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Progeroid syndromes
Progeroid syndromes
Progeroid syndromes
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Progeroid syndromes (PS) are a group of rare genetic disorders that mimic physiological aging, making affected individuals appear to be older than they are.[1][2] The term progeroid syndrome does not necessarily imply progeria (Hutchinson–Gilford progeria syndrome), which is a specific type of progeroid syndrome.

Progeroid means "resembling premature aging", a definition that can apply to a broad range of diseases. Familial Alzheimer's disease and familial Parkinson's disease are two well-known accelerated-aging diseases that are more frequent in older individuals. They affect only one tissue and can be classified as unimodal progeroid syndromes. Segmental progeria, which is more frequently associated with the term progeroid syndrome, tends to affect multiple or all tissues while causing affected individuals to exhibit only some of the features associated with aging.[citation needed]

All disorders within this group are thought to be monogenic,[3] meaning they arise from mutations of a single gene. Most known PS are due to genetic mutations that lead to either defects in the DNA repair mechanism or defects in lamin A/C.

Examples of PS include Werner syndrome (WS), Bloom syndrome (BS), Rothmund–Thomson syndrome (RTS), Cockayne syndrome (CS), xeroderma pigmentosum (XP), trichothiodystrophy (TTD), combined xeroderma pigmentosum-Cockayne syndrome (XP-CS), restrictive dermopathy (RD), and Hutchinson–Gilford progeria syndrome (HGPS). Individuals with these disorders tend to have a reduced lifespan.[3] Progeroid syndromes have been widely studied in the fields of aging, regeneration, stem cells, and cancer. The most widely studied of the progeroid syndromes are Werner syndrome and Hutchinson–Gilford progeria, as they are seen to most resemble natural aging.[3]

Defects in DNA repair

[edit]

One of the main causes of progeroid syndromes are genetic mutations, which lead to defects in the cellular processes which repair DNA. The DNA damage theory of aging proposes that aging is a consequence of the accumulation of naturally occurring DNA damages. The accumulated damage may arise from reactive oxygen species (ROS), chemical reactions (e.g. with intercalating agents), radiation, depurination, and deamination.[citation needed]

Mutations in three classes of DNA repair proteins, RecQ protein-like helicases (RECQLs), nucleotide excision repair (NER) proteins, and nuclear envelope proteins LMNA (lamins) have been associated with the following progeroid syndromes:[citation needed]

  • Werner syndrome (WS)
  • Bloom syndrome (BS)
  • Rothmund–Thomson syndrome (RTS)
  • Cockayne syndrome (CS)
  • Xeroderma pigmentosum (XP)
  • Trichothiodystrophy (TTD)

RecQ-associated PS

[edit]
Further information on RecQ: RecQ helicase and Helicase

RecQ is a family of conserved ATP-dependent helicases required for repairing DNA and preventing deleterious recombination and genomic instability.[4] DNA helicases are enzymes that bind to double-stranded DNA and temporarily separate them. This unwinding is required during replication of the genome under mitosis, but in the context of PS, it is a required step in repairing damaged DNA. Thus, DNA helicases, maintain the integrity of a cell, and defects in these helicases are linked to an increased predisposition to cancer and aging phenotypes.[5] Thus, individuals with RecQ-associated PS show an increased risk of developing cancer,[6] which is caused by genomic instability and increased rates of mutation.[7]

There are five genes encoding RecQ in humans (RECQ1-5), and defects in RECQL2/WRN, RECQL3/BLM and RECQL4 lead to Werner syndrome (WS), Bloom syndrome (BS), and Rothmund–Thomson syndrome (RTS), respectively.[4][8] On the cellular level, cells of affected individuals exhibit chromosomal abnormalities, genomic instability, and sensitivity to mutagens.[7]

Werner syndrome

[edit]
Werner syndrome is inherited in an autosomal recessive manner, which means both parents must contribute a dysfunctional allele for an individual to develop the disease.
Main article: Werner syndrome

Werner syndrome (WS) is a rare autosomal recessive disorder.[9][10] It has a global incidence rate of less than 1 in 100,000 live births,[9] although incidences in Japan and Sardinia are higher, where it affects 1 in 20,000-40,000 and 1 in 50,000, respectively.[11][12] As of 2006, there were approximately 1,300 reported cases of WS worldwide.[3] Affected individuals typically grow and develop normally until puberty, when they do not experience the typical adolescent growth spurt. The mean age of diagnosis is twenty-four.[13] The median and mean age of death are 47-48 and 54 years, respectively;[14] the main cause of death is cardiovascular disease or cancer.[3][13]

Affected individuals can exhibit growth retardation, short stature, premature graying of hair, hair loss, wrinkling, prematurely aged faces, beaked noses, skin atrophy (wasting away) with scleroderma-like lesions, loss of fat tissues, abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the Achilles tendon and malleoli. Other signs include change in voice, making it weak, hoarse, or high-pitched; atrophy of gonads, leading to reduced fertility; bilateral cataracts (clouding of lens); premature arteriosclerosis (thickening and loss of elasticity of arteries); calcinosis (calcium deposits in blood vessels); atherosclerosis (blockage of blood vessels); type 2 diabetes; loss of bone mass; telangiectasia; and malignancies.[3][9] In fact, the prevalence of rare cancers, such as meningiomas, are increased in individuals with Werner syndrome.[15]

Approximately 90% of individuals with Werner Syndrome have any of a range of mutations in the eponymous gene, WRN, the only gene currently connected to Werner syndrome.[14] WRN encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases. WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication.[10][11] Since WRNp's function depends on DNA, it is only functional when localized to the nucleus.[citation needed]

Mutations that cause Werner syndrome only occur at the regions of the gene that encode for protein and not at non-coding regions.[16] These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA (mRNA), which increases the rate at which they are degraded. With fewer mRNA, fewer are available to be translated into the WRNp protein. Mutations may also lead to the truncation (shortening) of the WRNp protein, leading to the loss of its nuclear localization signal sequence, which would normally transport it to the nucleus where it can interact with the DNA. This leads to a reduction in DNA repair.[16] Furthermore, mutated proteins are more likely to be degraded than normal WRNp.[11] Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increase the survival of these dysfunctional cells.[17]

Cells of affected individuals have reduced lifespan in culture,[18] more chromosome breaks and translocations[19] and extensive deletions.[20] These DNA damages, chromosome aberrations and mutations may in turn cause more RecQ-independent aging phenotypes.[citation needed]

Bloom syndrome

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Main article: Bloom syndrome

Bloom syndrome (BS) is a very rare autosomal recessive disorder.[21] Incidence rates are unknown, although it is known to be higher in people of Ashkenazi Jewish background, presenting in around 1 in 50,000. Approximately one-third of individuals who have BS are of Ashkenazi Jewish descent.[citation needed]

There is no evidence from the Bloom's Syndrome Registry or from the peer-reviewed medical literature that BS is a progeroid condition associated with advanced aging.[citation needed] It is, however, associated with early-onset cancer and adult-type diabetes and also with Werner syndrome,[citation needed] which is a progeroid syndrome, through mutation in the RecQ helicases. These associations have led to the speculation that BS could be associated with aging. Unfortunately, the average lifespan of persons with Bloom syndrome is 27 years; consequently, there is insufficient information to completely rule out the possibility that BS is associated with some features of aging.[citation needed]

People with BS start their life with a low weight and length when they are born. Even as adults, they typically remain under 5 feet tall.[22] Individuals with BS are characterized by low weight and height and abnormal facial features, particularly a long, narrow face with a small lower jaw, a large nose and prominent ears. Most also develop photosensitivity, which causes the blood vessels to be dilated and leads to reddening of the skin, usually presented as a "butterfly-shaped patch of reddened skin across the nose and cheeks".[23] Other characteristics of BS include learning disabilities, an increased risk of diabetes, gastroesophageal reflux (GER), and chronic obstructive pulmonary disease (COPD). GER may also lead to recurrent infections of the upper respiratory tract, ears, and lungs during infancy. BS causes infertility in males and reduced fertility and early-onset menopause in females. In line with any RecQ-associated PS, people with BS have an increased risk of developing cancer, often more than one type.[citation needed]

BS is caused by mutations in the BLM gene, which encodes for the Bloom syndrome protein, a RecQ helicase.[24] These mutations may be frameshift, missense, non-sense, or mutations of other kinds and are likely to cause deletions in the gene product.[25][26] Apart from helicase activity that is common to all RecQ helices, it also acts to prevent inappropriate homologous recombination. During replication of the genome, the two copies of DNA, called sister chromatids, are held together through a structure called the centromere. During this time, the homologous (corresponding) copies are in close physical proximity to each other, allowing them to 'cross' and exchange genetic information, a process called homologous recombination. Defective homologous recombination can cause mutation and genetic instability.[27] Such defective recombination can introduce gaps and breaks within the genome and disrupt the function of genes, possibly causing growth retardation, aging and elevated risk of cancer. It introduces gaps and breaks within the genome and disrupts the function of genes, often causing retardation of growth, aging and elevated risks of cancers. The Bloom syndrome protein interacts with other proteins, such as topoisomerase IIIα and RMI2,[28][29][30] and suppresses illegitimate recombination events between sequences that are divergent from strict homology, thus maintaining genome stability.[27] Individuals with BS have a loss-of-function mutation, which means that the illegitimate recombination is no longer suppressed, leading to higher rates of mutation (~10-100 times above normal, depending on cell type).[31][32]

NER protein-associated PS

[edit]
Further information: Nucleotide excision repair

Nucleotide excision repair is a DNA repair mechanism. There are three excision repair pathways: nucleotide excision repair (NER), base excision repair (BER), and DNA mismatch repair (MMR). In NER, the damaged DNA strand is removed and the undamaged strand is kept as a template for the formation of a complementary sequence with DNA polymerase. DNA ligase joins the strands together to form dsDNA. There are two subpathways for NER, which differ only in their mechanism for recognition: global genomic NER (GG-NER) and transcription coupled NER (TC-NER).[citation needed]

Defects in the NER pathway have been linked to progeroid syndromes. There are 28 genes in this pathway. Individuals with defects in these genes often have developmental defects and exhibit neurodegeneration. They can also develop CS, XP, and TTD,[33] often in combination with each other, as with combined xeroderma pigmentosa-Cockayne syndrome (XP-CS).[34] Variants of these diseases, such as DeSanctis–Cacchione syndrome and Cerebro-oculo-facio-skeletal (COFS) syndrome, can also be caused by defects in the NER pathway. However, unlike RecQ-associated PS, not all individuals affected by these diseases have increased risk of cancer.[3] All these disorders can be caused by mutations in a single gene, XPD,[35][36][37][38] or in other genes.[39]

Cockayne syndrome

[edit]
Main article: Cockayne syndrome

Cockayne syndrome (CS) is a rare autosomal recessive PS. There are three types of CS, distinguished by severity and age of onset. It occurs at a rate of about 1 in 300,000-500,000 in the United States and Europe.[40] [41] The mean age of death is ~12 years,[42] although the different forms differ significantly. Individuals with the type I (or classical) form of the disorder usually first show symptoms between one and three years and have lifespans of between 20 and 40 years. Type II Cockayne syndrome (CSB) is more severe: symptoms present at birth and individuals live to approximately 6–7 years of age.[3] Type III has the mildest symptoms, first presents later in childhood,[41] and the cause of death is often severe nervous system deterioration and respiratory tract infections.[43]

Individuals with CS appear prematurely aged and exhibit severe growth retardation leading to short stature. They have a small head (less than the -3 standard deviation),[44] fail to gain weight and failure to thrive. They also have extreme cutaneous photosensitivity (sensitivity to sunlight), neurodevelopmental abnormalities, and deafness, and often exhibit lipoatrophy, atrophic skin, severe tooth decay, sparse hair, calcium deposits in neurons, cataracts, sensorineural hearing loss, pigmentary retinopathy, and bone abnormalities. However, they do not have a higher risk of cancer.[citation needed]

Type I and II are known to be caused by mutation of a specific gene. CSA is caused by mutations in the cross-complementing gene 8 (ERCC8), which encodes for the CSA protein. These mutations are thought to cause alternate splicing of the pre-mRNA which leads to an abnormal protein.[45] CSB is caused by mutations in the ERCC6 gene, which encodes the CSB protein.[46] CSA and CSB are involved in transcription-coupled NER (TC-NER), which is involved in repairing DNA; they ubiquitinate RNA polymerase II, halting its progress thus allowing the TC-NER mechanism to be carried out.[47] The ubiquitinated RNAP II then dissociates and is degraded via the proteasome.[48] Mutations in ERCC8, ERCC6, or both mean DNA is no longer repaired through TC-NER, and the accumulation of mutations leads to cell death, which may contribute to the symptoms of Cockayne syndrome.[41]

Xeroderma pigmentosum

[edit]
An eight-year-old girl from Guatemala with xeroderma pigmentosum. Children with XP are often colloquially referred to as Children of the Night.[49]
Main article: Xeroderma pigmentosum

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder, affecting about one per million in the United States and autochthonic Europe populations[40] but with a higher incidence rate in Japan, North Africa, and the Middle East.[50] There have been 830 published cases from 1874 to 1982.[51] The disorder presents at infancy or early childhood.[citation needed]

Xeroderma pigmentosum mostly affects the eye and skin. Individuals with XP have extreme sensitivity to light in the ultraviolet range starting from one to two years of age,[51] and causes sunburn, freckling of skin, dry skin and pigmentation after exposure.[52] When the eye is exposed to sunlight, it becomes irritated and bloodshot, and the cornea becomes cloudy. Around 30% of affected individuals also develop neurological abnormalities, including deafness, poor coordination, decreased intellectual abilities, difficulty swallowing and talking, and seizures; these effects tend to become progressively worse over time. All affected individuals have a 1000-fold higher risk of developing skin cancer:[53] half of the affected population develop skin cancer by age 10, usually at areas most exposed to sunlight (e.g. face, head, or neck).[54] The risk for other cancers such as brain tumors, lung cancer and eye cancers also increase.[55]

There are eight types of XP (XP-A through XP-G), plus a variant type (XP-V), all categorized based on the genetic cause. XP can be caused by mutations in any of these genes: DDB2, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XPC. These genes are all involved in the NER repair pathway that repairs damaged DNA. The variant form, XP-V, is caused by mutations in the POLH gene, which unlike the rest does not code for components of the NER pathway but produces a DNA polymerase that allows accurate translesion synthesis of DNA damage resulting from UV radiation; its mutation leads to an overall increase in UV-dependent mutation, which ultimately causes the symptoms of XP.[citation needed]

Trichothiodystrophy

[edit]
Main article: Trichothiodystrophy

Trichothiodystrophy (TTD) is a rare autosomal recessive disease whose symptoms span across multiple systems[56] and can vary greatly in severity. The incidence rate of TTD is estimated to be 1.2 per million in Western Europe.[40] Milder cases cause sparse and brittle hair, which is due to the lack of sulfur,[57] an element that is part of the matrix proteins that give hair its strength.[58] More severe cases cause delayed development, significant intellectual disability, and recurrent infection; the most severe cases see death at infancy or early childhood.[citation needed]

TTD also affects the mother of the affected child during pregnancy, when she may experience pregnancy-induced high blood pressure and develop HELLP syndrome. The baby has a high risk of being born prematurely and will have a low birth weight. After birth, the child's normal growth is retarded, resulting in a short stature.

Other symptoms include scaly skin, abnormalities of the fingernails and toenails, clouding of the lens of the eye from birth (congenital cataracts), poor co-ordination, and ocular and skeletal abnormalities. Half of affected individuals also experience photosensitivity to UV light.[56]

TTD is caused by mutations in one of three genes, ERCC2, ERCC3, or GTF2H5, the first two of which are also linked to xeroderma pigmentosum. However, patients with TTD do not show a higher risk of developing skin cancer, in contrast to patients with XP.[57] The three genes associated with TTD encode for XPB, XPD and p8/TTDA of the general transcription factor IIH (TFIIH) complex,[59] which is involved in transcription and DNA damage repair. Mutations in one of these genes cause reduction of gene transcription, which may be involved in development (including placental development),[60] and thus may explain retardation in intellectual abilities, in some cases;[57] these mutations also lead to reduction in DNA repair, causing photosensitivity.[57][61]

A form of TTD without photosensitivity also exists, although its mechanism is unclear. The MPLKIP gene has been associated with this form of TTD, although it accounts for only 20% of all known cases of the non-photosensitive form of TTD, and the function of its gene product is also unclear. Mutations in the TTDN1 gene explain another 10% of non-photosensitive TTD.[62] The function of the gene product of TTDN1 is unknown, but the sex organs of individuals with this form of TTD often produce no hormones, a condition known as hypogonadism.[62]

Defects in Lamin A/C

[edit]
Lamin is required at the inner nuclear membrane to ensure the nucleus keeps its shape. Mutations in LMNA causes dysfunctional lamin, and the nucleus can no longer keeps its shape. This leads to mislocalisation of heterochromatin, which normally lie in close proximity, or with, the nuclear matrix, nuclear blebbing and misregulation of gene expression.
Further information on other diseases caused by defects in lamin: Laminopathy

Hutchinson–Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) are two PS caused by a defect in lamin A/C, which is encoded by the LMNA gene.[63][64] Lamin A is a major nuclear component that determines the shape and integrity of the nucleus, by acting as a scaffold protein that forms a filamentous meshwork underlying the inner nuclear envelope, the membrane that surrounds the nucleus.[citation needed]

Hutchinson–Gilford progeria syndrome

[edit]
Girl with HGPS (left). This condition is caused by dysfunctional lamin which is unable to maintain the nuclear shape (normal at top, abnormal at bottom).
Main article: Progeria

Hutchinson–Gilford progeria syndrome is an extremely rare developmental autosomal dominant condition, characterized by premature and accelerated aging (~7 times the normal rate)[65] beginning at childhood. It affects 1 in ~4 million newborns; over 130 cases have been reported in the literature since the first described case in 1886.[66] The mean age of diagnosis is ~3 years and the mean age of death is ~13 years. The cause of death is usually myocardial infarction, caused by the severe hardening of the arteries (arteriosclerosis).[67] There is currently no treatment available.[68]

Individuals with HGPS typically appear normal at birth, but their growth is severely retarded, resulting in short stature, a very low body weight and delayed tooth eruption. Their facial/cranial proportions and facial features are abnormal, characterized by larger-than-normal eyes, a thin, beaked nose, thin lips, small chin and jaw (micrognathia), protruding ears, scalp hair, eyebrows, and lashes, hair loss, large head, large fontanelle and generally appearing aged. Other features include skeletal alterations (osteolysis, osteoporosis), amyotrophy (wasting of muscle), lipodystrophy and skin atrophy (loss of subcutaneous tissue and fat) with sclerodermatous focal lesions, severe atherosclerosis and prominent scalp veins.[69] However, the level of cognitive function, motor skills, and risk of developing cancer is not affected significantly.[66]

HGPS is caused by sporadic mutations (not inherited from parent) in the LMNA gene, which encodes for lamin A.[63][64] Specifically, most HGPS are caused by a dominant, de novo, point mutation p.G608G (GGC > GGT).[64] This mutation causes a splice site within exon 11 of the pre-mRNA to come into action, leading to the last 150 base pairs of that exon, and consequently, the 50 amino acids near the C-terminus, being deleted.[64] This results in a truncated lamin A precursor (a.k.a. progerin or LaminAΔ50).[70]

After being translated, a farnesol is added to prelamin A using protein farnesyltransferase; this farnesylation is important in targeting lamin to the nuclear envelope, where it maintains its integrity. Normally, lamin A is recognized by ZMPSTE24 (FACE1, a metalloprotease) and cleaved, removing the farnesol and a few other amino acids.[citation needed]

In the truncated lamin A precursor, this cleavage is not possible and the prelamin A cannot mature. When the truncated prelamin A is localized to the nuclear envelope, it will not be processed and accumulates,[71] leading to "lobulation of the nuclear envelope, thickening of the nuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores", causing the nucleus to lose its shape and integrity.[72] The prelamin A also maintains the farnesyl and a methyl moiety on its C-terminal cysteine residue, ensuring their continued localization at the membrane. When this farnesylation is prevented using farnesyltransferase inhibitor (FTI), the abnormalities in nuclear shape are significantly reduced.[71][73]

HGPS is considered autosomal dominant, which means that only one of the two copies of the LMNA gene needs to be mutated to produce this phenotype. As the phenotype is caused by an accumulation of the truncated prelamin A, only mutation in one of the two genes is sufficient.[72] At least 16 Other mutations in lamin A/C,[74][75] or defects in the ZMPSTE24 gene,[76] have been shown to cause HGPS and other progeria-like symptoms, although these are less studied.

Repair of DNA double-strand breaks can occur by one of two processes, non-homologous end joining (NHEJ) or homologous recombination (HR). A-type lamins promote genetic stability by maintaining levels of proteins which have key roles in NHEJ and HR.[77] Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and have increased sensitivity to DNA damaging agents.[78] In HGPS, the inability to adequately repair DNA damages due to defective A-type lamin may cause aspects of premature aging (see DNA damage theory of aging).[citation needed]

Restrictive dermopathy

[edit]
Main article: Restrictive dermopathy

Restrictive dermopathy (RD), also called tight skin contracture syndrome, is a rare, lethal autosomal recessive perinatal genodermatosis.[79] Two known causes of RD are mutations in the LMNA gene, which lead to the production of truncated prelamin A precursor, and insertions in the ZMPSTE24, which lead to a premature stop codon.[79]

Individuals with RD exhibit growth retardation starting in the uterus, tight and rigid skin with erosions, prominent superficial vasculature and epidermal hyperkeratosis, abnormal facial features (small mouth, small pinched nose and micrognathia), sparse or absent eyelashes and eyebrows, mineralization defects of the skull, thin dysplastic clavicles, pulmonary hypoplasia and multiple joint contractures. Most affected individuals die in the uterus or are stillbirths, and liveborns usually die within a week.[citation needed]

Defects in FBN1

[edit]

Patients with Marfan-progeroid-lipodystrophy syndrome typically exhibit congenital lipodystrophy and a neonatal progeroid appearance.[80][81] Sometimes identified as having neonatal progeroid syndrome, the term is a misnomer since they do not exhibit accelerated aging.[82] The condition is caused by mutations near the 3'-terminus of the FBN1 gene.[80][81][82][83][84][85][excessive citations]

A common cause for premature aging

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Hutchinson–Gilford progeria syndrome, Werner syndrome, and Cockayne syndrome are the three genetic disorders in which patients have premature aging features. Premature aging also develops on some animal models which have genetic alterations.[86][87] Although the patients with these syndromes and the animal models with premature aging symptoms have different genetic backgrounds, they all have abnormal structures of tissues/organs as a result of defective development. Misrepair-accumulation aging theory[88][89] suggests that the abnormality of tissue structure is the common point between premature aging and normal aging.[90] Premature aging is a result of Mis-construction during development as a consequence of gene mutations, whereas normal aging is a result of accumulation of Misrepairs for the survival of an organism. Thus the process of development and that of aging are coupled by Mis-construction and Mis-re-construction (Misrepair) of the structure of an organism.[citation needed]

Unknown causes

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Wiedemann–Rautenstrauch syndrome

[edit]

Wiedemann–Rautenstrauch (WR) syndrome, also known as neonatal progeroid syndrome,[91] is an autosomal recessive progeroid syndrome. More than 30 cases have been reported.[92] Most affected individuals die by seven months of age, but some do survive into their teens.

WR is associated with abnormalities in bone maturation, and lipids and hormone metabolism.[93] Affected individuals exhibit intrauterine and postnatal growth retardation, leading to short stature and an aged appearance from birth. They have physical abnormalities including a large head (macrocephaly), sparse hair, prominent scalp veins, inward-folded eyelids, widened anterior fontanelles, hollow cheeks (malar hypoplasia), general loss of fat tissues under the skin, delayed tooth eruption, abnormal hair pattern, beaked noses, mild to severe intellectual disability and dysmorphism.[94]

The cause of WR is unknown, although defects in DNA repair have been implicated.[92]

Rothmund–Thomson syndrome

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Classified as an autosomal recessive defect, but the pathology has still yet to be well researched.[citation needed]

Cancer

[edit]

Some segmental progeroid syndromes, such as Werner syndrome (WS), Bloom syndrome (BS), Rothmund-Thomson syndromes (RTS) and combined xeroderma pigmentosa-Cockayne syndrome (XP-CS), are associated with an increased risk of developing cancer in the affected individual; two exceptions are Hutchinson–Gilford progeria (HGPS) and Cockayne syndrome.[95]

Animal models

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Within animal models for progeroid syndromes, early observations have detected abnormalities within overall mitochondrial function,[96][97] signal transduction between membrane receptors,[98] and nuclear regulatory proteins.

Other

[edit]

Alterations in lipid and carbohydrate metabolism, a triplet-repeat disorder (myotonic dystrophy) and an idiopathic disorder

[edit]

People

[edit]

Hayley Okines was an English girl with classic progeria famed for her efforts in spreading awareness of the condition. She was featured in the media.[99]

Lizzie Velásquez is an American motivational speaker who has a syndrome that resembles progeria, although the exact nature is unclear; it is now thought to be a form of neonatal progeroid syndrome.[100] Velásquez is an advocate of anti-bullying.[101][102]

Jesper Sørensen is widely recognized in Denmark as the only child in Denmark and Scandinavia with progeria (as of 2008).[103] His fame came about after a documentary in 2008 on TV 2 about Sørensen.[104]

Literature and Theatre

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F. Scott Fitzgerald's 1922 short story The Curious Case of Benjamin Button is about a boy who was born with the appearance of a 70-year-old and who ages backwards. This short story is thought to be inspired by progeria.[105] The description of the fictitious Smallweed family in the Charles Dickens' Bleak House suggests the characters had progeria.[106] Christopher Snow, the main character in Dean Koontz's Moonlight Bay Trilogy, has xeroderma pigmentosum, as does Luke from the 2002 novel Going Out by Scarlett Thomas. In the visual novel Chaos;Head, the character Shogun eventually dies of a progeroid syndrome, and in its sequel Chaos;Child, more characters get this same fictional progeroid syndrome, which by then is called Chaos Child Syndrome. In Kimberly Akimbo, a 2000 play by David Lindsay-Abaire, and its Tony Award for Best Musical-winning adaptation of the same name, the main character, Kimberly Levaco, has an unnamed progeria-like condition.[citation needed]

Film

[edit]

Paa, a 2009 Indian comedy-drama film, features a protagonist, Auro (Amitabh Bachchan), who has progeria. Jack is a 1996 American comedy-drama film, in which the titular character (portrayed by Robin Williams) has Werner syndrome. Taiyou no Uta, a 2006 Japanese film, features Kaoru Amane (portrayed by Yui), a 16-year-old girl has xeroderma pigmentosum.[citation needed]

See also

[edit]
  • DeSanctis–Cacchione syndrome, an extremely rare variant of xeroderma pigmentosum (XP)
  • Dyskeratosis congenita, a rare progressive congenital disorder of the skin and bone marrow in some ways resembling progeria
  • Fanconi anemia, a rare genetic defect in a cluster of proteins responsible for DNA repair
  • Li–Fraumeni syndrome, a rare autosomal genetic disorder caused by defects in DNA repair
  • Nijmegen breakage syndrome, a rare autosomal recessive genetic disorder caused by defect(s) in the Double Holliday junction DNA repair mechanism
  • Nestor-Guillermo progeria syndrome, an extremely rare genetic disorder which is unique from other PS because of the absence of any cardiovascular abnormalities (which lead to premature death in cases where they are present)

References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Progeroid syndromes

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from Grokipedia
Progeroid syndromes are a heterogeneous group of rare genetic disorders characterized by the accelerated appearance of aging-associated phenotypes, such as skin atrophy, , , , and shortened lifespan, often due to defects in , integrity, or telomere maintenance. These conditions mimic aspects of normal physiological aging but occur prematurely, typically in childhood or early adulthood, and are distinguished from typical aging by their segmental nature, affecting specific tissues while sparing others like cognitive function in many cases. Over 100 distinct progeroid syndromes have been identified, with a collective global incidence estimated at approximately 1 in 50,000 individuals, though individual syndromes are exceedingly rare, such as Hutchinson-Gilford progeria syndrome (HGPS) at 1 in 4-8 million births. The most well-studied progeroid syndromes include Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS), which provide key insights into the molecular underpinnings of accelerated aging. HGPS, caused by a de novo point mutation (c.1824C>T) in the LMNA gene leading to the production of a toxic protein called progerin, manifests in infancy with growth failure, loss of subcutaneous fat, scleroderma-like skin changes, and severe atherosclerosis, resulting in an average lifespan of 14.5 years without treatment (extended to approximately 18.7 years with lonafarnib therapy), primarily due to cardiovascular complications. In contrast, WS arises from biallelic mutations in the WRN gene, which encodes a RecQ helicase essential for DNA replication and repair; affected individuals develop bilateral cataracts, premature graying and hair loss, type 2 diabetes, and malignancies, with a mean lifespan of 54 years. Other notable examples encompass Cockayne syndrome, linked to mutations in ERCC6 or ERCC8 genes involved in nucleotide excision repair, featuring photosensitivity, neurological degeneration, and cachectic dwarfism with death around age 12; and Dyskeratosis congenita, resulting from telomere biology defects such as mutations in telomerase components, presenting with oral leukoplakia, nail dystrophy, and bone marrow failure. At the cellular and molecular levels, progeroid syndromes share hallmarks that parallel those of normal aging, including genomic instability from accumulated damage, telomere attrition, epigenetic alterations, disrupted nuclear architecture, cellular senescence, and stem cell dysfunction, though the extent of overlap with physiological aging remains under investigation. For instance, in HGPS, aberrant farnesylation of causes nuclear lamina deformities and heterochromatin loss, while WS involves impaired homologous recombination and telomere maintenance. These syndromes are classified mechanistically into categories such as laminopathies (nuclear envelope defects), segmental progerias ( deficiencies), and telomeropathies, facilitating targeted research. Animal models, particularly Zmpste24-deficient mice for HGPS and Wrn-knockout mice for WS, have recapitulated these features and supported therapeutic advancements, including farnesyltransferase inhibitors like (FDA-approved in 2020), which reduce progerin toxicity, improve vascular health, and extend lifespan in HGPS patients. Ongoing studies emphasize the value of progeroid syndromes as "experiments of nature" for elucidating aging mechanisms and developing interventions.

Overview

Definition

Progeroid syndromes, also referred to as segmental progeroid syndromes, are a heterogeneous group of rare genetic disorders characterized by the premature onset of aging-like phenotypes affecting multiple organs and tissues, setting them apart from the gradual, chronological process of normal aging. These conditions arise from underlying genetic mutations that accelerate physiological decline, leading to a shortened . Key characteristics include an accelerated physical deterioration manifesting typically in childhood or early adulthood, with prominent features such as skin wrinkling and scleroderma-like changes, (alopecia), , and cardiovascular complications like . Affected individuals often exhibit additional signs of premature aging, including , loss of subcutaneous fat, joint contractures, and a markedly reduced lifespan due to these systemic effects. In distinction from normal chronological aging, which involves uniform progression across the body over decades, progeroid syndromes cause segmental aging through specific genetic defects, disproportionately impacting certain systems—such as the skin, , and cardiovascular apparatus—while often sparing others, like the . This selective acceleration highlights their role as models for studying aging mechanisms without replicating the full spectrum of age-related changes. The term "" originates from the Greek words "pro," meaning "before" or "premature," and "" or "geron," meaning "," reflecting the condition's hallmark of early-onset . These syndromes were first clinically described in the , laying the foundation for recognizing premature aging as a distinct pathological entity.

Classification and Epidemiology

Progeroid syndromes are broadly classified into segmental and unimodal types based on the extent of organ involvement. Segmental progeroid syndromes affect multiple organs or tissues, exhibiting premature aging-like features across various systems such as cardiovascular, skeletal, and cutaneous, thereby mimicking aspects of physiological aging. In contrast, unimodal progeroid syndromes primarily impact a single organ or tissue, with limited systemic manifestations. The majority of identified progeroid syndromes fall into the segmental category. At the molecular level, progeroid syndromes are grouped according to the primary affected cellular pathways, including defects in DNA repair mechanisms, nuclear envelope integrity, mitochondrial function, and RNA processing. DNA repair-associated syndromes encompass defects in RecQ helicases (e.g., Werner and Bloom syndromes) and nucleotide excision repair pathways (e.g., Cockayne and xeroderma pigmentosum syndromes). Nuclear envelope-related syndromes, often termed laminopathies, arise from mutations in genes like LMNA (e.g., Hutchinson-Gilford progeria syndrome). Other categories include mitochondrial disorders and those involving RNA polymerase III, with ongoing classifications updated in resources like GeneReviews. Progeroid syndromes are extremely rare genetic disorders, with an overall incidence estimated at approximately 1 in 50,000 live births across all types. For instance, Hutchinson-Gilford progeria syndrome has an incidence of approximately 1 in 4 to 8 million live births worldwide. occurs at a frequency of about 1 in 200,000 individuals in the United States, though rates vary globally. Over 100 distinct progeroid syndromes have been identified, with new entities such as SLC25A24-related Fontaine progeroid syndrome described in the late . Epidemiological patterns show geographic and ethnic variations, particularly for , which exhibits higher prevalence in (up to 1 in 100,000) due to founder mutations in the WRN gene. Similar founder effects contribute to elevated rates in Sardinian and South Asian (Indian and Pakistani) populations, where specific WRN variants predominate. These variations highlight the role of population-specific genetic bottlenecks in the distribution of progeroid syndromes.

DNA Repair-Associated Progeroid Syndromes

RecQ Helicase Defects

RecQ constitute a conserved family of enzymes that utilize to unwind double-stranded DNA, facilitating essential cellular processes such as , repair, and , thereby preserving genomic integrity. These helicases resolve complex DNA structures that arise during replication fork progression and DNA damage response, preventing stalled forks and aberrant recombination events. in human RecQ helicase genes disrupt these functions, resulting in chromosomal instability, elevated mutation rates, and premature , which manifest as progeroid syndromes characterized by accelerated aging phenotypes. Werner syndrome (WS), the archetypal RecQ-associated progeroid disorder, arises from biallelic mutations in the WRN gene on chromosome 8p12, following autosomal recessive inheritance. Clinical onset typically occurs in the second decade of life, with hallmark features including , premature graying and thinning of , bilateral cataracts, non-insulin-dependent diabetes mellitus, and premature leading to cardiovascular complications. Affected individuals exhibit a markedly reduced lifespan, with median survival in the mid-50s, primarily due to or , alongside an elevated cancer risk, particularly for soft tissue sarcomas and melanomas. Bloom syndrome (BSyn), caused by mutations in the BLM gene on 15q26.1 and also inherited autosomal recessively, presents with severe prenatal and postnatal growth retardation, resulting in proportionate . Key features include with a characteristic butterfly-shaped facial erythema and telangiectasias, mild predisposing to recurrent infections, and . Cancer predisposition is profound, with a 150- to 300-fold increased risk for leukemias and lymphomas, as well as solid tumors, often occurring at young ages due to hypermutability and sister exchanges. Rothmund-Thomson syndrome (RTS), resulting from mutations in the RECQL4 gene on 8q24.3 under autosomal recessive transmission, is distinguished by —a mottled pigmentation with and —appearing in early infancy, primarily on sun-exposed areas. Additional manifestations encompass sparse hair and eyebrows, juvenile cataracts, skeletal dysplasias such as radial ray defects and , and without marked sunburn propensity. Patients face a substantially heightened risk of , particularly in , alongside non-melanoma cancers, linked to RECQL4's role in maintenance and replication. These RecQ defects share a genetic basis of autosomal recessive and induce systemic chromosomal instability, exemplified by variegated translocation mosaicism and in WS fibroblasts, quadriradial figures in BSyn cells, and radial figures in RTS lymphocytes, underscoring their common in replication stress and recombinational repair . Recent preclinical studies have explored WRN restoration via /Cas9-mediated gene correction in patient-derived induced pluripotent stem cells and mesenchymal stem cells, demonstrating improved proliferative capacity, reduced markers, and enhanced angiogenic function in cellular models, offering promising avenues for development. As of 2025, a double-blind randomized crossover demonstrated that supplementation elevates NAD+ levels and improves clinical markers in WS patients.

Nucleotide Excision Repair Defects

Nucleotide excision repair (NER) is a conserved DNA repair pathway that removes bulky, helix-distorting lesions from the genome, such as cyclobutane pyrimidine dimers and 6-4 photoproducts induced by ultraviolet (UV) radiation. The process involves damage recognition, incision, excision of the damaged oligonucleotide, and resynthesis using the intact strand as a template, primarily through global genome NER (GG-NER) and transcription-coupled NER (TC-NER) subpathways. Defects in NER components lead to accumulation of unrepaired DNA damage, which triggers cellular senescence, apoptosis, and transcriptional dysregulation, contributing to neurodegeneration, photosensitivity, and premature aging phenotypes observed in associated progeroid syndromes. This genomic instability from persistent DNA lesions parallels broader repair deficiencies seen in other progeroid conditions but is particularly linked to UV sensitivity and transcription impairment in NER disorders. Cockayne syndrome (CS), an autosomal recessive disorder, arises from biallelic mutations in ERCC6 (encoding CSB, ~75% of cases) or ERCC8 (encoding CSA, ~25% of cases), impairing TC-NER and leading to failure in repairing transcription-blocking lesions. Clinical features include cachectic with postnatal growth failure, cutaneous , progressive neurologic decline manifesting as and , and sensorineural deafness, often culminating in death between ages 12 and 20 due to neurodegeneration and respiratory complications. Unlike other NER defects, CS spares high cancer risk but emphasizes systemic aging-like decline from and mitochondrial dysfunction secondary to unrepaired damage. Xeroderma pigmentosum (XP), also autosomal recessive, results from mutations in any of eight genes (XPA through XPG, or XPV/pol eta), disrupting GG-NER and/or TC-NER to varying degrees across complementation groups A through G (XPA-G) and variant (XPV). Core manifestations encompass extreme UV sensitivity with acute sunburns, freckling, and early-onset skin cancers like basal and squamous cell carcinomas, alongside ocular involvement such as . Neurologic forms, prominent in XP-A, XP-D, and XP-G groups, incorporate progeroid elements including , , and , with severity correlating to residual NER activity—e.g., XP-A often presents profound deficiency and early neurodegeneration. Trichothiodystrophy (TTD), autosomal recessive, stems from mutations in ERCC2 (XPD), ERCC3 (XPB), or GTF2H5, affecting TFIIH subunits critical for both NER and basal transcription, with overlaps in XP complementation groups B, D, and a TTD-specific group. Hallmark features include brittle hair exhibiting a diagnostic "tiger tail" banding pattern under polarized microscopy due to low sulfur content, congenital ichthyosis, intellectual disability, and photosensitivity in ~50% of cases; non-photosensitive variants manifest progeroid cachexia with short stature and premature aging without UV hypersensitivity. These transcription defects exacerbate developmental and neurologic issues, distinguishing TTD by its ectodermal dysplasia alongside variable NER impairment. Recent laboratory advances include /Cas9-mediated correction of ERCC6 mutations in patient-derived induced pluripotent stem cells (iPSCs), which restored NER efficiency, mitigated premature , and improved neuronal differentiation in models, offering potential therapeutic insights for CS and related NER defects. As of 2025, preclinical (AAV)-mediated for ERCC8 in CS models is advancing toward clinical trials.

Lamin-Associated Progeroid Syndromes

Hutchinson-Gilford Progeria Syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal characterized by accelerated aging in children, primarily due to a de novo heterozygous (c.1824C>T) in 11 of the LMNA gene. This mutation activates a cryptic splice site, resulting in aberrant splicing of prelamin A mRNA and production of a truncated protein called , which lacks the cleavage site for the ZMPSTE24 protease. Consequently, progerin remains permanently farnesylated and accumulates abnormally at the , disrupting the structure. This genetic defect, first identified in a seminal study, accounts for approximately 90% of classic HGPS cases and is not inherited but arises sporadically in the parental gamete. Clinically, infants with HGPS appear normal at birth but exhibit between 6 and 12 months of age, followed by progressive symptoms mimicking premature aging. Key features include alopecia, scleroderma-like skin changes with loss of subcutaneous fat, stiff joints with contractures, and prominent manifesting as and . Other manifestations involve a characteristic craniofacial appearance with a large head, small , and beaked , as well as delayed and voice changes. Without treatment, the average lifespan is 14.5 years, with death typically resulting from or due to vascular complications. The pathophysiology of HGPS stems from progerin's toxic effects on nuclear integrity, leading to nuclear blebbing, altered chromatin organization, and impaired gene expression. These disruptions cause stem cell dysfunction, particularly in mesenchymal lineages, contributing to defective tissue repair and regeneration, including in cardiovascular, musculoskeletal, dermatological, and adipose tissues. Progerin accumulation also induces DNA repair defects and telomere attrition, exacerbating cellular senescence and systemic degeneration. Diagnosis is primarily clinical, based on pathognomonic features such as growth failure and aged appearance, confirmed by molecular for the classic LMNA c.1824C>T , present in about 90% of cases. Atypical HGPS forms, comprising roughly 10% of cases, involve other LMNA variants in 11 or adjacent introns, identified through targeted sequencing or full-gene analysis. is available for at-risk families, though the de novo nature limits its routine use. As of 2025, the primary treatment is the FDA-approved farnesyltransferase inhibitor lonafarnib (Zokinvy), which reduces progerin farnesylation and nuclear accumulation, extending median lifespan from 14.5 years to approximately 19 years while improving weight gain, bone density, and vascular stiffness. Supportive therapies include low-dose aspirin for cardiovascular protection, physical therapy for joint mobility, and growth hormone if indicated. Ongoing clinical trials explore combinations such as lonafarnib with everolimus (an mTOR inhibitor) to further address stem cell dysfunction and vascular benefits (NCT02579044). Prior completed trials, such as NCT00916747, investigated combinations including statins like pravastatin and bisphosphonates like zoledronic acid with lonafarnib, demonstrating benefits in mitigating atherosclerosis progression. Emerging preclinical approaches, including RNA therapies targeting progerin production, show promise in mouse models but await human trials. Epidemiologically, HGPS has an estimated incidence of 1 in 4 to 8 million live births, with no ethnic or geographic predisposition. Approximately 150 cases are known worldwide, reflecting its ultra-rare status and challenges in ascertainment.

Other Laminopathies

Mandibuloacral (MAD) is an autosomal recessive progeroid caused by mutations in either the LMNA , which encodes lamin A/C, or the ZMPSTE24 , which encodes the metalloprotease responsible for prelamin A processing. Clinical features include mandibular and clavicular , acroosteolysis of the distal phalanges, generalized with loss of subcutaneous fat, , and progeroid skin changes such as and mottling that typically emerge in adulthood. Patients with ZMPSTE24 mutations often exhibit a more severe , including earlier onset of and skeletal abnormalities, compared to those with LMNA mutations. Restrictive dermopathy (RD) represents a severe, lethal form of arising from biallelic mutations in ZMPSTE24, leading to complete loss of functional enzyme activity. It is characterized by tight, rigid skin with prominent erosions and fissures at flexion sites, prominent facial dysmorphism including a beaked nose and , and due to restricted fetal movements. Most affected infants succumb to or within hours to weeks of birth, underscoring its perinatal lethality. Atypical progeroid syndrome (APS) encompasses a spectrum of milder laminopathies due to heterozygous or compound heterozygous missense variants in LMNA, often inherited in an autosomal dominant or recessive manner. These variants result in HGPS-like features but with delayed onset, including partial , scleroderma-like skin changes, and metabolic disturbances, while allowing longer survival into adolescence or adulthood. Unlike classic HGPS, APS phenotypes vary widely, with some patients showing prominent cardiac or renal involvement alongside reduced accumulation. Nestor-Guillermo progeroid syndrome (NGPS) is an autosomal recessive disorder caused by homozygous mutations in BANF1, encoding barrier-to-autointegration factor 1 (BAF), a protein essential for integrity. Key manifestations include generalized lipoatrophy, severe with low density, early , sparse and thin , and progressive joint contractures, with normal early development followed by aging signs in childhood. The BANF1 defect disrupts assembly, leading to envelope abnormalities similar to those in other laminopathies. These syndromes share a core pathophysiological mechanism involving defective processing of prelamin A, where farnesylation occurs but cleavage by ZMPSTE24 is impaired in LMNA and ZMPSTE24-related cases, resulting in accumulation of farnesylated prelamin A that anchors to the nuclear membrane and causes structural instability. In BANF1-related NGPS, the mechanism converges on nuclear envelope disruption through altered BAF-lamin interactions. Recent studies have further linked these defects to epigenetic dysregulation, including disorganized chromatin organization and altered histone modifications that impair gene expression and accelerate cellular senescence. All these conditions are extremely rare, with estimated prevalences below 1 in 1,000,000 live births, and diagnosis relies on targeted to identify causative variants in LMNA, ZMPSTE24, or BANF1. Early molecular confirmation is crucial for distinguishing them from other progeroid syndromes and guiding supportive .

Other Progeroid Syndromes

RNA polymerase III (Pol III), encoded by genes such as POLR3A, is responsible for transcribing small non-coding RNAs, including transfer RNAs (tRNAs) and (rRNA), which are essential for protein synthesis and . Defects in Pol III function disrupt tRNA synthesis, leading to impaired translation efficiency and imbalance, where and degradation pathways are overwhelmed, contributing to accelerated cellular aging phenotypes observed in progeroid syndromes. This transcriptional dysregulation mimics aspects of chronological aging by reducing cellular resilience to stress and promoting senescence-like states. Wiedemann-Rautenstrauch syndrome (WRS), also known as neonatal progeroid syndrome, is an autosomal recessive disorder primarily caused by biallelic mutations in POLR3A on chromosome 10q22.3. Affected individuals present with a striking neonatal progeroid appearance, including a triangular face, sparse hair, and generalized with loss of subcutaneous fat except in areas like the . Additional features encompass ichthyosiform skin changes, natal teeth, feeding difficulties, recurrent respiratory infections, joint contractures, , intellectual ranging from mild to severe, and seizures in some cases. The condition is marked by intrauterine and postnatal growth retardation, with most patients succumbing in early infancy; average survival is approximately 7 months, though rare cases extend into the third decade. Clinically, RNA Pol III-related progeroid syndromes overlap with hypomyelinating leukodystrophies, sharing features such as developmental delay and ; brain imaging consistently reveals hypomyelination as a hallmark, with diffuse T2 hyperintensity and T1 hypointensity, often accompanied by cerebellar and thinning of the . Genetically, these syndromes arise from biallelic loss-of-function variants in POLR3A or related subunits, with over 50 cases of WRS reported worldwide as of 2022. Emerging research links Pol III defects to accelerated through impaired rRNA processing, as reduced transcription of 5S rRNA disrupts assembly and , exacerbating proteotoxic stress and limiting cellular proliferation in aging models. This mechanism provides a molecular basis for the premature aging hallmarks in these syndromes, with Pol III inhibition paradoxically enhancing in non-disease contexts by optimizing away from excessive .

Miscellaneous Genetic Defects

Miscellaneous genetic defects contribute to a heterogeneous group of progeroid syndromes that do not align with primary DNA repair or lamin-related pathways, often involving disruptions in mitochondrial function, signaling, vesicular trafficking, , and (ECM) . These rare conditions typically present with premature aging features such as wrinkled skin, growth retardation, and skeletal abnormalities, though their molecular bases vary widely. Additional examples include disorders of , such as those caused by mutations in PYCR1. A with phenotypic overlap to WRS associated with biallelic mutations in PYCR1, located on 17q25, involves disruptions in due to impaired function of the mitochondrial pyrroline-5-carboxylate reductase 1. This autosomal recessive disorder manifests as autosomal recessive type 2B with progeroid features, including wrinkled and lax skin, sparse hair, , and , often accompanied by mild but without the severe neurological progression seen in classic WRS. Unlike POLR3A-related WRS, PYCR1 defects lead to altered mitochondrial redox balance and increased , contributing to fragility and a less lethal progeroid . Fontaine progeroid syndrome is an autosomal dominant disorder caused by heterozygous mutations in the SLC25A24 gene, which encodes a mitochondrial ATP-Mg/Pi carrier protein essential for energy and calcium in s. Affected individuals exhibit , downslanting palpebral fissures, progeroid facial features, wrinkled , , and early mortality often due to respiratory or cardiac complications, with onset evident from infancy. The syndrome's progeroid appearance stems from impaired mitochondrial function leading to fragility, as demonstrated in patient fibroblasts showing disrupted calcium . Penttinen syndrome, also autosomal dominant, arises from gain-of-function mutations in the PDGFRB gene encoding platelet-derived growth factor receptor beta, a tyrosine kinase involved in cell proliferation and vascular development. Clinical manifestations include premature aging with loose, translucent skin, corneal clouding, arachnodactyly, short stature, and vascular anomalies such as aneurysms, reflecting dysregulated growth signaling that accelerates connective tissue degeneration. As of 2025, therapeutic approaches, including imatinib to inhibit the aberrant receptor activity, have shown promise in stabilizing progeroid features and preventing vascular complications in pediatric cases. Gerodermia osteodysplastica is an autosomal recessive progeroid syndrome resulting from biallelic mutations in the GORAB gene, which encodes a golgin protein critical for vesicular trafficking and Golgi apparatus function in ECM production. Patients display lax, wrinkled skin resembling , severe , , and mandibular , with symptoms progressing from early childhood and leading to fractures and joint laxity. The underlying defect disrupts glycosaminoglycan chain assembly in the ECM, contributing to the aging-like tissue fragility observed in affected individuals. Other notable examples include Berardinelli-Seip congenital lipodystrophy, caused by mutations in AGPAT2 or BSCL2 genes involved in lipid biosynthesis, which manifests progeroid features such as , accelerated epigenetic aging, and lipoatrophy alongside severe and hepatic steatosis. Similarly, spondylodysplastic Ehlers-Danlos syndrome variants due to defects in B3GALT6 or B4GALT7—genes encoding enzymes for —present with wrinkled, aging-like skin, , kyphoscoliosis, and joint hypermobility, highlighting ECM glycosylation's role in dermal integrity. As of 2025, advances in whole-exome sequencing have identified novel progeroid cases with growth retardation emphasis, including additional reports of WRS linked to POLR3A variants or de novo mutations in LEMD2 causing Marbach-Rustad progeroid syndrome, with only three cases reported as of 2023. These discoveries underscore the expanding , often tying back to metabolic or structural disruptions. A unifying theme across these miscellaneous defects is the perturbation of ECM organization or cellular metabolism, which mimics age-related tissue decline without direct involvement in DNA maintenance or nuclear envelope stability. Lipodystrophic elements in some cases, like Berardinelli-Seip, briefly overlap with laminopathy features but arise from distinct lipid-handling pathways.

Pathophysiological Mechanisms

Shared Features of Premature Aging

Progeroid syndromes exhibit several molecular hallmarks that mirror those of normal aging, including genomic instability, attrition, epigenetic alterations, and loss of . Genomic instability arises from defects in pathways, leading to accumulated mutations and chromosomal aberrations across affected tissues. attrition, prominent in syndromes like , results in critically short telomeres that trigger replicative in proliferating cells. Epigenetic alterations, such as aberrant and modifications, disrupt gene expression patterns essential for cellular maintenance. Loss of proteostasis involves impaired and degradation, culminating in toxic aggregates that compromise cellular function. At the tissue level, progeroid syndromes manifest shared premature aging phenotypes, particularly in cardiovascular, skeletal, and s. Cardiovascular effects include accelerated , observed in Hutchinson-Gilford progeria syndrome (HGPS) and , where vascular smooth muscle cell loss and fibrosis promote arterial stiffening and reduced elasticity. Skeletal involvement features , characterized by decreased bone mineral density and increased fracture risk due to impaired function and enhanced activity. In the , atrophy and loss of subcutaneous fat lead to thinning, wrinkling, and scleroderma-like changes, reflecting diminished dermal production. Cellular senescence plays a central role in driving these phenotypes, with persistent activation of the pathway inducing irreversible arrest in response to DNA damage and stress signals. This senescence is amplified by the (SASP), a pro-inflammatory secretome comprising cytokines, , and growth factors that fosters chronic and paracrine effects on neighboring cells. Mitochondrial dysfunction contributes to accumulation in multiple progeroid syndromes, where impaired activity elevates levels, exacerbating DNA damage and energy deficits. In 2025, studies have explored therapy in HGPS, showing improvements in and bone mineral density in a .

Cancer Predisposition

Progeroid syndromes characterized by defective mechanisms exhibit elevated cancer predisposition primarily due to genomic instability, where unrepaired or misrepaired damage accumulates mutations and chromosomal aberrations that promote oncogenesis. In RecQ helicase defects, such as those seen in Bloom and Werner syndromes, impaired and recombination lead to increased sister chromatid exchanges and loss of heterozygosity, heightening the odds of leukemias and sarcomas. This genomic instability arises from mutations in genes like BLM and WRN, which normally maintain telomere integrity and suppress tumor formation, resulting in a hypermutable cellular environment that fosters malignant transformation. Syndrome-specific cancer risks vary markedly, reflecting the underlying repair pathway defects. In Bloom syndrome, caused by BLM mutations, individuals face a substantially elevated overall cancer —estimated at 25- to 300-fold for certain malignancies—with common sites including cancers, , and leukemias, often manifesting in early adulthood. , due to WRN mutations, predisposes to approximately 10-15% incidence of sarcomas and a notable of carcinomas, alongside and meningiomas, accounting for over two-thirds of reported neoplasms in affected patients. (XP), a (NER) defect, confers an extraordinarily high of skin cancers, exceeding 10,000-fold for non-melanoma types and 2,000-fold for compared to the general population, primarily due to unchecked UV-induced DNA lesions. Rothmund-Thomson syndrome, linked to RECQL4 mutations, carries a significant of , affecting up to two-thirds of patients with biallelic variants, often in childhood or adolescence. In contrast, non-DNA repair progeroid syndromes like Hutchinson-Gilford progeria syndrome (HGPS), caused by LMNA mutations, show paradoxically low cancer incidence despite genomic instability, with affected individuals rarely developing malignancies and instead succumbing primarily to atherosclerosis-related . Werner syndrome, while featuring DNA repair defects, also presents with relatively rare tumor types uncommon in the general population, such as soft tissue sarcomas and thyroid cancers, underscoring a selective oncogenic predisposition. Overall, lifetime cancer risk in DNA repair-deficient progeroid syndromes ranges from 20% to over 50%, far exceeding the general population's baseline risk for comparable early-onset malignancies, though exact figures vary by syndrome and environmental factors. Management strategies emphasize early screening to mitigate these risks, including annual dermatological examinations for XP patients to detect precancerous lesions promptly. Rigorous sun avoidance and photoprotection in NER defects like XP can substantially reduce the incidence of cancers. For RecQ-related syndromes, for sarcomas and issues via and is recommended starting in , though no syndrome-specific 2025 incidence reduction data beyond photoprotection benefits is available. These interventions highlight the critical role of proactive monitoring in improving outcomes for this high-risk group.

Diagnosis and Management

Diagnostic Approaches

Diagnosis of progeroid syndromes begins with a thorough clinical evaluation, focusing on characteristic features of premature aging that manifest in childhood or early adulthood, such as severe growth failure, alopecia, scleroderma-like skin changes, and in Hutchinson-Gilford progeria syndrome (HGPS). For , key signs include bilateral cataracts, premature graying or thinning of hair, characteristic skin pathology, and , with onset typically after age 10. In , clinical suspicion arises from postnatal growth retardation below the 5th percentile by age 2, progressive , and neurologic dysfunction, often accompanied by . Multidisciplinary assessments, including growth charts to track , dermatologic examinations for skin or , and neurologic evaluations for neuropathy or , are essential to identify red flags like pediatric in HGPS or intracranial calcifications in Cockayne syndrome. Imaging plays a critical role in confirming organ involvement and monitoring progression. In HGPS, radiographs reveal musculoskeletal abnormalities such as osteolysis of the clavicles and , while annual MRI or (MRA) detects vascular stenoses contributing to cardiovascular risk. For Cockayne syndrome, brain MRI demonstrates white matter dysmyelination, cerebral and cerebellar atrophy, and calcifications, which are in advanced cases. is recommended in HGPS to assess cardiac structure and function, given the high incidence of myocardial fibrosis. In Werner syndrome, scans identify , and head MRI is used if neurologic symptoms like meningiomas are present. Biochemical tests provide supportive evidence by highlighting metabolic derangements associated with accelerated aging. Elevated markers of , such as products, are observed in several progeroid syndromes due to underlying defects. Lipid profiles often show in HGPS, contributing to , while fasting glucose or hemoglobin A1c testing detects mellitus in up to 50% of cases. In , assays measuring recovery of RNA synthesis after UV exposure in cultured fibroblasts confirm transcription-coupled deficiency. Genetic testing is the gold standard for definitive diagnosis, with targeted panels or next-generation sequencing (NGS) enabling rapid identification of causative variants. In HGPS, sequencing of LMNA 11 detects the heterozygous c.1824C>T in approximately 90% of classic cases. For , biallelic pathogenic variants in WRN, such as the common c.1105C>T allele, are identified via sequence analysis in 97% of affected individuals. diagnosis relies on biallelic variants in ERCC6 (65%) or ERCC8 (35%), often using multigene panels that include genes. Whole-exome sequencing is recommended for atypical or unknown cases, with prenatal diagnosis possible through or when familial risk is established. Current NGS-based guidelines, updated as of 2025, emphasize comprehensive panels covering up to 20 genes (e.g., LMNA, WRN, ERCC6/8, POLR3A) for efficient diagnosis in suspected progeroid syndromes. Differential diagnosis is challenging due to phenotypic overlap with cachectic conditions like or other syndromes such as . HGPS must be distinguished from non-progerin-producing laminopathies or ZMPSTE24-related disorders, while overlaps with in features like and skin changes. is differentiated from Pelizaeus-Merzbacher disease via , as both present with demyelination but differ in photosensitivity. Challenges in diagnosis stem from the rarity of these syndromes, leading to delayed recognition, and the broad phenotypic spectrum, including variants of unknown significance in genetic tests that require expert interpretation. Multidisciplinary input from geneticists, pediatricians, and neurologists is crucial to navigate overlaps and ensure timely confirmation, particularly in resource-limited settings where access to NGS may be restricted.

Treatment Strategies

Treatment strategies for progeroid syndromes primarily focus on supportive care, targeted therapies addressing underlying molecular defects, and emerging genetic interventions, as no curative options exist. Supportive management involves a multidisciplinary approach, including nutritional support to address growth deficiencies, physiotherapy to maintain mobility and prevent contractures, and for associated discomfort. In Hutchinson-Gilford progeria syndrome (HGPS), cardioprotective measures such as low-dose aspirin to reduce thrombotic risk and statins like pravastatin to improve vascular function are commonly employed to mitigate cardiovascular complications, the leading cause of mortality. Targeted therapies aim to correct specific pathogenic mechanisms. For HGPS, , a farnesyltransferase inhibitor, reduces farnesylation, thereby improving nuclear morphology and cellular function; it was approved by the FDA in 2020 based on clinical trials demonstrating reduced mortality and extended survival. In , antioxidants and NAD+ precursors, such as , have shown promise in alleviating and improving span; a double-blind randomized crossover published in 2025 demonstrated benefits in cardiovascular , reduced skin area, and slowed kidney function decline in patients. Gene therapy approaches are in early stages. For HGPS, CRISPR-based editing of LMNA mutations, including base editors to correct the c.1824C>T variant, has demonstrated symptom amelioration and lifespan extension in models, remaining preclinical as of 2025. Emerging preclinical therapies for HGPS include RNA-based interventions, such as Cas13d-mediated targeting of mRNA, which reversed symptoms like and improved weight gain in models as reported in 2025. base editing has also shown significant lifespan improvement and vascular benefits in HGPS models in 2025 studies. An ongoing phase 2 of Progerinin, an oral investigational drug combined with , is evaluating safety, tolerability, and in HGPS patients as of late 2024, with enrollment continuing into 2025. Symptom-specific interventions address secondary manifestations. In (XP), rigorous sun protection with high-SPF sunscreens and UV-blocking clothing is essential, alongside surgical excision for skin cancers to prevent progression. For , hearing aids mitigate , improving quality of life. In Bloom syndrome, hematopoietic stem cell transplantation has been explored to correct and reduce infection risk, with successful haploidentical procedures reported in pediatric cases. These strategies modestly impact prognosis, with extending mean survival in HGPS by approximately 2.5 years compared to untreated cohorts, though overall remains limited to around 14.5 years. No therapies cure progeroid syndromes, but ongoing explorations like transplants for Bloom syndrome-associated failure offer potential for managing complications. Ethical considerations in clinical trials emphasize , given the pediatric population and rarity of these conditions, prioritizing equitable access and minimizing risks in vulnerable participants.

Research and Models

Animal Models

Animal models have been instrumental in elucidating the mechanisms of progeroid syndromes, particularly through genetic manipulations that recapitulate key human phenotypes. In mice, knock-in models harboring the Lmna^G609G , which produces progerin similar to that in Hutchinson-Gilford progeria syndrome (HGPS), exhibit abnormalities, growth retardation, and a markedly shortened lifespan of approximately 120-150 days. These models demonstrate segmental aging features, including loss of subcutaneous fat and bone abnormalities, but with variable severity across strains. For , standard Wrn knockout mice (Wrn^{-/-}) exhibit subtle genomic instability but no overt premature aging phenotypes or shortened lifespan (mean ~21 months). They develop late-onset features like cataracts around 8-12 months of age. When combined with p53 deficiency, these mice show increased tumor incidence and reduced lifespan (~4 months), though fertility remains normal. These mice show genomic instability and elevated cancer rates in certain genetic backgrounds, mirroring aspects of human , though they lack some dermal and vascular changes observed in patients. Invertebrate and lower vertebrate models complement mammalian studies by focusing on conserved pathways. In Caenorhabditis elegans, mutations in the RecQ helicase homolog wrn-1 result in reduced lifespan (median of 6.8 days versus 9 days in wild-type) and increased sensitivity to DNA damage, providing insights into DNA repair's role in longevity. Zebrafish with ercc8 mutations, orthologous to the Cockayne syndrome gene CSA, exhibit UV hypersensitivity and neurological defects, recapitulating photosensitivity and transcription-repair coupling deficiencies. Key insights from these models highlight therapeutic reversibility. Progerin-expressing mice show accelerated vascular cell loss and arterial stiffening, but treatment with farnesyltransferase inhibitors like reverses nuclear defects and improves survival by up to 50%, underscoring the role of farnesylation in vascular aging. Recent studies on III-related syndromes, such as Wiedemann-Rautenstrauch syndrome, have utilized conditional knockouts in mice to replicate and growth failure, though full embryonic lethality in homozygous Polr3a nulls limits direct modeling. Despite these advances, mouse models have limitations, including incomplete recapitulation of human phenotypes; for instance, standard Lmna^G609G mice often lack overt unless crossed with E-deficient strains. To bridge this gap, human (iPSC)-derived models from progeroid patients generate affected cell types like vascular cells, revealing disease-specific defects not fully captured . These models facilitate preclinical applications, such as testing lonafarnib analogs, which extend lifespan and reduce progerin accumulation in HGPS mice, informing drug optimization for clinical translation.

Ongoing Research

Recent advances in progeroid syndrome research emphasize epigenetic modifications as a key therapeutic target, particularly in laminopathies like Hutchinson-Gilford progeria syndrome (HGPS). Histone deacetylase (HDAC) inhibitors have shown promise in restoring chromatin structure and alleviating premature senescence by counteracting the aberrant histone hypoacetylation observed in progerin-expressing cells. For instance, treatment with HDAC inhibitors has rescued the early senescence phenotype in HGPS patient-derived fibroblasts and extended lifespan in Zmpste24-null mouse models of progeria. Valproic acid, a broad-spectrum HDAC inhibitor, is under investigation for its potential to modulate lamin A/C-HDAC2 interactions and reduce progerin-induced cellular defects, with ongoing preclinical studies exploring its efficacy in HGPS models as of 2025. Senolytic therapies are emerging as another frontline approach to mitigate the accumulation of senescent cells, a hallmark shared across progeroid syndromes. The combination of and selectively clears senescent cells in preclinical models, including those mimicking , by targeting pro-survival pathways like proteins. In models, this cocktail has reduced (SASP) factors, improved tissue function, and extended healthspan, suggesting potential translation to human segmental progeroid disorders. Clinical pilot studies have further demonstrated that plus decreases senescent cell burden in humans, paving the way for trials in progeroid populations. Multi-omics approaches are uncovering shared molecular underpinnings of progeroid syndromes, with highlighting defects in as a common thread. Global plasma proteomic analyses in Lmna^G609G/G609G and Zmpste24^{-/-} mouse models have revealed dysregulated secretomes involving proteostasis pathways, such as impaired and clearance, that mirror aging-related disruptions. Complementing this, AI-driven tools are enhancing variant prediction for undiagnosed cases by integrating genomic, epigenomic, and phenotypic data to classify pathogenicity in rare Mendelian disorders, including progeroid syndromes. For example, classifiers trained on large variant datasets achieve high accuracy in forecasting functional impacts of novel mutations in genes like LMNA or WRN. International consortia, led by organizations like the Progeria Research Foundation (PRF), are driving collaborative efforts toward combination therapies. PRF initiatives in 2024-2025 include the ongoing of Progerinin, a novel therapy targeting , which is showing promise in preclinical HGPS mouse models for extending lifespan. Recent approaches, including CRISPR-Cas9 editing of WRN mutations in patient-derived cells, have restored functions in models, while trials for dyskeratosis congenita report improved function as of 2025. These efforts build on prior evidence for triple therapies incorporating with statins and bisphosphonates to address cardiovascular complications. Research is also addressing gaps in non-laminopathies, such as Fontaine progeroid syndrome, where mitochondrial dysfunction plays a central role. Recent studies have identified SLC25A24 mutations disrupting mitochondrial phosphate transport, leading to energy deficits and progeroid features, with 2025 classifications increasingly incorporating mitochondrial pathways across progeroid disorders to refine diagnostic criteria. This expands beyond lamin-centric views, highlighting and bioenergetic failures in syndromes like Fontaine. Potential breakthroughs include base editing strategies for correcting de novo LMNA mutations prevalent in HGPS. base editors have successfully reversed the c.1824 C>T mutation in patient fibroblasts, reducing levels, nuclear abnormalities, and markers. applications in HGPS mouse models demonstrate lifespan extension and phenotypic rescue, with 2025 advancements in mutation-agnostic editing platforms targeting the farnesylation site to broaden applicability across LMNA variants.

Societal Aspects

Notable Individuals

(1997–2015) was a British advocate for Hutchinson-Gilford progeria syndrome (HGPS) awareness, diagnosed at age two and living to 17, far exceeding the typical of 13 years for the condition. She co-authored the autobiography Old Before My Time at age 13, detailing her experiences with accelerated aging, including participation in clinical trials for , a farnesyltransferase inhibitor that showed promise in slowing disease progression. Okines used and public speaking to campaign for research funding, inspiring global support for progeria initiatives before her death from cardiovascular complications. Sam Berns (1996–2014), an American teenager from , with HGPS, became a prominent figure in raising awareness through the Emmy-winning documentary (2013), which chronicled his family's efforts to advance research into the disease. Diagnosed at nearly two years old, Berns lived to 17 and actively collaborated with the Progeria Research Foundation (PRF), delivering a TEDx talk in 2013 on his philosophy for a happy life despite physical limitations like joint stiffness and . His advocacy, including high school involvement in marching band and football managing, directly inspired the PRF's founding by his mother, Leslie Gordon, accelerating clinical trials and genetic studies. Adalia Rose Williams (2007–2022), a Texas-based social media influencer with HGPS diagnosed at three months, amassed nearly three million subscribers and over 12 million followers by sharing makeup tutorials, comedy skits, and daily life updates that highlighted joy and resilience amid symptoms like frail skin and growth failure. Living to 15, she emphasized positivity in videos, such as her "Sunset makeup look," fostering a supportive and drawing attention to progeria's emotional toll before her passing from related complications. In , a progeroid condition more prevalent in where approximately 75% of global cases originate, patient cohorts have benefited from robust cultural support systems, including nationwide surveys and multidisciplinary care networks that facilitate early and family assistance. For instance, a Japanese survey identified 116 confirmed cases, underscoring community-driven efforts like genetic registries that enhance access to specialized treatments for complications such as cataracts and . These individuals' stories have profoundly influenced progeroid syndrome research, driving increased funding and public engagement; for example, PRF has awarded over $9.1 million in grants across 85 projects in 18 states and 14 countries, partly fueled by awareness from cases like Berns and Okines. In 2025, ongoing memorials and campaigns honoring figures like Williams continue to support initiatives such as the PRF's "One Possible 2025" program, which advances clinical trials and longevity gene therapies.

Representation in Media

Progeroid syndromes, most notably Hutchinson-Gilford progeria syndrome (HGPS), have appeared in literature as both fictional explorations of accelerated aging and personal non-fiction narratives that humanize the lived experience of the condition. F. Scott Fitzgerald's 1922 short story "The Curious Case of Benjamin Button" depicts a character who ages in reverse, serving as an early literary inversion of progeria-like premature aging themes, with scholars noting its conceptual parallels to the syndrome's manifestations in oral and physical features. In non-fiction, , a British teenager with HGPS who lived to 17, co-authored memoirs such as Old Before My Time (2011), which chronicles her daily challenges, medical treatments, and optimism despite aging eight times faster than peers, and Young at Heart (2014), focusing on her teenage aspirations amid the disease's progression. Film and television representations of progeroid syndromes emphasize documentary formats to convey real stories, though scripted medical dramas occasionally reference the condition. The 2013 documentary , directed by Sean Fine and Andrea Nix Fine, follows , one of fewer than 400 known children worldwide with HGPS at the time, as he advocates for research while navigating adolescence, highlighting his humor and activism before his death at 17. Other documentaries, such as the 2005 episode of Medical Incredible titled "Progeria," explore clinical cases and family impacts, including a child with the syndrome alongside rare conditions like . Fictional TV portrayals remain sparse, but episodes in medical series have touched on rapid-aging disorders akin to , often using them to dramatize diagnostic puzzles without deep exploration. Theatre offers rare but poignant depictions, typically through adaptations that blend progeria-inspired elements with broader themes of youth and mortality. David Lindsay-Abaire's play (2000), later adapted into a Tony Award-winning musical in , centers on a 16-year-old with an unnamed resembling HGPS, causing her to age four-and-a-half times faster, as she grapples with family dysfunction and fleeting normalcy in suburban . Productions emphasize her resilience and wit, avoiding overt tragedy while underscoring the isolation of premature aging. In public culture, media coverage of progeroid syndromes often veers into , portraying affected individuals as tragic anomalies or "others" to evoke rather than , which can reinforce stigma and overlook their agency. For instance, headlines dubbing HGPS the "Benjamin Button disease" perpetuate misconceptions by conflating it with reverse aging fiction, despite the syndrome's forward acceleration of cardiovascular and skeletal decline. Countering this, the Progeria Research Foundation (PRF) has launched awareness campaigns, including public service announcements (PSAs) and videos shared via their official channels, to promote accurate portrayals of children with HGPS as vibrant individuals deserving of research support. In 2025, PRF's initiatives, such as the International Scientific Workshop and Race for Research, integrated media outreach to highlight treatment advances like , fostering narratives of hope over inevitability. These media representations have amplified societal awareness of progeroid syndromes, contributing to increased funding for —PRF's efforts, boosted by exposure, have supported clinical trials extending average lifespans from 13 to nearly 20 years—yet they simultaneously risk stigmatizing affected families by emphasizing rarity and fatality at the expense of normalcy.

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