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Progeria

Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is an extremely rare genetic disorder where symptoms resembling aging are manifested at a very early age. Progeria is one of several progeroid syndromes which mimic physiological aging such as Wiedemann-Rautenstrauch syndrome or Werner syndrome. The disorder has a very low incidence rate, occurring in an estimated 1 per 8 million live births. Kids born with progeria typically live to their mid-teens to early twenties, many die from strokes and heart attacks. It is a genetic condition that occurs as a new mutation in the LMNA gene, and is rarely inherited, as patients usually do not live to reproduce. The disease affects both sexes and all races equally.

 

The LMNA gene mutation causes cells to express an abnormal version of the Lamin A protein. When cells use this protein, called progerin, they break down more easily. Lamin A is a protein crucial for the stability of the cell nucleus and involved in many essential nuclear functions.  Progerin builds up in many cells of kids with progeria and is known to be responsible for many of the characteristics of the disease.


Scientists are particularly interested in progeria because it’s revealing clues about the normal process of aging. Children with progeria live very normal lives and the only aspects that prevent them from doing anything “normal” is their height and issues with stiff joints. Progeria was first described in 1886 by Jonathan Hutchinson. It was also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson–Gilford progeria syndrome. Unlike many genetic mutations, progeria isn’t passed down in families. Rather, the gene change is a chance occurrence that researchers believe affects a single sperm or egg just before conception. Neither parent is a carrier, so the mutations in the child’s genes are new (de novo).

Symptoms

Most kids with progeria look healthy when they’re born, but they start to show signs of the disease during their first year. The earliest symptoms may include a failure to thrive and a localized scleroderma-like skin condition. As children with progeria get older, they get diseases you’d expect to see in people age 50 and older such as: limited growth, full-body alopecia (hair loss), and a distinctive appearance (a small face with a shallow recessed jaw, and a pinched nose).

 

Signs and symptoms of this progressive disease tend to become more marked as the child ages. Later, Progeria causes wrinkled skin, atherosclerosis, kidney failure, loss of eyesight, and cardiovascular problems. Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is prevalent. Kids diagnosed with this disorder usually have small, fragile bodies, like those of elderly people. Their faces are usually wrinkled, with a larger head in relation to the body, a narrow face and a beak nose. Prominent scalp veins are noticeable (made more obvious by alopecia), as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population. Progeria doesn’t affect a child’s intelligence or brain development at all.

Treatment

Presently, there is no cure for progeria. Kids can be treated with drugs called FTIs (farnesyltransferase inhibitors), which were initially developed to treat cancer. These drugs improve some aspects of the disease, such as bone structure, arterial stiffness, and increase estimated lifespan by at least 1.6 years.  Starting in 2007 a clinical trial was conducted with an FTI, Lonafarnib and in 2009 this trial was expanded to a “Triple Trial” with the addition of two more drugs, Pravastatin and Zoledronate.  The “Triple Trial” ran for 5 years, originally with 45 children in 24 countries and was subsequently expanded to 80 kids after a protocol change to switch back to just Lonafarnib.  All 3 drugs in the “Triple Trail” block production of the farnesyl molecule which is needed to create progerin.

 

In 2016 a new clinical trial was started that combines Lonafarnib with Everolimus.   Everolimus is a derivative of Rapamycin.  Rapamycin is what’s known as an mTOR inhibitor and appears to allow cells to more rapidly clear out the toxic progerin protein.  Rapamycin has been shown to increase the life span of non-Progeria mouse models.  The hope is that since Everolimus works is a different biological pathway than Lonafarnib the two drugs together will have an significant improvement in Progeria.

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