Getting older is the normal and inevitable path of life, and it’s accompanied by a lot of physical and mental changes along with the different age stages. Many people are willing to get older quickly in order to be able to do whatever they want. However, fast ageing can be dangerous and fatal sometimes, like having a certain disorder that makes the person age quickly, and this disorder is called progeria syndrome.

What is progeria syndrome?

• Hutchinson-Gilford progeria syndrome (HGPS) is a condition in which children suffer from premature ageing with obvious ageing phenotypes.¹
• This disorder is extremely rare, and it approximately affects 1 in every 20 million people, and it’s estimated that there are about 350-400 children who have progeria worldwide.¹

The cause of progeria syndrome

This condition is caused by a gene mutation that leads to the oversynthesis of a substance called progerin, which, in turn, disrupts and interferes with several nuclear and molecular processes and, in the end, causes the adverse effects of progeria syndrome.²

Progeria and heart disease

• HGPS patients suffer from several physical symptoms and medical problems, yet the most serious medical issue is cardiovascular alterations, especially atherosclerosis and cardiac electrical abnormalities, which lead to premature death mostly from myocardial infarction or stroke at an average age of 14.6 years.³
• Approximately one-third of HGPS patients have elevated diastolic and/or systolic blood pressure readings that might be associated with tachycardia. There are some cases who have peripheral arterial disease as well.⁴

Atherosclerosis and cardiovascular calcification

It has been found that cardiac complications in HGPS patients due to cardiomyopathy were rare after conducting the reviews of several autopsies, yet most of the cardiac manifestations were a result of coronary artery narrowing or occlusion that is related to atherosclerosis.⁵

Vascular smooth muscle cell (VSMC) loss and vascular fibrosis

Some specialists made a cardiovascular tissue comparison between the two groups in 2010. The first group was HGPS patients who died of myocardial infarction and the second was non-HGPS individuals with or without a cardiovascular disease, and their ages ranged from 1 month to 97 years. They found that atherosclerosis in both groups had some similar characteristics, such as extensive arterial calcification, severe stenosis, and atherosclerotic lesions, and these findings point to inflammation, calcification, and erosion or rupture.⁵

Vascular stiffening

HGPS is classified as the disease of vascular stiffening because numerous studies showed that all progeria patients suffer from vascular stiffening, which causes several changes and might lead to occlusive stenosis and peripheral vascular disease.⁵

Cardiac dysfunction

Several cardiac defects have been detected in HGPS patients through electrocardiography, and the most frequent abnormality that has been observed to be more prevalent with age is left ventricular (LV) diastolic dysfunction, which was thought to be caused by myocardial interstitial fibrosis and endocardial thickening. There are other less common cardiac alterations that were observed like LV hypertrophy and aortic valve calcification and dysfunction. Three-dimensional echocardiography was also applied to HGPS patients, and they found one case of diastolic dysfunction and another of aortic valve calcification, in addition to severe aortic stenosis and LV hypertrophy.⁵

As a conclusion, HGPS cardiovascular outcomes are characterised by generalised atherosclerosis, VSMC loss, vascular stiffening, calcification, fibrosis, cardiac repolarization abnormalities, LV diastolic dysfunction, and cardiac valve disease. All these manifestations probably have a role in the death of HGPS patients from myocardial infarction, stroke, or heart failure.⁵

• Progeria patients are susceptible to the aforementioned cardiovascular complications and strokes that might lead to several physical limitations, cognitive decline, or both, although they have normal serum cholesterol, LDL, and triglyceride.⁶
• Lonafarnib is the first drug that was approved by the FDA (Food and Drug Administration) for the management of HGPS⁵ because it has been proven that it improves vascular stiffness and can reduce fatal and non-fatal HGPS cardiovascular events and strokes, which, in turn, might lower the mortality rate, after indicating that cardiovascular issues are responsible for around 80% of death cases, and lonafarnib has also increased the life span from about 14.5 years to 17-19.5 years.⁶

Progeria symptoms

HGPS patients might have several symptoms and characteristics:

• Infants with HGPS usually have a normal weight at birth, and the disorder effects begin to occur during the first year. Patients start to lose subcutaneous fat and have trouble gaining weight, which leads to a distinctly low weight for height.⁶
• The head looks disproportionately larger than the face; narrow nasal ridge and tip; a small mouth; an unusual mandible position; micrognathia; a narrow airway; and rigid laryngeal structures, which cause a high-pitched voice.⁶
• Delayed tooth eruption and delayed loss of primary teeth.⁶
• Skin changes could have existed at birth and are present in all patients by the age of two. The skin might be taut, thickened, fibrotic, indurated, or rippled.⁶
• The patients’ fingers and toenails could be deformed or thickened. They also might suffer from eyebrow loss and sometimes the loss of eyelashes.⁶
• Hip dislocation could happen to HGPS patients, and it can be accompanied by hip necrosis. This condition causes hip pain, osteolysis in some particular bones, a thorax that has an abnormal shape, and mildly low bone density for such age.⁶
• Patients with HGPS don’t become sexually mature and they are also infertile.⁶
• They also are commonly affected by nocturnal lagophthalmos, which is the inability to fully close the eyes during sleep, and that could lead to corneal dryness, and they also might suffer from conductive hearing loss.⁶

Progeria diagnosis

The diagnosis of HGPS depends on both physical symptoms and signs, and gene-specific testing.⁶

There are other syndromes that contain some similar features to premature ageing, such as:⁶

• Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome)
• Acrogeria
• Hallermann-Streiff syndrome
• Petty-Laxova-Weidemann progeroid syndrome
• Mandibuloacral dysplasia
• Penttinen Syndrome
• POLR3A-related Wiedemann-Rautenstrauch syndrome
• PYCR1-related Wiedemann-Rautenstrauch-like syndrome
• Cockayne syndrome
• Gerodermia osteodysplastica
• Berardinelli-Seip congenital lipodystrophy
• Ehlers-Danlos syndrome, progeroid form
• Werner syndrome
• Nestor-Guillermo syndrome

Progeria management

There are several recommended evaluations to establish the progression of the disorder, which are:⁶

• Weight and height
• Electrocardiogram (EKG) and echocardiogram
• Carotid artery duplex scans
• MRI/MRA of the brain and neck
• Skeletal X-rays to evaluate for characteristic findings
• Orthopaedic evaluation
• Assessment of bone mineral density
• Occupational and physical therapy assessments
• Nutritional assessment
• Audiologic, ophthalmologic, and dental examinations
• Genetic counselling

The management contains several steps:⁶

• Targeted therapy: It was proven that lonafarnib is effective in the improvement of vascular distensibility, increasing bone rigidity and neurosensory hearing, decreasing headaches, and increasing the life span between 2.5 and 5 years on average
• Supportive care and the management of the disorder’s symptoms and outcomes
• Surveillance: It’s necessary to apply annual or semiannual measures and tests to the patients to observe if there is any improvement or regression in their condition

FAQs

How does progeria affect the heart?

HGPS causes several heart outcomes, especially atherosclerosis and cardiac electrical abnormalities, which lead to premature death mostly from myocardial infarction or stroke at an average age of 14.6 years.

What organs are affected by progeria?

A lot of organs and body characteristics can be impacted by progeria, such as head and face shape, airways, teeth, skin, finger and toenails, bone density, puberty and fertility, and ophthalmic issues.

What are the risk factors for progeria?

There are no specific, known risk factors for HGPS. However, the age of the father has been observed to be a possible risk factor. Moreover, if you’ve had a child with progeria, there is a slightly higher chance than other people to have a second one with progeria as well.

Summary

Progeria, or HGPS, is a genetic disorder that causes premature ageing with other serious symptoms and complications. The most severe outcome of progeria is the cardiovascular alterations, which are responsible for most of the death cases in progeria patients. Lonafarnib is an FDA-approved medicine that increases the lifespan of patients from 2.5 to 5 years. Patients with HGPS need regular and continuous surveillance in addition to managing the complications.