year to 17 years who make up nearly half the world’s HGPS patients. The mean age at diagnosis in these children was 19 months; diagnosis was based on failure to thrive and skin abnormalities in all 15. Examination confirmed classic clinical features of HGPS: sclerotic skin, joint contractures, bone abnormalities, alopecia, decreased body fat, and growth impairment. Cardiovascular disease, transient ischemic attack, seizures, and arteriosclerosis were also documented in these patients. Newly described in this report are findings of prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, decreased range of joint motion, farsightedness, low-frequency conductive hearing loss, speech deficits, and oral motor and dental abnormalities.

The authors refer to earlier findings in transgenic mouse models and in molecular studies of progeria that inhibition of farnesyl transferase prevented the permanent anchoring of progerin to the inner nuclear membrane. This action normalized the nuclear morphology of fibroblasts and suggests a possible therapy for HGPS. An open-label clinical trial of farnesyl transferase inhibition is currently underway in patients with HGPS.

Comment: HGPS is a rare, striking, and tragic genetic disorder in children, with manifestations that are difficult to comprehend. However, two universal biologic processes of life, growth and aging, are brought into focus by study of this condition. If the mysteries of suppressed growth and accelerated aging in this condition are solvable, we not only might bring hope to affected families but also may even find the fountain of youth.

— Mary Wu Chang, MD

Published in Journal Watch Dermatology February 6, 2008

Citation(s):

Merideth MA et al. Phenotype and course of Hutchinson–Gilford progeria syndrome. N Engl J Med 2008 Feb 7; 358:592.

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