From the Guidelines
Progeria, a rare genetic disorder characterized by accelerated aging, is best managed with lonafarnib (Zokinvy), which can extend lifespan by blocking the accumulation of defective proteins, as evidenced by recent studies 1.
Overview of Progeria
Progeria is caused by a mutation in the LMNA gene, producing an abnormal form of the protein lamin A called progerin, which accumulates in cells, causing them to become unstable and leading to premature aging symptoms. Children with progeria typically appear normal at birth but begin showing signs within their first year, including growth failure, hair loss, aged-looking skin, joint stiffness, and cardiovascular problems.
Diagnosis and Monitoring
The diagnosis of progeria can be challenging, but recent advances in DNA methylation aging clocks have shown promise in monitoring the disease progression. For instance, the "Skin-Blood" clock has been devised to estimate advanced age in Hutchinson-Gilford progeria syndrome with higher sensitivity for specific tissue types 1. This clock can potentially identify age acceleration in progeroid disorders, enabling early intervention and management.
Treatment and Management
Until recently, treatment for progeria was primarily supportive, focusing on managing symptoms. However, with the FDA approval of lonafarnib (Zokinvy) in 2020, there is now a medication specifically for progeria that can extend lifespan by blocking the accumulation of defective proteins. The use of lonafarnib (Zokinvy) is recommended as the primary treatment for progeria, given its potential to improve outcomes and extend lifespan 1.
Prognosis and Quality of Life
The average life expectancy for those with progeria is about 14-15 years, with heart disease being the most common cause of death. Despite its devastating effects, progeria is extremely rare, affecting approximately 1 in 4 million newborns worldwide. With proper management and treatment, it is possible to improve the quality of life for individuals with progeria and extend their lifespan. Early diagnosis and intervention are crucial in managing progeria, and the use of lonafarnib (Zokinvy) and other supportive treatments can significantly improve outcomes 1.
From the Research
Definition and Characteristics of Progeria
- Progeria, also known as Hutchinson-Gilford progeria syndrome (HGPS), is an extremely rare and fatal disease characterized by premature aging symptoms 2, 3, 4.
- It is caused by a de novo point mutation in the LMNA gene, leading to the production of a truncated toxic form of lamin A, called progerin 2, 5, 4.
- Children with HGPS exhibit phenotypes that may give insights into the aging process at both the cellular and organismal levels 2.
Clinical Presentation and Morbidity
- Initial presentation in early childhood is primarily based on growth and dermatologic findings 2.
- Primary morbidity and mortality for children with HGPS is from atherosclerotic cardiovascular disease and strokes, with death occurring at an average age of 14.6 years 2, 3, 6.
- Strokes in HGPS can occur downstream of carotid artery and/or vertebral artery occlusion, stenosis, and calcification, with prominent collateral vessel formation 2.
Treatment Strategies
- A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease 3.
- A combination therapy of pravastatin, zoledronic acid, and lonafarnib was evaluated, showing improved per-patient rate of weight gain or carotid artery echodensity 3.
- A targeted antisense therapeutic approach using antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) has shown promise in reducing progerin transcripts in patient fibroblasts and increasing lifespan in a transgenic mouse model of HGPS 5.
Potential Therapies and Future Directions
- Several landmark studies have revealed novel mechanisms underlying cardiovascular pathologies in HGPS, and implicate future potential therapies for HGPS, and possibly physiological aging 6.
- Recent medical advances and treatment approaches for patients affected with HGPS have been reported, highlighting possible mechanisms involved in normal aging 4.