Hutchinson-Gilford Progeria Treatment & Management

Updated: Feb 08, 2017
  • Author: Kara N Shah, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Treatment

Approach Considerations

Pharmacologic approaches to the treatment of Hutchinson-Gilford progeria syndrome (HGPS) may involve attempts to reduce the expression or accumulation of progerin and promote autophagy.

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Medical Care

To date, there is no approved therapy for HGPS.

In vitro, exposure of cultured HGPS fibroblasts to rapamycin, a macrolide antibiotic that has been shown to regulate aging-related cellular pathways, and its analog temsirolimus, has been demonstrated to prevent or reverse nuclear blebbing, retard cellular senescence, enhance autophagic degradation of progerin, and delay the development of cellular senescence, suggesting that it may be a useful therapy for children with progeria. [34, 35, 36, 37, 38] The addition of all-trans retinoic acid to low-dose rapamycin reduces the expression of progerin and prelamin A in cultured fibroblasts and suggests an additional pharmacologic treatment for progeria. [39]

Careful monitoring for cardiovascular and cerebrovascular disease is essential. The use of low-dose aspirin is recommended as prophylaxis against cardiovascular and cerebrovascular atherosclerotic disease.

Physical and occupational therapy can help to maintain physical activity and an active lifestyle. The use of hydrotherapy may be particularly effective in improving joint mobility and minimizing symptoms of arthritis.

Infants with HGPS may exhibit poor feeding. Provision of adequate nutritional intake may require placement of a gastrostomy tube for supplemental enteral feeding. In older children, the daily consumption of high-energy supplements is recommended, along with careful monitoring of growth and nutrition.

The use of growth hormone has been used to decrease catabolic demands and augment weight gain and linear growth in a small number of patients with progeria. [40]

Sulforaphane, an antioxidant derived from cruciferous vegetables, has been demonstrated to stimulate proteasome activity and autophagy in cultured HGPS fibroblasts, to enhance progerin clearance by autophagy, and to restore a normal cellular phenotype. [41]

In vitro studies also suggest a possible role for the use of farnesyltransferase inhibitors (FTIs) in HGPS. [42] FTIs appear to promote the release of the mutant prelamin A (preprogerin) from the nuclear membrane, allowing it to be correctly incorporated into the nuclear lamina, thus correcting the structural and functional nuclear defects, although it remains to be determined whether use of FTIs also has an effect on the abnormalities seen in HGPS that result from loss of normal lamin A function.

In vivo studies using FTIs in transgenic mouse models have demonstrated encouraging results with regards to prevention of the cardiovascular complications seen in progeria [43] as well as reversal of the cutaneous manifestations [44] and overall improvement in many of the phenotypic features of progeria, including increased longevity. [45, 46]

Treatment of transgenic mice expressing progerin in the epidermis with FTI-276, a farnesyltransferase inhibitor, or a combination of pravastatin, a lipid-lowering agent, and zoledronic acid, an agent used to increase bone mineral density, has been shown to reverse the morphological nuclear abnormalities that are seen in HGPS. [47]

Results from a clinical trial of lonafarnib, an FTI, in progeria have indicated that treatment with lonafarnib may improve weight gain, increase bone mineral density, reduce vascular stiffness, and result in improved sensorineural hearing in patients with progeria. [48] Lonafarnib treatment has also been shown to reduce the frequency of clinical stroke, headaches, and seizures. [49]

Results from a clinical trial that combined use of lonafarnib with two additional protein farnesylation inhibitors, pravastatin and zoledronic acid, demonstrated increased bone mineral density without any additional cardiovascular benefit as compared with lonafarnib monotherapy. [50]

Preliminary in vitro studies using transfection of modified oligonucleotides that target the cryptic splice site that occurs in patients with the common 1824C-->T mutation have also produced encouraging results. Transfection of an exon 11 antisense oligonucleotide reduced lamin A expression in wild-type mice and progerin expression in an HGPS mouse model. [51] By eliminating the production of the mutant LMNA mRNA and protein, normal nuclear morphology is restored, with resultant normalization of heterochromatin structure and gene expression. These nascent studies provide early support for the rationalization of genetic therapy for HGPS patients.

In vitro, use of rapamycin, a macrolide antibiotic, and its analog temsirolimus, has been demonstrated to prevent nuclear blebbing, enhance autophagic degradation of progerin, and delay the development of cellular senescence, suggesting that it may be a useful therapy for children with progeria. [34, 35, 36, 37, 38]

Patients, families, and physicians may obtain further information, including opportunities for possible enrollment in clinical trials, through the Progeria Research Foundation.

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Consultations

Appropriate care for children with HGPS requires coordinated care from several specialists.

Pediatric cardiologists provide regular assessment of cardiovascular status, including monitoring and treatment for early atherogenic cardiac disease.

Physical and occupational therapists can develop individualized physical therapy programs to help to maintain physical activity, coordination, and flexibility.

Dermatologists and/or geneticists may be the first specialists to evaluate an infant with suspected HGPS and can perform diagnostic testing, including genetic mutation analysis and skin biopsies, as needed.

Pediatric gastroenterologists, feeding therapists, and nutritionists can aid in diagnosing and treating feeding disorders and failure to thrive.

Pediatric dentists with experience in treating children with dental anomalies can be helpful. Routine fluoride supplementation should be provided to minimize the risks of dental caries. Regular, gentle dental care minimizes the development of periodontal disease.

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Diet

Infants and children with HGPS may experience feeding difficulties and failure to thrive. The use of age-appropriate nutritional supplements is recommended.

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Activity

Children with HGPS do not require activity restrictions. With adequate supervision, most children are able to experience a wide range of physical activities.

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