INTRODUCTION
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder that causes premature, rapid aging shortly after birth.
It was discovered in 1886 by Jonathan Hutchinson, who documented the clinical features of a boy aged 6 years who had congenital absence of the hair and atrophy of the skin.
Congenital Absence of Hair and Mammary Glands 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
Hastings Gilford followed up this patient and another and in 1897 recognized it as a clinical entity and introduced the word progeria, which comes from the Greek words "pro" (πρό), meaning "before" or "premature", and "gēras" (γῆρας), meaning "old age".
On a Condition of Mixed Premature and Immature Development
The disorder has a very low incidence rate, occurring in an estimated 1 per 8 million live births. Over 150 cases have been reported in literature throughout the world. Prevalence of sex has not been evidenced so far. The average life expectancy for a patient with HGPS is 13 years, with an age range of 7 to 27 years old. The 97% of HGPS patients is Caucasian and cardiovascular abnormalities account for 75% of death in patients with the syndrome. It frequently is a genetic condition that occurs as a new mutation and is rarely inherited, as patients usually do not live enough to reproduce.
Although the term progeria is often used to identify all diseases characterized by premature aging symptoms, called progeroid syndromes, it can be specifically applied in reference to HGPS.
Molecular ageing in progeroid syndromes: Hutchinson-Gilford progeria syndrome as a model
CLINICAL DESCRIPTION
Children with progeria usually develop the earliest symptoms during their first few months of life, in particular failure to thrive and skin abnormalities (sclerotic and wrinkled skin).
These patients have a distinctive appearance: a larger head in relation to body, a narrow face with a shallow recessed jaw (micrognathism), a beaked nose, prominent eyes, cutaneous and scalp vasculature, eyelashes and eyebrow alopecia, protruding ears with absent lobes, thin lips with centrofacial cyanosis and high-pitched voice.
Additional signs usually appear around 18–24 months and become more marked as the child ages. In fact, as time passes, the syndrome begins to envolve the entire body, causing premature atherosclerosis and cardiovascular problems, kidney failure and loss of eyesight. People diagnosed with this disorder have small, fragile bodies, like those of elderly people, due to a generalized anomaly in bone development. Furthermore musculoskeletal degeneration causes loss of subcutaneous fat and muscle, stiffness of the joints, hip dislocations and other symptoms generally absent in the non-elderly population. However, children affected by HGPS usually retain normal mental development.
Patients who have most of the aforementioned characteristics are considered to have a classic case of progeria. Nevertheless, individuals who have more or less intense features of the syndrome are considered patients with atypical progeria.
THE GENETIC CAUSE
HGPS as a laminopathy
HGPS belongs to a group of disorders called laminopathies, classified together as they all affect nuclear lamins.
Lamins are proteins with a basic structural role in the nuclear lamina, which is that dense (~30 to 100 nm thick) fibrillar network inside the nucleus composed of intermediate filaments and membrane associated proteins. In particular lamins A/C, encoded by LMNA gene, form a proteinaceous network underlying the inner nuclear membrane which determines the shape, the integrity and the size of the nucleus.
Furthermore lamins play an important part in the organization of the pore complex and recruit other proteins such as emerin for the nuclear envelope.
Due to the multiple interactions between chromatin and the nuclear matrix, mutations in lamins A and C are thought to impair several nuclear functions including chromatin and chromosome stability, telomere integrity, regulation of transcription, DNA replication, cell cycle control and cellular differentiation, causing a variety of disorders which first affect striated muscle, adipocytes and peripheral nerves.
LMNA mutation: the molecular mechanism
Mutations in two genes, LMNA and ZMPSTE24, have been found in patients affected by HPGS . These genes are both envolved in prelamin A processing. Mutations in LMNA have been detected in 88% of patients with HGPS, while the genetic mechanism of the remaining 12% is still unknown.
The LMNA gene is 57.6 kb long and is located on the long (q) arm of chromosome 1 at position 22. It consists of 12 exons, encoding two globular domains and a central alpha-helical coiled-coil domain. Lamin C is encoded by exons 1 to 9 and a portion of exon 10. Lamin A results from alternative splicing, which adds exons 11 and 12 and removes the lamin-C-specific portion of exon 10. Lamin A is normally synthesized as a precursor molecule (prelamin A). Lamin A and C, with a molecular weight ranging from 60 to 78 kDa, are identical in the first 566 amino acids. As lamin A contains a carboxyl-terminal CAAX box (C is cysteine, A is an aliphatic amino acid and X is any amino acid), it is modified by farnesylation, which does not occur in lamin C. Following farnesylation, the cleavage of the three last amino acids and methylation of the carboxyl-terminal, an internal proteolytic cleavage takes place removing the last 15 coding amino acids, in order to generate a mature lamin A with 646 amino acids.
The frequent mutation p.G608G in position 1824 of the LMNA gene and the consequent abnormal splicing produce a prelamin A that still retains the CAAX box but is missing a part for endoproteolytic cleavage. This mutation causes the transcription of a shorter than normal mRNA that, when translated, yields an abnormal variant of the prelamin A protein whose farnesyl group cannot be removed. This abnormal protein, referred to as progerin, is permanently affixed to the nuclear rim and therefore does not become part of the nuclear lamina. Without lamin A, the nuclear lamina is unable to provide the nuclear envelope with adequate structural support, causing it to take on an abnormal shape. Furthermore, the disruption of the normal lamina architecture leads to fragility, vulnerability to mechanical stresses and nuclear blebbing. Other consequences include disrupted interactions with other nuclear envelope proteins, such as nesprin, emerin and lamina associated protein 2 (LAP2), and clustering of nuclear pores.
Cells expressing progerin may experience delayed mitotic progression which would be consistent with the early onset and global growth deficit of the HGPS phenotype.
It has been discovered that progerin also plays a role in normal human aging, since its production is activated in senescent wildtype cells.
Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts.
ZMPSTE24 and other minor mutations
While mutations in LMNA gene is certainly the main cause of Hutchinson Gilford Progeria Syndrome, in several patients a mutation in ZMPSTE24 gene has been found. ZMPSTE24 gene is located on the short (p) arm of chromosome 1 at position 34 and encodes for a metalloproteinase specifically involved in the post-translational proteolytic processing of prelamin A to mature lamin A. In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur. Consequently, no mature lamin A is formed and the farnesylated mutant prelamin A (progerin) accumulates in cells, as it occurs in LMNA mutation.
The inheritance pattern in progeria syndrome is autosomal dominant or less frequently recessive, when involving the ZMPSTE24 gene . All subjects with HGPS have the disease as result of a de novo mutation, as their parents are not affected. Furthermore patients usually die young and do not live enough to reproduce. The most frequent mutation is p.G608G but five other different de novo dominant LMNA mutations have been found: p.E145K, p.S143F, p.R644C, p. T10I and p.E578V.
In 2007 a study was carried out with the attempt to establish whether the LMNA p.G608G mutation is associated with a particular phenotype of HGPS.
Hutchinson-Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature
Although a prevalence of sex has not been identified, according to a study mutations in HGPS could have a paternal origin.
Paternal origin of LMNA mutations in Hutchinson-Gilford progeria.
DIAGNOSIS
Diagnosis is usually suspected according to the typical signs and symptoms, such as the skin abnormalities and the distinctive appereance aforementioned.
However, some clinical tests can be used for a confirmatory diagnosis. Sequential analysis of the gene LMNA reveals point mutations in approximately 90% of the patients with HGPS, and the test for uniparental disomy of chromosome 1 and deletions associated with HGPS. Imaging studies may also be performed. Radiography detects manifestations that usually occur in the skull, thorax, long bones, and phalanges.
Moreover under light microscopy, histological tests using skin biopsies from HGPS patients exhibit irregular nuclear envelope outlines, indicating the massive and global alterations of chromatin functions, including alterations of gene expression.
So, the diagnostic methods to confirm HGPS pattern are:
- clinical (serum lipid levels, hyaluronic acid excretion, blood count)
- histological (biopsies from areas of abdominal skin with abnormal nuclear morphology)
- radiological (abnormality found in the brain, thorax, long bones and phalanges).
As progeria is extremely rare no laboratory offers a specific molecular genetic testing for prenatal diagnosis. Nevertheless, prenatal testing may be offered to families in which the causative mutation of the disorder has been identified in a family member.
Tests using keratinocytes from transgenic mice expressing progerin revealed alterations in nuclear shape such as decreased nuclear circularity, resulting in greater nuclear surface area and greater morphological diversity, thereby, microscopic analysis of the nuclear shape could be an interesting diagnostic alternative to be studied.
Epidermal expression of the truncated prelamin A causing Hutchinson-Gilford progeria syndrome: effects on keratinocytes, hair and skin.
THERAPY
There is no known cure for progeria. Nonetheless, there are treatments in order to improve the clinical conditions. Regular diets may be prescribed, as well as routine immunizations, inspection for cardiovascular diseases, surgical procedures and physical and psychological therapies.
Supplements with fluoride are recommended, since there are dental problems. It is advised to occasionally give small doses of aspirin to children with HGPS, aimed at reducing the occurrence of heart attack and strokes. Nitroglycerin may be useful to avoid the development of angina.
The drug doses must be based on weight and the anesthetics must be used cautiously.
As these children are susceptible to fractures, they should be routinely accompanied. Due to the susceptibility to dislocation of the hip bone because of coxa valga, conservative care and surgical procedures are recommended. Physical and psychological therapies are important to help maintain the joints with good movement amplitude.
Hutchinson-Gilford progeria syndrome
Other possibilities of treatment involve the use of low levels of growth hormone, but hormonal replacement has had unsatisfactory effects in these patients.
A new frontier in the therapeutic approach involves the use of farnesyltransferase inhibitors (FTIs) in order to reverse nuclear abnormalities in cells expressing progerin. In vitro studies in fibroblasts have shown the capacity of farnesyltransferase inhibitors to reverse nuclear alterations and have given a promising response. In fact the systemic administration of FTI-276 or pravastatin plus zoledronate was prooved to significantly improve nuclear morphological abnormalities in keratinocytes of transgenic mice.
Blocking protein farnesylation improves nuclear shape abnormalities in keratinocytes of mice expressing the prelamin A variant in Hutchinson-Gilford progeria syndrome.
Using transgenic mice expressing progerin, a reversion of cardiovascular phenotype, a reduction of the spontaneous rib fractures and an improved survival and growth was observed, indicating that these compounds are an interesting pharmacological alternative for future treatment of HGPS and progeroid syndromes, as well as anti-aging.
A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model
