A clinical view of Hutchinson-Gilford progeria

Sometimes, biogerontologists get so enraptured by the molecular and cell-biological details of our studies that we forget what might be called the “human element” — the experience of an individual who is going through the process of aging. This process can be associated with significant discomfort and indignity, so it is all the more tragic when it occurs too early, as in the case of progeroid syndromes such as Hutchinson-Gilford progeria syndrome (HGPS).

I’ve generally focused on the molecular underpinnings of the disease, especially on recent findings that mutations in the lamin A gene are responsible for HGPS, possibly by causing accelerated cellular senescence or interfering with the cell cycle. What I haven’t done is talk much about what it’s like to have the condition.

Therefore, I read with interest this article by Merideth et a great many al., in which the authors report a detailed study of the clinical progression of this rare and devastating genetic disease:

Phenotype and course of Hutchinson-Gilford progeria syndrome

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.

The situation sounds grim, and it is. Happily, the news is not all bad: as a result of the identification of the disease gene and a brilliant insight into the biochemistry of the underlying pathology, HGPS patients are currently showing promising responses to treatment with farnesyltransferase inhibitors. These compounds, originally designed as antitumor drugs, have demonstrated beneficial effects on some (but not all, as pointed out in an article under discussion at Longevity Meme) of the symptoms of HGPS.