Progeria

Source: Wikipedia, the free encyclopedia.
Progeria
Other namesHutchinson–Gilford progeria syndrome (HGPS),
genetic tests[5]
Differential diagnosisHallermann–Streiff syndrome, Gottron's syndrome, Wiedemann–Rautenstrauch syndrome[5]
TreatmentMostly symptomatic[5]
MedicationLonafarnib[6][7]
PrognosisAverage age of death is 15 years[citation needed]
FrequencyRare: 1 in 18 million[5]

Progeria is a specific type of progeroid syndrome, also known as Hutchinson–Gilford syndrome or Hutchinson–Gilford progeroid syndrome (HGPS).[8] A single gene mutation is responsible for causing progeria. The gene, known as lamin A (LMNA), makes a protein necessary for holding the nucleus of the cell together. When this gene gets mutated, an abnormal form of lamin A protein called progerin is produced. Progeroid syndromes are a group of diseases that causes individuals to age faster than usual, leading to them appearing older than they actually are. Patients born with progeria typically live to an age of mid-teens to early twenties.[9][10]

Severe cardiovascular complications usually develop by puberty, later on resulting in death.

Signs and symptoms

Progeria in a 19-year-old male, compared to male of same age without.

Most children with progeria appear normal at birth and during early infancy.

cardiovascular problems.[12] Scleroderma, a hardening and tightening of the skin on trunk and extremities of the body, is prevalent. People diagnosed with this disorder usually have small, fragile bodies, like those of older adults. The head is usually large relative to the body, with a narrow, wrinkled face and a beak nose. Prominent scalp veins are noticeable (made more obvious by alopecia), as well as prominent eyes. Musculoskeletal degeneration causes loss of body fat and muscle, stiff joints, hip dislocations, and other symptoms generally absent in the non-elderly population. Individuals usually retain typical mental and motor function.[citation needed
]

Pathophysiology

Hutchinson-Gilford progeroid syndrome (HGPS) is an extremely rare

sporadic germline mutation; although HGPS is genetically dominant, people rarely live long enough to have children, preventing them from passing the disorder on in a hereditary manner.[13]

Ultrastructural analysis of the nuclear envelope in fibroblasts from a subject with HGPS. Low magnification transmission electron microscopic image of a passage 10 PT001 nucleus showed several herniations (a). Two higher-magnification images of the same nucleus at sites of blebs (b and c) showed a close apposition of the chromatin to the nuclear envelope. In a, b, and c, the nucleus is to the left. Scale bars correspond to 2 μm in panel a, and 500 nm in panels b and c.

HPGS is caused by mutations that weaken the structure of the cell nucleus, making normal cell division difficult. The

lamin A. Lamin A is made but is not processed properly. This poor processing creates an abnormal nuclear morphology and disorganized heterochromatin. Patients also do not have appropriate DNA repair, and they also have increased genomic instability.[14]

In normal conditions, the

transported through a nuclear pore to the interior of the nucleus. Once in the nucleus, the protein is cleaved by a protease called zinc metallopeptidase STE24 (ZMPSTE24), which removes the last 15 amino acids, which includes the farnesylated cysteine. After cleavage by the protease, prelamin A is referred to as lamin A. In most mammalian cells, lamin A, along with lamin B1, lamin B2, and lamin C, makes up the nuclear lamina, which provides shape and stability to the inner nuclear envelope.[citation needed
] Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered to be a
cryptic splice site within exon 11, resulting in a shorter than normal mRNA transcript. When this shorter mRNA is translated into protein, it produces an abnormal variant of the prelamin A protein, referred to as progerin. Progerin's farnesyl group cannot be removed because the ZMPSTE24 cleavage site is lacking from progerin, so the abnormal protein is permanently attached to the nuclear rim. One result is that the nuclear lamina does not provide the nuclear envelope with enough structural support, causing it to take on an abnormal shape.[17] Since the support that the nuclear lamina normally provides is necessary for the organizing of chromatin during mitosis, weakening of the nuclear lamina limits the ability of the cell to divide.[18] However, defective cell division is unlikely to be the main defect leading to progeria, particularly because children develop normally without any signs of disease until about one year of age. Farnesylated prelamin A variants also lead to defective DNA repair, which may play a role in the development of progeria.[19] Progerin expression also leads to defects in the establishment of fibroblast cell polarity, which is also seen in physiological aging.[20]

To date over 1,400 SNPs in the LMNA gene are known.[21] They can manifest as changes in mRNA, splicing, or protein amino acid sequence (e.g. Arg471Cys,[22] Arg482Gln,[23] Arg527Leu,[24] Arg527Cys,[25] Ala529Val[26]).

Progerin may also play a role in normal human aging, since its production is activated in typical senescent cells.[18]

Unlike other "accelerated aging diseases" (such as Werner syndrome, Cockayne syndrome or xeroderma pigmentosum), progeria may not be directly caused by defective DNA repair. These diseases each cause changes in a few specific aspects of aging, but never in every aspect at once, so they are often called "segmental progerias".[27]

A 2003 report in Nature[28] said that progeria may be a de novo dominant trait. It develops during cell division in a newly conceived zygote or in the gametes of one of the parents. It is caused by mutations in the LMNA (lamin A protein) gene on chromosome 1; the mutated form of lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who did not know anything about progeria until her own son, Sam, was diagnosed at 22 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.[29]

Male patient age 22
Female patient age 40
A male patient age 22 (top) and a female patient age 40 (bottom) with atypical progeria

A subset of progeria patients with heterozygous mutations of LMNA have presented an atypical form of the condition, with initial symptoms not developing until late childhood or early adolescence. These patients have had longer lifespans than those with typical-onset progeria.[11] This atypical form is extremely rare, with presentations of the condition varying between patients with even the same mutation.[30] The general phenotype of atypical cases is consistent with typical progeria, but other factors (severity, onset, and lifespan) vary in presentation.[31]

Lamin A

scaffold on the inner edge of the nucleus called the nuclear lamina that helps organize nuclear processes such as RNA and DNA synthesis.[citation needed
]

Prelamin A contains a CAAX box at the

amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein, now lamin A, is no longer membrane-bound and carries out functions inside the nucleus.[citation needed
]

In HGPS, the recognition site that the enzyme requires for cleavage of prelamin A to lamin A is mutated. Lamin A cannot be produced, and prelamin A builds up on the nuclear membrane, causing a characteristic nuclear

blebbing.[32]
This results in the symptoms of progeria, although the relationship between the misshapen nucleus and the symptoms is not known.

A study that compared HGPS patient cells with the skin cells from young and elderly normal human subjects found similar defects in the HGPS and elderly cells, including

down-regulation of certain nuclear proteins, increased DNA damage, and demethylation of histone, leading to reduced heterochromatin.[33] Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes.[34] These studies suggest that lamin A defects are associated with normal aging.[33][35]

Mitochondria

The presence of progerin also leads to the accumulation of dysfunctional mitochondria within the cell. These mitochondria are characterized by a swollen morphology, caused by a condensation of mtDNA and TFAM into the mitochondria, which is driven by a severe mitochondrial dysfunction (low mitochondrial membrane potential, low ATP production, low respiration capacity and high ROS production).[36][37][38] Therefore, contributing substantially to the senescence phenotype. Although, the explanation for this defective-mitochondria accumulation in progeria is about to be elucidated, it has been proposed that low PGC1-α expression[36][37][39] (important for mitochondrial biogenesis, maintenance and function) along with low LAMP2 protein level and lysosome number (both important for mitophagy: the degradation of defective mitochondria pathway),[36] could be implicated.

Diagnosis

Skin changes, abnormal growth, and loss of hair occur. These symptoms normally start appearing by one year of age. A genetic test for LMNA mutations can confirm the diagnosis of progeria.[40][41] Prior to the advent of the genetic test, misdiagnosis was common.[41]

Differential diagnosis

Other syndromes with similar symptoms (non-laminopathy progeroid syndromes) include:[42]

Treatment

In November 2020, the U.S. Food and Drug Administration approved lonafarnib, which helps prevent buildup of defective progerin and similar proteins.[43] A clinical trial in 2018 points to significantly lower mortality rates – treatment with lonafarnib alone compared with no treatment (3.7% vs. 33.3%) – at a median post-trial follow-up time span of 2.2 years.[44] The drug, given orphan drug status and Pediatric Disease Priority Review Voucher, is taken twice daily in the form of capsules and may cost US$650,000 per year, making it prohibitive for the vast majority of families. It is unclear how it will be covered by health insurance in the United States. Common side effects of the drug include "nausea, vomiting, diarrhea, infections, decreased appetite, and fatigue".[13]

Other treatment options have focused on reducing complications (such as cardiovascular disease) with coronary artery bypass surgery and low-dose acetylsalicylic acid.[45]

Growth hormone treatment has been attempted.[46] The use of Morpholinos has also been attempted in mice and cell cultures in order to reduce progerin production. Antisense Morpholino oligonucleotides specifically directed against the mutated exon 11–exon 12 junction in the mutated pre-mRNAs were used.[47]

A type of anticancer drug, the

zoledronate are effective drugs when it comes to the blocking of farnesyl group production.[citation needed
]

Farnesyltransferase inhibitors (FTIs) are drugs that inhibit the activity of an enzyme needed to make a link between progerin proteins and farnesyl groups. This link generates the permanent attachment of the progerin to the nuclear rim. In progeria, cellular damage can occur because that attachment occurs, and the nucleus is not in a normal state. Lonafarnib is an FTI, which means it can avoid this link, so progerin can not remain attached to the nucleus rim, and it now has a more normal state.[citation needed]

Studies of sirolimus, an mTOR Inhibitor, demonstrate that it can minimize the phenotypic effects of progeria fibroblasts. Other observed consequences of its use are abolishing nuclear blebbing, degradation of progerin in affected cells, and reducing insoluble progerin aggregates formation. These results have been observed only in vitro and are not the results of any clinical trial, although it is believed that the treatment might benefit HGPS patients.[17]

Recently, it has been demonstrated that the CRM1 protein (a key component of the nuclear export machinery in mammalian) is upregulated in HGPS cells, which drives to the abnormal localization of NES containing proteins from the nucleus to the cytoplasm.[51] Moreover, the inhibition of CRM1 in HGPS alleviates the associated-senescence phenotype[51] as well as the mitochondrial function (an important determinant in senescence) and lysosome content.[36] These results are under in vivo validation with selinexor (a more suitable CRM1 inhibitor for human use[52]).

Prognosis

As there is no known cure, few people with progeria exceed 16 years of age.[53] At least 90 percent of patients die from complications of atherosclerosis, such as heart attack or stroke.[54]

Mental development is not adversely affected; in fact, intelligence tends to be average to above average.

cataracts (caused by UV exposure) and osteoarthritis.[40]

Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems. People with progeria have normal reproductive development, and there are known cases of women with progeria who delivered healthy offspring.[56]

Epidemiology

A study from the Netherlands has shown an incidence of 1 in 20 million births.[57] According to the Progeria Research Foundation, as of September 2020, there are 179 known cases in the world, in 53 countries; 18 of the cases were identified in the United States.[58][13] Hundreds of cases have been reported in medical history since 1886.[59][60][61] However, the Progeria Research Foundation believes there may be as many as 150 undiagnosed cases worldwide.[62]

There have been only two cases in which a healthy person was known to carry the LMNA mutation that causes progeria.[63] One family from India had four of six children with progeria.[64]

Research

Mouse model

A mouse

LMNA prelamin A is not mutated. Instead, ZMPSTE24
, the specific protease that is required to remove the C-terminus of prelamin A, is missing. Both cases result in the buildup of farnesylated prelamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing.

In 2020

BubR1[67] which is known to regulate aging in mice.[68]

DNA repair

Repair of DNA double-strand breaks can occur by either of two processes, non-homologous end joining (NHEJ) or homologous recombination (HR). A-type lamins promote genetic stability by maintaining levels of proteins that have key roles in NHEJ and HR.[69] Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and have increased sensitivity to DNA damaging agents.[19] In progeria, the inability to adequately repair DNA damages due to defective A-type lamin may cause aspects of premature aging[70] (also see DNA damage theory of aging).

Epigenetic clock analysis of human HGPS

Fibroblast samples from children with progeria syndrome exhibit accelerated epigenetic aging effects according to the epigenetic clock for skin and blood samples.[71]

History

Progeria was first described in 1886 by Jonathan Hutchinson.[72] It was also described independently in 1897 by Hastings Gilford.[73] The condition was later named Hutchinson–Gilford progeria syndrome. Scientists are interested in progeria partly because it might reveal clues about the normal process of aging.[74][63][75]

Etymology

The word progeria comes from the Greek words pro (πρό) 'before, premature', and gēras (γῆρας), 'old age'.[76]

Society and culture

Notable cases

Yan Hui, a student of Confucius, aged rapidly and died at a young age, appearing as an old man by his late 20s. He may be one of the earliest potential examples of progeria in history.[77][failed verification]

In 1987, fifteen-year-old Mickey Hays, who had progeria, appeared along with Jack Elam in the documentary I Am Not a Freak.[78] Elam and Hays first met during the filming of the 1986 film The Aurora Encounter,[79] in which Hays was cast as an alien. The friendship that developed lasted until Hays died in 1992, on his 20th birthday. Elam said, "You know I've met a lot of people, but I've never met anybody that got next to me like Mickey."[This quote needs a citation]

Harold Kushner, who among other things wrote the book When Bad Things Happen to Good People, had a son, Aaron, who died at the age of 14 in 1977 of progeria.[80]

Margaret Casey, a 29-year-old woman with progeria who was then believed to be the oldest survivor of the premature aging disease, died on Sunday, May 26, 1985. Casey, a freelance artist, was admitted to

Yale-New Haven Hospital on the night of May 25 with respiratory problems, which caused her death.[81]

Sam Berns was an American activist with the disease. He was the subject of the HBO documentary Life According to Sam. Berns also gave a TEDx talk titled "My Philosophy for a Happy Life" on December 13, 2013.[82]

Hayley Okines was an English progeria patient who spread awareness of the condition.[83]

Leon Botha, the South African painter and DJ who was known, among other things, for his work with the hip-hop duo Die Antwoord, lived with progeria.[84] He died in 2011, aged 26.

Tiffany Wedekind of Columbus, Ohio, is believed to be the oldest survivor of progeria at 44 years old as of September 2022.[85]

Alexandra Peraut is a Catalan girl with progeria; she has inspired the book Una nena entre vint milions ('A girl in 20 million'), a children's book to explain progeria to youngsters.[86][87]

Adalia Rose Williams, born December 10, 2006, was an American girl with progeria, who was a notable YouTuber and vlogger who shared her everyday life on social media. She died on January 12, 2022, at the age of 15.[88]

Amy Foose, born September 12, 1969, was an American girl with progeria, who died at the age of 16 on December 19, 1985. [89] Sister of American automobile designer, artist, and TV star, Chip Foose, who started a foundation in her name called Amy's Depot. [90] The Progeria Research Foundation gives out The Amy Award every few years, in honor of Amy. [91]

References

  1. ISBN 978-0-7216-2921-6
    .
  2. ^
    ISBN 978-1-4160-2999-1.[page needed
    ]
  3. ^ Dictionary Reference: Progeria Archived 2013-04-10 at the Wayback Machine
  4. The Free Dictionary: Progeria Archived 2013-05-15 at the Wayback Machine
  5. ^ a b c d e f g h "Hutchinson–Gilford Progeria – NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). 2014. Archived from the original on April 13, 2020. Retrieved 21 April 2017.
  6. ^ "FDA Approves First Treatment for Hutchinson-Gilford Progeria Syndrome and Some Progeroid Laminopathies". U.S. Food and Drug Administration (FDA) (Press release). 20 November 2020. Retrieved 20 November 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  7. ^ "Drug Trials Snapshots: Zokinvy". U.S. Food and Drug Administration. 20 November 2020. Retrieved 11 December 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  8. ^
    PMID 25027075
    .
  9. ISBN 978-0-521-78153-4
    .
  10. ISBN 978-0-12-010333-1
    .
  11. ^ a b "Hutchinson-Gilford syndrome (Concept Id: C0033300)". www.ncbi.nlm.nih.gov. Retrieved 2023-11-12.
  12. PMID 20798379
    .
  13. ^ a b c Hall H (8 December 2020). "Progeria". Science-Based Medicine. Archived from the original on 23 April 2021. Retrieved 23 April 2021.
  14. S2CID 2459118
    .
  15. ^ LMNA Archived 2015-12-28 at the Wayback Machine At Genes Archived 2015-12-22 at the Wayback Machine At Genetics Home Reference Archived 2019-02-04 at the Wayback Machine
  16. S2CID 33927803
    .
  17. ^
    S2CID 206678031
    .
  18. ^
    UCSF. Archived
    from the original on 2011-10-25. Retrieved 2011-10-25.
  19. ^
    S2CID 11798376
    .
  20. PMID 30808750
    .
  21. ^ "LMNA Gene" Archived 2017-10-12 at the Wayback Machine. GeneCards. Retrieved June 6, 2015.
  22. S2CID 205309256
    .
  23. PMID 10587585
    .
  24. PMID 22549407
    .
  25. PMID 18796515
    .
  26. PMID 15998779
    .
  27. PMID 19594328
    .
  28. S2CID 4420150
    .
  29. S2CID 220095842
    .
  30. PMID 33859056
    .
  31. ^ "UpToDate". www.uptodate.com. Retrieved 2023-11-12.
  32. S2CID 4387289
    .
  33. ^
    PMID 16645051
    .
  34. PMID 16269543
    .
  35. ^ Zagorski N (November 2006). "A Comeback for the Ages: Lamin's connection with aging has reinvigorated research". Johns Hopkins University. Archived from the original on 2017-03-28. Retrieved 2020-05-22.
  36. ^
    PMID 36672210
    .
  37. ^
    PMID 26663466
    .
  38. PMID 33619770
    .
  39. PMID 36099415
    .
  40. ^ a b "Learning About Progeria". genome.gov. Archived from the original on 16 April 2008. Retrieved 17 March 2008.
  41. ^ a b "Progeria Research Foundation | The PRF Diagnostic Testing Program". Archived from the original on 28 August 2016. Retrieved 16 November 2011.
  42. PMID 20301300
    , retrieved 2023-11-12
  43. ^ "FDA Approves First Drug For Rare, Rapid-Aging Genetic Disorder". NPR.org. Archived from the original on 2020-11-22. Retrieved 2020-11-22.
  44. PMID 29710166
    .
  45. ^ "Progeria: Treatment". MayoClinic.com. Archived from the original on 2007-12-19. Retrieved 2008-03-17.
  46. S2CID 5988572
    .
  47. PMID 15750600
    .
  48. PMID 16942914
    .
  49. ^ Clinical trial number NCT00425607 for "Phase II Trial of Lonafarnib (a Farnesyltransferase Inhibitor) for Progeria" at ClinicalTrials.gov
  50. doi:10.1126/science.333.6039.142-b
    .
  51. ^
    PMID 31305018
    .
  52. PMID 32574233
    .
  53. ^ Sternberg S (April 16, 2003). "Gene found for rapid aging disease in children". USA Today. Archived from the original on July 12, 2017. Retrieved December 12, 2013.
  54. ^ "Progeria". MayoClinic.com. Archived from the original on May 11, 2008. Retrieved March 17, 2008.
  55. PMID 1590260
    .
  56. S2CID 72618179
    .
  57. S2CID 15692098
    .
  58. ^ "Meet the Kids". Progeria Research Foundation. 1 September 2019. Archived from the original on 16 June 2019. Retrieved 29 September 2019.
  59. ^ "Progeria Info". Archived from the original on 2 December 2013. Retrieved 28 November 2013.
  60. ^ "In loving memory of those children who have passed away since The Progeria Research Foundation was formed in 1999". Progeria Research Foundation. 9 July 2019. Archived from the original on 16 June 2019. Retrieved 24 September 2019.
  61. ^ "Progeria 101". Progeria Research Foundation. August 2019. Archived from the original on 16 June 2019. Retrieved 29 September 2019.
  62. ^ "GLOBALHealthPR Co-Founder and Chair, John J. Seng, Receives Award from Progeria Research Foundation". Business Insider. 30 April 2018. Archived from the original on 20 April 2019. Retrieved 20 April 2019.
  63. ^
    S2CID 44499453
    .
  64. ^ Grant M (22 February 2005). "Family tormented by ageing disease". BBC News. Archived from the original on 19 July 2018.
  65. PMID 33408413
    .
  66. ^ LaMotte S (31 May 2022). "Changing our DNA: 'The age of human therapeutic gene editing is here'". CNN. Retrieved 2022-06-01.
  67. S2CID 256559744
    .
  68. S2CID 7871496
    .
  69. PMID 21701264
    .
  70. ISBN 978-1-60456-581-2. Archived from the original
    on 2014-10-25.
  71. PMID 30048243
    .
  72. doi:10.1016/S0140-6736(02)06582-0
    . p. 923: Mr. JONATHAN HUTCHINSON contributed a paper on a case of congenital Absence of Hair, with Atrophic Condition of the Skin and its Appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. This paper described the case of a boy three years and a half old, who presented a very withered 'old-manish' appearance.
  73. PMID 14409225
    .
  74. PMID 18060063
    .
  75. PMID 18256394
    .
  76. ^ "DICTIONARY". Archived from the original on 2016-03-04. Retrieved 2015-06-22.
  77. ^ Confucius & Legge 2009, p. 113
  78. IMDb Edit this at Wikidata
    . Retrieved 2009-11-27.
  79. IMDb Edit this at Wikidata
    . Retrieved 2009-11-27.
  80. ^ Patricia Montemurri (August 3, 2008). "'One of a kind': Little girl with progeria makes a big impact on loved ones". Detroit Free Press. Archived from the original on April 26, 2009.
  81. ^ "Woman, Believe to be World's Oldest Progeriac, Dead At Age 29". The Associated Press. May 26, 1985. Archived from the original on November 5, 2019. Retrieved November 5, 2019.
  82. ^ "My philosophy for a happy life - Sam Berns - TEDxMidAtlantic - YouTube". YouTube. Archived from the original on 2019-07-14. Retrieved 2016-11-26.
  83. ^ "Hayley Okines, a teen trapped in a 104-year-old's body, dies at 17 - The Washington Post". The Washington Post. Archived from the original on 2019-12-04. Retrieved 2020-05-22.
  84. Mail and Guardian, 6 June 2011, archived from the original
    on February 4, 2021, retrieved February 4, 2021
  85. ^ Diaz A (12 September 2022). "One of the oldest living survivors of rapid aging disease at 44: 'Right now is all we have'". New York Post.
  86. ^ 324cat (2021-02-28). ""Has vist mai una nena de 10 anys que és com una iaia?", el conte que explica la progèria". CCMA (in Catalan). Retrieved 2021-03-06.{{cite web}}: CS1 maint: numeric names: authors list (link)
  87. ^ "Asociación Progeria ALEXANDRA PERAUT" (in Spanish). Retrieved 2021-07-28.
  88. ^ King C (13 January 2022). "Texas YouTuber Adalia Rose dies at 15 after battle with rare genetic condition, family confirms". KSAT. Retrieved 13 January 2022.
  89. ^ "The Progeria Research Foundation" (PDF). The Progeria Research Foundation.
  90. ^ "Instagram Page for Amy's Depot".
  91. ^ "The Amy Awards". The Progeria Research Foundation.

Sources

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