Progeria-Hutchinson-Gilford Progeria Syndrome (HGPS)- Pathogenesis, Clinical Features and Treatment

Progeria is a rare genetic syndrome characterized by premature aging.  It is also called Hutchinson-Gilford Progeria Syndrome (HGPS). It is fatal and inherited in nature. It is a rare syndrome with incidence recorded in one in four million live births, and its prevalence is one in 20 million living individuals. The syndrome does not show a predilection for gender, region, or ethnicity.

Etiopathogenesis of Progeria

• It is a sporadic autosomal dominant genetic disorder caused by a mutation in chromosome 1q.  The cause of the mutation is unknown, and the defective gene is less likely to be passed on to progenies as the affected baby does not live into adulthood.  The disease mechanism is dominant-negative in expression. The abnormal protein does not cause pathological changes. But the abnormal protein expressed due to mutation affects the protein expressed by unmutated alleles. The causative mutation occurs in the gene LMNA that codes for Lamin A/C. It activates an internal alternative splice site that causes the deletion of 150 base pairs in the 3’ end of exon 11 of the LMNA gene. Common mutations include- A single C to T transition at nucleotide 1824 in 90% of the cases. Single base mutations in the intron 11 splice donor site.

WHAT CAUSES PROGERIA?

• The activation of the splice site affects the gene expression at translation and post-translational modification of the protein, resulting in a shorter abnormal protein called progerin.  This progerin has 50 amino acids less at the C-end.  In normal individuals, the LMNA gene expresses functional Lamin A/C proteins through transcription, translation, and post-translational modifications. The proteins reach the inner membrane of the nucleus in cells and play a role in following cellular functions- Nuclear scaffolding, DNA replication, mRNA translation, signalling and control of apoptosis.  In a patient with progeria, mRNA translation from the defective gene produces shortened protein. At the stage of post-translational modification, the protein undergoes farnesylation, resulting in progerin.  Progerin damages the nuclear membrane, causing premature aging in the patient. 

Farnesylation Process

• It is a post-translational modification of the LMNA gene, which follows the following steps. The protein enters the endoplasmic reticulum or golgi complex from the ribosome. The enzyme farnesyl transferase mediates the addition of the farnesyl group into a cysteine amino acid residue at the c-terminal end of the protein. The cysteine has a tripeptide denoted by AAX.
• In the second step, a zinc-based metallopeptidase ZMPSTE-24 or RAS converting enzyme-1 (RCE-1) cleaves the tripeptide from the protein. In the third step, Isoprenylcysteine Carboxyl Methyl Transferase (ICMT) enzyme adds a methyl group to the carboxyl end of the cysteine amino acid residue.  In the final step, ZMPSTE-24 cleaves the protein removing carboxy-terminal 15 amino acids, producing unfarnesylated, unmethylated mature Lamin A protein. In patients with progeria, the site of final cleavage is absent due to the lack of 50-amino acid peptide, which contains the cleavage site. It results in the production of farnesylated and methylated immature proteins called progerin. A disease-modifying drug called lonafarnib inhibits the first step, preventing progerin production. It reduces the effects of progerin on functional Lamin proteins. 

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METHYLATED FARNESYL GROUP

• It is a lipophilic moiety that facilitates the intercalation of proteins into the inner nuclear membrane. In normal individuals, the enzymatic removal of the methylated farnesyl group releases prelamin from the nuclear membrane, rendering it soluble for autophagic degradation. The farnesyl group remains anchored to the membrane in individuals with progeria and binds with other proteins. It results in blebbing of the nucleus, disruption of mitosis, and altered gene expression. In addition, progerin retains a methyl moiety. 

Also Read: The Genetics of Down Syndrome

CLINICAL FEATURES OF PROGERIA

• Progeria affects multiple organs and causes anatomical abnormalities. But it does not affect IQ, gastrointestinal tract, CNS, liver, thyroid, kidneys, and immune system.

1. DERMATOLOGICAL MANIFESTATIONS

Skin is the first organ to undergo pathological changes. Children lose hair resulting in alopecia on the head and eyebrows within the first few months of birth. Skin loses subcutaneous fat and becomes abnormally thin. They exhibit areas of mottled hyperpigmentation, sometimes alternating with hypopigmentation. Contractures in the hands associated with significant nail dystrophy are present in more than 60% of cases.

FAILURE TO THRIVE

• At birth, weight and height are normal or slightly less than normal. Within 1 or 2 years, weight and height drop significantly. Weight gain is more impaired than height gain. Due to the loss of subcutaneous fat, their sensitivity to temperature increases, and develops hypothermia. They experience pain when they jump or walk for a long time due to pathological changes in heels.  

2. OCULAR ABNORMALITIES 

• Ocular abnormalities result from skin tightening and a lack of subcutaneous fat around the eyes. Photophobia is common. Nocturnal lagophthalmos and exposure keratopathy may lead to corneal ulceration and scarring.  Reduced visual acuity is observed in advanced cases. Hence, a yearly ophthalmological examination is recommended to prevent worsening ocular conditions. Ocular lubricants and tape tarsorrhaphy at night help improve the symptoms. 

3. CRANIOFACIAL AND DENTAL ABNORMALITIES

• Craniofacial abnormalities are as follows: Loss of hair, prominent eyes, thin nose with a beaked or hooked tip, thin lips, mandibular hypoplasia produces micrognathia and retrognathia, ankyloglossia and median sagittal palatal fissure, delay in tooth eruption in primary and secondary dentation by 1.5 or 2 years. Crowded teeth with the abnormal site of tooth eruption in lingual, gingival, or anterior aspects of the gum. The appearance of secondary teeth before shedding of primary teeth, gum recession.

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4. BONY AND CARTILAGINOUS ABNORMALITIES

• Early features appear as early as three months of age: Acro-osteolysis of distal phalanges, shortened clavicle due to distal clavicular resorption, causing glenohumeral instability, thin and tapered ribs. Later features are as follows: Flaring of humeral and femoral metaphysis and constriction of the radial neck, normal bone age and spine development, (bone mineralization is normal, osteoporosis is insignificant), the severity and degree of joint contractures worsen with age. Peripheral quantitative computed tomography (pQCT) of radius shows changes consistent with skeletal dysplasia. Bone mineral density on the DEXA scan shows insignificant osteoporosis. About 80% of affected individuals have normal bone density until disuse atrophy overcomes at 15-17 years of age. Hip abnormalities- Coxa valga is an increased angle between the femoral neck and head to more than 125 degrees. Coxa magna refers to a femoral head larger than the acetabulum. These two-cause hip dysplasia and instability, which leads to osteoarthritis and recurrent dislocation in the hip joint.  

5. HEARING ABNORMALITIES 

• Low-tone conductive deafness is common due to a stiff tympanic membrane or middle ear defect. Overall, hearing ability is unaffected.

6. SEXUAL DEVELOPMENT 

• Sexual development is absent in males and has not been studied extensively. Most females show the development rating of Tanner 2 and seize to develop further. Menarche occurs at the age of about 14 years. It may cause severe bleeding leading to anemia. 

7. CVS INVOLVEMENT 

• Primary vasculopathy causes early atherosclerosis plaques in large arteries. It increases the risk of stroke, TIAs, angina, and myocardial infarction. Atherosclerosis may cause congestive cardiac failure caused by left ventricular diastolic dysfunction, which is more common than systolic dysfunction. Affected children fail to thrive and eventually suffer cardiac ailments, a common cause of death. 

Also Read : Pigmentary Disorders in Children

CAUSES OF DEATH

• The average life expectancy of babies diagnosed with progeria is 14.5 years, which may vary from 5 to 20 years. Cardiovascular involvement is the cause of about 80% of deaths due to progeria, usually due to congestive cardiac failure related to atherosclerosis. Subdural hematoma causes 15% of deaths. Stroke contributes to 1—3% of deaths. The remaining deaths occur during operative procedures to rectify the abnormalities. Progeria does not affect CNS directly because the brain produces a micro-RNA called mi-RNA-9 that downregulates progerin expression.

INVESTIGATIONAL FINDINGS IN PROGERIA

• In more than 90% of cases, serum leptin is low. In more than 60%, insulin resistance causes mild hyperglycaemia. HDL and adiponectin levels decrease with age. Other biochemical tests, including renal and liver function tests, show values within the normal range. 

TREATMENT OF PROGERIA 

• Lonafarnib: Lonafarnib is a farnesyltransferase inhibitor that prevents the adverse effects of progerin. Studies have shown the drug to improve cardiovascular ailments and overall mortality. However, it does not improve dermatological, dental, ocular, bony, and cartilaginous manifestations. Lonafarnib combined with mTOR inhibitor sirolimus is an experimental therapy. 2.Supportive therapy- Human recombinant growth hormone at 0.05 mg/Kg/day subcutaneously helps growth-related abnormalities and short stature. Low-dose, 2 mg/Kg/day of aspirin helps reduce the risk of cerebrovascular incidents.