What Is Progeria?

Introduction

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, segmental "premature ageing" disease that is invariably fatal. It is commonly known as progeria. A genetic mutation is the disease's aetiology. Signs of ageing include wrinkles and baldness caused by progeria.

Are you intrigued by the mysterious world of progeria? Explore the genetics, current research causes and treatment. Continue reading for a thorough knowledge of this unusual ailment and its impact on those affected.

Children with HGPS display characteristics that could provide an understanding of the ageing process at both the cellular and organismal levels. Early childhood presentations generally vary by growth and dermatological findings. Atherosclerotic cardiovascular disease and strokes account for the majority of morbidity and death in children with HGPS, with deaths occurring at an average age of 14.6 years. 

Progeria, Hutchinson-Gilford syndrome, and progeria of childhood are other names for HGPS.¹ Drs. Hastings Gilford and Jonathan Hutchinson initially described HGPS in 1897 and 1886, respectively (Gilford, 1904; Hutchinson, 1886). Its cause remained a medical mystery for over a century. 

Gilford categorised the illness as a premature ageing syndrome because of the patients' general ageing-related characteristics and the presence of age-related symptoms such as hair loss, joint contractures, absence of subcutaneous fat, atherosclerosis-like cardiovascular disease, and childhood heart attacks and stroke deaths (Merideth et al., 2008).

According to research on disease gene mapping, a mutation in LMNA causes HGPS, an autosomal dominant, sporadic disease (De Sandre-Giovannoli et al., 2003; Eriksson et al., 2003). The proteins lamins A and C, which are essential structural components of eukaryotic nucleus cells, are produced by this gene. HGPS belongs to a class of disorders known as laminopathies, caused by mutations in different regions of the LMNA gene that cause a broad range of overlapping illnesses.²

How often does progeria occur? 

With an incidence of 1 in 8 million births, HGPS is a rare condition. However, because many cases probably go undetected or are misdiagnosed, the exact rate has been estimated to be closer to 1 in 4 million births. 

Race

97% of patients reported are White. This racial discrepancy's cause is uncertain.

Sex

HGPS has a 1.5:1 assigned male at birth (AMAB)-to-assigned female at birth (AFAB) ratio, with a slight AMAB bias.

Age

While many affected children come with sclerodermatous skin abnormalities, clinical signs of HGPS may not be identified or apparent at birth. It may take until the child is 6–12 months old or older to see the distinctive facial features' cutaneous and musculoskeletal manifestations.^3,4

Clinical features

The clinical aspects are listed in the graphic below, along with comprehensive details as follows. Clinical characteristics that emerge in childhood and reflect certain aspects of accelerated ageing define classic and non-classic genotype HGPS. Progeria children appear normal at birth and in the first few months of life. Clinical features include:⁶

Created by: Deepika Rana (Created with BioRender.com)

Diagnosis

Several screening techniques serve to diagnose HGPS. Here is a synopsis of the steps involved:^3,4

Physical examination

Together with a comprehensive clinical evaluation, a meticulous physical examination determines the distinctive characteristics of HGPS.

Genetic testing

Phenotype recognition combined with a progerin-producing mutation in the LMNA gene, either at the exon 11 intronic border (atypical form) or within exon 11 (classic type), is the diagnostic criteria for HGPS.

Imaging studies

Findings from radiography typically appear in the first or second year of life and are related to the thorax, phalanges, skull, and long bones. 

Computed tomography (CT) and magnetic resonance imaging (MRI) revealed many craniofacial structural bone and soft tissue abnormalities. Brain magnetic resonance angiography (MRA) establishes cerebrovascular occlusive disease. Checking for coronary artery disease and congestive heart failure should be done using serial electrocardiography (ECG) and echocardiography.

Biopsy findings

Scleroderma features emerge from skin biopsy specimens from firm, sclerotic regions.^3,4

Treatment and management

HGPS treatment and management entail a multidisciplinary approach. 

Pharmacological treatment

• Protein farnesyltransferase inhibitors (FTIs) are the most often utilised therapeutic medicines among various pharmacological techniques. Progeria symptoms and nuclear scaffolding breakdown improve by blocking protein farnesylation
• The finding that lonafarnib therapy enhances the bone structure, auditory status, and neurologic function of children with HGPS lends credibility to this
• Given the potential for cardiotoxicity and safety issues associated with long-term FTI usage, a clinical trial conducted over the past ten years has investigated the use of lonafarnib in combination with pravastatin and zoledronic acid
• Of the patients, 71% have completed the primary result after receiving the triple therapy. Patients benefit from increased bone mineral density due to the triple therapy.

Nucleic acid therapy

• Over 40% of the examined publications that reported preclinical and clinical trials used nucleic acid therapy as an option for treating HGPS 
• Neonatal genetic modification, antisense oligonucleotide (ASO) treatment, CRISPR/Cas9-based therapy, and ex vivo genetic manipulation are the documented strategies to carry out the procedure. It is necessary to administer the intervention before birth

Cardiovascular management

• It's vital to monitor for cardiovascular and cerebrovascular diseases. Individuals must take low doses of aspirin to avoid atherosclerotic brain and heart disease.

Physical and occupational therapy

• Maintaining an active lifestyle and physical activity can be aided by physical and occupational therapy. Hydrotherapy can relieve arthritis symptoms and improve joint flexibility.

Medical experts' assistance

• Children with HGPS require coordinated assistance from many professionals, such as paediatric dentists, cardiologists, gastroenterologists, physical and occupational therapists, dermatologists, geneticists, and nutritionists. 

Psychosocial support

• Progeria patients and their families benefit from psychological services like counselling and support groups. Providing coping mechanisms and attending to mental health are essential components of encompassing care

Diet

• Children and infants with HGPS struggle to eat and may not develop. Age-appropriate nutritional supplements are advisable.^3,9

Prognosis

Patients diagnosed with HGPS typically live 13 years, although they can range in age from 7 to 27. Based on a median follow-up of 5.3 years from therapy beginning, data from the largest cohort of HGPS patients showed a mean survival of 14.6 years, with enhanced mean survival of 1.6 years in patients treated with a protein farnesylation inhibitor.³

Recent developments

Future discoveries and advancements in the knowledge and treatment of HGPS are anticipated due to continued research and participation in clinical trials. Pictured below is a list of a few of them.^10,11,12

PPMO, splicing, statins, and amino bisphosphonates

Created by: Deepika Rana (Canva)^10,11,12

Summary

Progeria is a rare and challenging genetic illness that needs constant attention, understanding, and assistance. A multidisciplinary approach to care, coping mechanisms, and medical experts' guidance all help to improve the quality of life for affected individuals. Enhanced support for impacted individuals and their families could be possible as medical science advances and therapies become more effective.