HUTCHINSON-GILFORD PROGERIA SYNDROME

Disease

Brief Summary

Hutchinson–Gilford progeria syndrome is a rare genetic disease that causes premature aging. Rapid aging of different tissues causes death by teenage years, normally due to cardiovascular complications.

Source

Image:

Child affected by HGPS

Frequency

This condition is very rare; it is reported to occur in 1 in 4 million newborns worldwide. More than 130 cases have been reported in the scientific literature since the condition was first described in 1886.

Inheritance

The majority of patients with Hutchunson-Gilford progeria syndrome have acquired from their parents heterozygous dominant mutations in the LMNA gene. there have been reports suggesting an Autosomal Recessive Inheritance but no solid evidence that can support Hutchinson-Gilford progeria syndrome being autosomal recessive

Brief Summary

History of Disease

In 1886, Jonathan Hutchinson was the first to describe progeria. It was described independently by Hasting Gilford in 1897. The disorder was later called Hutchinson–Gilford Progeria Syndrome.

Pathogenesis

The origin of progeria is a mutation in the lamin A gene located in chromosome number 1—responsible for fabricating structural proteins that help keep the cell nucleus sturdy and the genome intact. The mutated lamin A protein “progerin” destabilizes the cell nucleus, progerin damages DNA by slowing replication, such stress is detected by special proteins like cGAS and STING that activate a type of immune response that leads to cellular decline.

In order to have the disease, only one of the mutated genes is required out of the two copies of the LMNA genes, the disease is dominantly inherited. This mutation is not normally passed on from generation to generation, but is more likely to occur when the child is born.

Image:

Pathogenesis of HGPS

Source

Symptoms

Slowed growth of limbs

The face is narrow with a small lower jaw, thinner lips and beaked-like nose.

Head disproportionately large for the face.

Loss of hair, eyelash and eyebrows

The eyes protrude and incomplete closing of the eyelids.

Veins are visible.

High-pitched voice.

Signs and symptoms also include health issues:

It can severely progressive to heart and blood vessel disease

The skin on the trunk and extremities may harden and tighten

The tooth formation is delayed

Hearing loss

Loss of muscle mass and fat under the skin

Fragile bones

Stiff joints

Dislocation of hips

Insulin resistance

Social Concerns

People with progeria may experience discrimination and social exclusion in every aspect of their lives for their physical appearance, hence, the reason why patients prefer to stay in a hospital or other medical care facility.

Treatment

Diagnosis of progeria largely depend on the basis of physical symptoms, however, genetic testing may be conducted which may enable physicians to diagnose the child at an earlier age and facilitate early management of the disease.

Treatment with calcitriol, a form of vitamin D, may rescue cells from the progerin that causes glitches in DNA replication, hence, it plays a role in repairing damaged DNA and slowing progeria cell decline.

A high-fat diet can vastly improve progeria mice—namely, by doubling their lifespan. This suggests that metabolism might play a more important role in disease pathology, and nutritional approaches could be powerful therapeutic tools in both mice and humans.

Farnesyltransferase inhibitor- a class of cancer experimental drug that may improve cardiovascular status, bone structure, and audiological (hearing) status in affected children with progeria.

There is currently no cure for progeria, however, management focuses to ease or delay some individual signs and symptoms of the condition.

Low-dose aspirin.
Physical and occupational therapy
Maintain adequate nutrition.
Dental care

Source

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Treatment for HGPS

Clinical Trials

Title:

A Study of Zoledronic Acid, Pravastatin, and Lonafarnib for Patients With Progeria

Intervention:

Drug: Lonafarnib, Zoledronic Acid & Pravastatin

Phase:

Phase 2

Procedure:

This is a single-arm open-label feasibility study. Two oral medicines (pravastatin and lonafarnib) and one intravenous (IV) medication (zoledronic acid) will be given at doses and schedules similar to those used in pediatrics. These medicines all target various parts of the farnesylation pathway. This approach will be open to patients with genetically diagnosed progeria. The treatment will last for four weeks and may be prolonged based on tolerability. The feasibility of this treatment regimen will be evaluated in the first four weeks of this trial. Patients can be treated with this regimen for up to 6 months if it is tolerated for 4 weeks.

Goal:

This study will investigate the feasibility of utilizing three drugs (zoledronic acid, pravastatin, and lonafarnib) to suppress farnesylation of abnormal lamin, the disease-causing protein in Progeria, for a minimum of four weeks in individuals with Progeria.

Further details at:

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00879034

https://clinicaltrials.gov/ct2/show/NCT00879034

Clinical Trials

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