International Journal of Pharma and Bio Sciences

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1 International Journal of Pharma and Bio Sciences HUTCHINSON-GILFORD SYNDROME (PROGERIA): A REVIEW SACHIN KUMAR 1 *, AMIT KUMAR 2, MOHIT SINGLA 1 AND ABHISHEK SINGH 3 1. K.N.G.D Modi Institute of Pharmaceutical Education & Research, Modinagar, Uttar Pradesh, India M.S. Ramaiah College of Pharmacy, Bengaluru, Karnataka 3. Meerut Institute of Engineering and Technology, Meerut, Uttar Pradesh *Corresponding author sonuniper@gmail.com ABSTRACT Progeria, also known as the Hutchinson-Gilford syndrome, is an extremely rare condition that was initially reported by Jonathan Hutchinson in 1886 and further described by Hastings Gilford in Hutchinson Gilford progeria syndrome is a disorder characterized by premature aging of postnatal onset. The main clinical and radiological features include alopecia, thin skin hypoplasia of nails, loss of subcutaneous fat, and osteolysis. Intelligence is not impaired. Early death is caused by atherosclerosis. Transmission is most likely from a sporadic autosomal dominant mutation. Clinical manifestations are evident by the first or second year of life and include the physical characteristics usually associated with the elderly. Mentally, patients are alert and attentive with normal intelligence and emotions. Histopathologic changes occur primarily in the skin, bone, and cardiovascular tissues, while other organs appear to be unaffected. Laboratory findings are unremarkable, with the exception of an increased urinary excretion of hyaluronic acid. Death results from cardiovascular abnormalities in the majority of cases and usually occurs between the ages of 10 and 15 years. KEYWORDS Hutchinson-Gilford progeria,, HGPS, HGP syndrome, premature senility syndrome, progeria of childhood, progeria, aging syndrome, premature aging, progeria syndrome, progeria INTRODUCTION (HGPS) is an extremely rare hereditary disease that affects the skin, musculoskeletal system, and vasculature. HGPS is characterized by signs of premature aging. The term progeria is derived from the Greek word geras, meaning old age. Significant morbidity and mortality result from accelerated atherosclerosis of the carotid and 1

2 coronary arteries, leading to premature death during the first or second decade of life. Progeria is an extremely rare, severe, genetic condition wherein symptoms resembling aspects of aging are manifested at an early age 1. The disorder has a very low incidence and occurs in one per eight million live births 2. Those born with progeria typically live about thirteen years, although many have been known to live into their late teens and early twenties and rare individuals may even reach their forties 3-4. It is a genetic condition that occurs as a new mutation and is not usually inherited, although there is a uniquely heritable form 5. This is in contrast to another rare but similar premature aging syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be expressed multiple times in a family line 6. Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging. Progeria was first described in 1886 by Jonathan Hutchinson and also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS). Disease name and synonyms 7 Progeria Progeria is a term recognized by many physicians as applying to individuals who appear prematurely aged. Misdiagnosis of HGPS is frequently made in patients presenting with some of the features of the syndrome, i.e. alopecia and skin with an aged appearance. Diagnosis criteria / definition Association of: Prematurely aged phenotype of postnatal onset Rapidly progressive growth failure Characteristic facies, alopecia, loss of subcutaneous fat, hypotrichisis, wrinkled skin with prominent superficial veins Stiffness of joints, osteolysis Early death by atherosclerosis 8. Clinical description Clinical manifestations are evident by the first or second year of life. The failure to grow and to gain weight at a normal rate usually appears abruptly during the first year of life and can recur later at times of illness. Linear growth tends to be about half the normal rate, and shows no rapid increase at perpubertal or pubertal ages. The weight defict is greater than the height defict. By the time growth failure can be noticed, the patients usually have a cranium which appears to be large in comparison with the face and the body. Intelligence and brain development is not impaired. The mean age of death is 14 years. This death is often secondary to coronary artery disease 9. Consistent clinical features include lower weight and less subcutaneous fat, craniofacial disproportion, micrognathia, prominent scalp veins, alopecia, pluckered bird appearance, abnormal teeth, pyriform thorax, short clavicles, horse riding stance, wide-based gait, coxa valga, thin limbs, prominent and stiff joints, and distal osteolysis 10. Other anomalies frequently present in Hutchinson-Gilford progeria are thin, wrinkled, sclerodermatous and brown spotted skin, hypotrichosis, absence of eyebrows and eyelashes, patent fontanels and sutures, beaked nose, circumoral cyanosis, thin lips, protruding ears with absent lobes, and dystrophic nails with short terminal phalanges. Autopsy reports have described varying degrees of generalized atherosclerosis, mainly involving the larger arteries. Coronary occlusions with myocardial infractions were found more frequently than cerebral vascular lesions 11. 2

3 DIAGNOSIS Many other premature aging syndromes, which are called progeroid syndromes and which also mimic senescence, need to be distinguished from progeria.neonatal progeroid syndromes are evident at birth and include wiedemannrautenstrauch syndrome, hallerman streiff syndrome and de barsy syndrome. Others, including mandibuloacral dysplasia or cockayne syndrome are diagnosed later in life, although they may have a neonatal onset 12. Diagnostic methods Imaging Studies Diagnosis currently depends upon recognition of clinical and radiographic findings. However, a truncating mutation within the lamin A gene has recently been reported in the majority of the Laboratory Studies Abnormalities in serum lipid levels are limited to low high-density lipoprotein levels, which are associated with atherosclerotic disease. Serum low-density lipoprotein and total cholesterol levels are normal in patients with (HGPS). Elevated levels of hyaluronic acid excretion are seen in the urine of patients with HGPS but are not diagnostic. The significance is unknown 15. Other Tests Serial ECG and echocardiography should be performed to monitor for coronary artery disease and congestive heart failure. Pathophysiology Patients with Hutchinson-Gilford progeria syndrome (HGPS) develop accelerated atherosclerosis of the cerebral and coronary patient with Hutchinson- Gilford progeria; this genetic anomaly may lead to molecular diagnosis of the disease. The characteristic radiological abnormalities are to be found in the skull, thoracic cage, long bones and phalanxes. The cranial bones tend to be hypoplastic and the fontanels and sutures remain open longer than expected. Wormain bones are common. Thinning and resorption of the distal clavicles is the most consistent abnormality to be found in the thorax. Narrowing of the posterior ribs is frequent. The long bones are slender with these cortices. Severe coxa vara is a consistent finding, and moderate genu valgum is frequently present. The progressive bone loss from the distal phalanxes of the fingers and toes is one of the hallmarks of the disease arteries. Unlike arteriosclerosis in the general population, however, in progeria, the only lipid abnormality is decreased high-density lipoprotein cholesterol levels. Patients with HGPS also develop other clinical signs of accelerated aging, including loss of subcutaneous fat and muscle, skin atrophy, osteoporosis, arthritis, poor growth, and alopecia. Interestingly, patients with HGPS do not develop other disease processes associated with aging, such as increased tumor formation, cataract development, or senility. In this sense, HGPS is considered a segmental progeroid syndrome in that it does not recapitulate all of the characteristic phenomena of aging. Extensive lipofuscin deposition, a marker for aging, is extensively distributed in patients with HGPS. Affected organs include the kidneys, brain, adrenal glands, liver, testes, and heart 16. Frequency International HGPS is a rare disease with a reported prevalence of 1 in 8 million births. The true 3

4 prevalence, however, has been suggested to be closer to 1 in 4 million births because many cases likely go undiagnosed or are misdiagnosed. The incidence in the Netherlands over the last century was 1:4,000,000. Approximately 100 cases of HGPS have been reported in the literature 17. Mortality/Morbidity Morbidity and mortality in persons with HGPS occur primarily as a result of atherosclerosis of the coronary and cerebrovascular arteries, with at least 90% of patient deaths directly related to complications of progressive atherosclerosis. The average life expectancy for a patient with HGPS is 13 years, with an age range of 7-27 years. Cardiovascular complications include myocardial infarction and congestive heart failure. Interstitial fibrosis, diffuse myocardial fibrosis, and calcification of the mitral and aortic valves may occur. Cerebrovascular complications occurring as a result of cerebrovascular infarction include hemiplegia, subdural hematoma, and seizures. Other causes of morbidity and mortality include marasmus, loss of mobility, and inanition 18. Sex HGPS has a slight male predilection; the maleto-female ratio is 1.5:1. Age Clinical manifestations of HGPS may not be recognized or apparent at birth, although many affected children present with sclerodermatous skin changes. Delayed recognition of the characteristic facial features along with the cutaneous and musculoskeletal manifestations may not occur until age 6-12 months or older, when the development of failure to thrive engenders a more thorough evaluation 19. Clinical History Evidence of Hutchinson-Gilford progeria syndrome (HGPS) begins within the first 2 years of life. At birth, infants usually appear healthy, although sclerodermatous skin changes have been noted in some patients. Typically, the onset of the disease occurs at age 6-12 months, when skin changes and alopecia are first noted and when the infant fails to gain weight. The following are other suggestive findings: High-pitched voice Short stature and low weight for height, with prenatal onset of growth failure Incomplete sexual maturation Generalized osteoporosis and pathologic fractures Feeding difficulties Delayed dentition, anodontia, hypodontia, or crowding of teeth Low-frequency conductive hearing loss Hypertension Prolonged prothrombin time, elevated platelet counts, and elevated serum phosphorus levels 20 Emotionally, patients with HGPS share the same feelings as age matched healthy persons with regard to expressing proper mood and affect. Patients with HGPS are keenly aware of their different appearance and remain reserved in the company of strangers; in the presence of friends, they display affection and good social interaction. Intelligence is normal 21, 22. Physical The characteristic clinical findings of (HGPS) include abnormalities of the skin and hair in conjunction with characteristic facial 4

5 features and skeletal abnormalities. The composite appearance of the characteristic facies and parieto-occipital alopecia create a "plucked-bird" appearance. Evidence of significant growth failure manifests within the first 1-2 years of life and prenatal growth failure is often apparent. Delayed, abnormal dentition is also common 23. Skin and hair Sclerodermatous skin changes involving the trunk and extremities but sparing the face: These are usually present within the first 6-12 months of life, although they may be present at birth. The skin changes manifest as indurated, shiny, inelastic skin. Prominent scalp veins Generalized lipodystrophy with loose, aged-appearing skin: Areas of skin may appear loose, wrinkled, and aged because of the loss of subcutaneous fat, particularly over the hands and feet. Progressive freckle like hyper pigmentation in sun-exposed areas Causes (HGPS) is related to aberrant processing of the nuclear envelope protein lamin A and accumulation of farnesylated prelamin A Autosomal dominant mutations in the LMNA gene, located on band 1q21.1-1q21.3, are responsible for most cases of HGPS. De novo mutations associated with advanced paternal age are responsible for most cases, although maternal transmission of a mutant LMNA gene from an asymptomatic mother who manifested somatic and gonadal mosaicism has also been reported. In addition, autosomal recessive transmission has also been suggested to account for the reported development of HGPS in several sets of siblings born to unaffected parents. The LMNA genes encodes the nuclear A- type lamins, which are type V intermediate Hair loss: Scalp hair and eyelashes are progressively lost, resulting in baldness with only a few vellus hairs remaining 24. Characteristic facies Protruding ears with absent lobes Beaked nose Thin lips with centrofacial cyanosis Prominent eyes Frontal and parietal bossing with pseudohydrocephaly Midface hypoplasia with micrognathia Large anterior fontanel Musculoskeletal abnormalities Thin limbs with prominent joints Joint contractures and coxa valga with mild flexion of the knees resulting in a wide gait and "horse-riding" stance Pyriform (pear-shaped) thorax with short, dystrophic clavicles Bilateral hip dislocations Other reported anomalies Dystrophic nails Hypertrophic scars Hypoplastic nipples filament proteins that localize to the cell nucleus and form the nuclear lamina, a structure that supports the nuclear envelope. They are important in maintaining nuclear stability and organizing nuclear chromatin. The nuclear lamins may also play a role in regulating gene expression, DNA synthesis, and DNA repair 25, 26, 27. The most common LMNA mutation involves a C-->T transition at nucleotide 1824 (G608G). This substitution results in the activation of a cryptic splice donor site in exon 11, which results in a 150-base pair deletion and a truncated lamin A protein, called progerin. The abnormal progerin protein acts in a dominant-negative manner to prevent the normal assembly of nuclear lamins into the nuclear lamina. After translation, the mutant preprogerin protein undergoes normal farnesylation 5

6 of a CAAX tetrapeptide motif located at the carboxyterminus. The farnesylated preprogerin protein is then incorporated into the nuclear membrane. However, the mutant, truncated protein lacks an important posttranslational processing signal required for cleavage of the preprogerin protein at the carboxyterminus. This cleavage is required for the release of prelamin A from the nuclear membrane, thus allowing its incorporation into the nuclear lamina. The abnormal progerin protein forms insoluble cytoplasmic aggregates 28. As a result of the absence of lamin A in the nuclear lamina, the cell nuclei from HGPS patients display abnormal nuclear blebbing and aberrant nuclear shapes. Abnormal chromosome segregation and delayed onset and progression of mitosis have also been demonstrated 29. The presence of the homozygous missense mutation G1626C (K542N) in LMNA was demonstrated in 5 siblings born to asymptomatic, consanguineous carrier parents. This study confirms that autosomal recessive inheritance of HGPS can also occur. A transgenic mouse model for HGPS has been created by introducing a splicing defect into intron 9 of the mouse LMNA gene. Transgenic mice display many of the features of HGPS, including loss of subcutaneous fat, decreased bone density, growth failure, craniofacial deformities, skeletal abnormalities, and early death. Using microarray analyses, 3 recent studies 30, 31, 32, compared the gene expression profiles of cultured fibroblasts from patients with progeria with those of healthy people of various ages. In general, changes in gene activity detected in older patients correlated with changes in gene activity in progeria patients. Of the genes expressed differentially in progeria patients, several that help control mitosis were down-regulated. Many genes that control cell division and DNA or RNA synthesis and processing were also shown to be down-regulated in progeria patients; many of these changes are also seen with normal aging. Some of these changes were postulated to lead to genetic instability and a variety of disturbances in gene function. Changes were also seen in the expression of many genes involved in collagen remodeling and the formation of the extracellular matrix. In general, the changes favored excess extracellular matrix deposition, which may lead to the characteristic changes seen in the skin and the vasculature in progeria patients. Expression of transforming growth factor-beta, a factor that regulates tissue homeostasis and whose sustained expression is responsible for tissue fibrosis, is highly up-regulated in patients with progeria. The expression of several transcription factors, including many involved in musculoskeletal development, were also decreased in progeria patients. Expression of MEOX/GAX, a negative regulator of cell proliferation in mesodermal tissue, is elevated almost 30-fold in patients with HGPS, suggesting a contributory role in the development of the musculoskeletal abnormalities seen in HGPS 33. A characteristic finding in persons with progeria is an increase in hyaluronic acid excretion. In addition to persons with progeria, it is only detected in those with Werner syndrome, a disease characterized by a later onset of premature aging that occurs during the second decade of life. Usually, hyaluronic acid and other glycosaminoglycan production increases during the fifth to seventh decades of life. 6

7 Possibly, the increase in hyaluronic acid is a normal feature of advancing age. Fibroblasts from patients with progeria show a 3-fold increase in total glycosaminoglycan production and, in particular, hyaluronic acid production, compared with age-matched control groups. This increase results from an abnormality in degradation and is not caused by increased synthesis. Data from embryonic development suggest that changes in the level of hyaluronic acid are extremely important for morphological development. Experiments performed in chick embryos have demonstrated a correlation between cell differentiation and hyaluronic acid degradation. Hyaluronic acid is also necessary for the morphologic development of blood vessels in chick embryos. A reduction or absence of blood vessels is noted in regions of high hyaluronic acid levels. The decreased density of vasculature, sclerodermatous changes in the skin, and the high prevalence of cardiovascular disease present in persons with progeria may be induced by increased hyaluronic acid levels. Increased hyaluronic acid levels may also promote calcification of blood vessels, thus contributing to arteriosclerosis. In the past, studies of the link between progeria and aging (among other topics) have investigated the role of fibroblast life span 34. Cells from older donors exhibit a reduced number of cell divisions in comparison to younger donor cells. The reduction of life span in cultured fibroblasts derived from patients with progeria has revealed inconsistent results. A significant reduction in fibroblast life span has been claimed in some studies but has been questioned in later investigations. A recent thorough study indicates the life span of fibroblasts in culture is independent of donor age. Further abnormalities observed in cultured fibroblasts from patients with progeria include reduced mitotic activity, DNA synthesis, and cloning efficiency and a reduced capacity for DNA repair in cultured progeria fibroblasts after gamma irradiation. Mutant fibroblasts have been shown to demonstrate impaired DNA damage checkpoint signaling, which results in increased DNA double-strand breaks 35. Treatment Medical Care To date, no effective therapy is available for Hutchinson-Gilford progeria syndrome (HGPS). 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 7

8 a small number of patients with progeria 37. In vitro studies suggest a possible role for the use of farnesyltransferase inhibitors (FTIs) in HGPS. 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. A phase II trial of lonafarnib, an FTI, in progeria is currently ongoing. In vivo studies using FTIs in transgenic mouse models have demonstrated encouraging results with regards to prevention of the cardiovascular complications seen in progeria as well as reversal of the cutaneous manifestations and overall improvement in many of the phenotypic features of progeria, including increased longevity 38. 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 produced encouraging results. 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. A clinical trial investigating the use of pravastatin, a lipid-lowering agent, and zoledronic acid, an agent used to increase bone mineral density, in patients with progeria is currently recruiting patients. Recruitment information is available through Patients, families, and physicians may obtain further information, including opportunities for possible enrollment in clinical trials, through the Progeria Research Foundation 39. COMPLICATIONS Death due to cardiovascular abnormalities occurs in approximately 75% of Hutchinson- Gilford progeria syndrome (HGPS) patients. Other causes of death mentioned in the literature include stroke, marasmus, inanition, seizures, and accidental head trauma. CONCLUSION Progeria, eponymously named Hutchinson- Gilford syndrome, is a rare disease with less than 80 cases reported since the time of Hutchinson and Gilford at the turn of the century. Skin, bone, and cardiovascular structures are primarily involved. Skin and bone abnormalities account largely for a premature aged appearance, and cardiovascular changes account largely for death. Research has shown that progeria does not unequivocally parallel the normal aging process at an accelerated rate and that a connective tissue defect may possibly explain the syndrome. Elevated levels of a ground substance component, hyaluronic acid, which normally increases with advancing age, have been detected, but whether this elevation is of sole causal significance remains to be shown. Further inquiry is warranted to explain the fundamental determinants of this disorder fully. 8

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