Hutchinson-Gilford Progeria syndrome

Mbah Dukun watched Bollywood movie, “PAA”. Story of Auro ( Amitabh Bachchan ), a 12 years old boy who because of genetic abnormalities called progeria have sightings like people aged 60 years. So what is Progeria?

Disease name and synonyms

• Progeria

• Hutchinson-Gilford progeria syndrome

(HGPS)

Hutchinson-Gilford progeria syndrome is a rare genetic disorder characterized by many features reminiscent of marked premature ageing. The characteristic features include short stature, prominent eyes, micrognathia, craniofacial disproportion, loss of subcutaneous fat, alopecia, beaked nose, "plucked-bird" appearance, coax valga, pathologic bone fractures, atherosclerosis, and cardiovascular disorders. Other clinical features include abnormal and delayed dentition, thin and highpitched voice, pyriform thorax, and short dystrophic clavicles.

At birth, the appearance of patients with Hutchinson-Gilford progeria syndrome is generally normal, but by the first year of age patients show severe growth retardation, balding and sclerodermatous skin changes. Affected children are usually short and thin with an average height of 100 cm or so and average weight of 12-15 kg or even less. Death usually occurs from 7 to 28 years, with a median age of 13.4 years. Over 80% of deaths are due to heart attacks or congestive heart failure.

Molecular Genetics

Hutchinson-Gilford progeria syndrome is caused by mutation in the lamin A (LMNA) gene. Lamins are type V intermediate filament proteins and have a short N-terminal "head" domain, an alpha-helical "central rod" domain, and a globular tail domain. Lamins are classified as either A or B type according to their primary sequence, expression pattern, and biochemical properties. B-type lamins are expressed in all cells during development and in adult animals, whereas A-type lamins are expressed in differentiated cells. The LMNA gene encodes three A-type lamins: lamin A (LA), lamin C, and lamin A delta-10. Lamin A contains a C-terminal CAAX box, which undergoes methyl esterification and farnesylation. In the process of LA maturation, the C-terminal 18 residues, which include the modified C-terminal cysteine, are removed in two specific cleavage steps.

The most frequent LMNA mutation in Hutchinson-Gilford progeria syndrome is a nucleotide substitution at position 1824, C-to-T, resulting in a silent gly-to-gly mutation at codon 608 (G608G) within exon 11 of the LMNA gene. This predicts a deletion of 50 basepairs of prelamin A near the C terminus. Low levels of both the mutant mRNA and the mutant protein, LA delta-50, are expressed in fibroblasts derived from Hutchinson-Gilford progeria syndrome patients. In addition, Hutchinson- Gilford progeria syndrome cell nuclei frequently display irregular shapes.

Etiology

Hutchinson-Gilford Progeria Syndrome (HGPS) is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene, replacing cytosine with thymine, creating a form of the Lamin A protein which can not be processed properly and accumulates in the cell nucleus. Lamin A is a major structural protein of the human cell nucleus. Before the late 20th century, research on progeria yielded very little information about the syndrome. In 2003, the cause of progeria was discovered. The LMNA gene is responsible for producing lamin proteins, which provide strength and stability in cells. Lamin A and Lamin C support the nuclear envelope. When Lamin A is altered, it affects the shape and the function of the nuclear envelope. These changes cause other cells to die prematurely.

Unlike "accelerated aging diseases" (such as Werner's syndrome, Cockayne's syndrome, or xeroderma pigmentosum), progeria is not caused by defective DNA repair. Because these diseases display what are considered different aspects of aging but never every aspect, they are often called "segmental progerias".

Signs and symptoms
Diagnosis
Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test.

 

Clinical Diagnosis
The diagnosis of classic Hutchinson-Gilford progeria syndrome (HGPS, progeria) is based on recognition of common clinical features and detection of the classic c.1824C>T (p.Gly608Gly) heterozygous LMNA mutation; the diagnosis of atypical HGPS is made in individuals with more or less severe features or the non-classic LMNA mutations, for example, c.1822 G>A (p.Gly608Ser), c.1821G>A (p.Val607Val), or c.1968+1G>A.
Individuals having the p.Gly608Gly LMNA silent mutation and most of the following features after age three years are considered to have the classic Hutchinson-Gilford progeria syndrome:
•    Growth
o    Short stature (<3rd percentile), lifelong
o    Weight (<3rd percentile), lifelong
o    Weight distinctly low for height
o    Head disproportionately large for face
o    Thin, high-pitched voice
•    Body fat. .Diminished subcutaneous fat globally, with the following sequellae:
o    Prominent scalp veins
o    Prominent veins over most of body
o    Irregular small outpouchings of skin over lower abdomen and/or proximal thighs
o    Circumoral cyanosis
o    Prominent eyes
o    Lack of ear lobes, in some but not all cases
•    Skin/hair/nails
o    Taut, dry skin that is variably pigmented (spotty)
o    "Sclerodermatous" skin over lower abdomen and proximal thighs
o    Generalized alopecia with sparse downy hairs on the occiput
o    Loss of eyebrows and sometimes eyelashes
o    Dystrophic fingernails and toenails
o    Lagophthalmos (the inability to fully close the eye) and, in a minority of cases, corneal ulceration
o    Thin lips
•    Teeth
o    Delayed eruption of primary teeth
o    Delayed loss of erupted primary teeth
o    Partial secondary tooth eruption
o    Dental crowding as a result of small mouth, lack of primary tooth loss, and secondary tooth eruption behind primary teeth
•    Skeletal system/joints
o    Narrow nasal bridge, pointed nasal tip
o    Osteolysis of the distal phalanges
o    Delayed closure of the anterior fontanelle
o    Pear-shaped thorax
o    Retrognathia and micrognathia
o    Short, dystrophic clavicles
o    Osteoarthritis
o    "Horse-riding" stance and wide-based, shuffling gait
o    Coxa valga
o    Low bone density
o    Thin limbs
o    Tightened joint ligaments globally but variable in severity
•    Cardiovascular/neurovascular
o    Severe progressive atherosclerosis with variable age of clinical manifestation resulting in:
    Cardiac manifestations: angina, congestive heart failure, myocardial infarction
   Stroke, including transient ischemic attacks and silent strokes that are seen on MRI or CT of the head but do not manifest as clinical deficits
o    Raynaud phenomenon in fingers of some but not all individuals
•    Audiologic. Low-frequency conductive hearing loss
•    Endocrine
o    Failure to complete secondary sexual development
o    Low serum leptin concentration
o    Insulin resistance in up to 50% of individuals. Note that frank diabetes mellitus is unusual.


Treatment
There's no cure for progeria. Regular monitoring for cardiovascular disease may help with  managing your child's condition. Some children undergo coronary artery bypass surgery or dilation of cardiac arteries (angioplasty) to slow the progression of cardiovascular disease.
Certain therapies may ease or delay some of the signs and symptoms. They include:
•    Low-dose aspirin. A daily dose may help prevent heart attacks and stroke.
•    Other medications. Depending on your child's condition, your doctor may prescribe other medications, such as statins to lower cholesterol or anticoagulants to help prevent blood clots. The use of growth hormone may help increase height and weight.
•    Physical and occupational therapy. These may help with joint stiffness and hip problems and may allow your child to remain active.
•    Extraction of primary teeth. Your child's permanent teeth may start coming in before his or her baby teeth fall out. Extraction may help prevent problems associated with the delayed loss of baby teeth, including overcrowding and developing a second row of teeth when permanent teeth come in.

Prognosis
There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.
Mental development is not affected. With respect to the features of aging that progeria appears to manifest, the development of symptoms is comparable to aging at a rate eight to ten times faster than normal. With respect to features of aging that progeria does not exhibit, patients show no neurodegeneration or cancer predisposition. They also do not develop the so-called "wear and tear" conditions commonly associated with aging, such as cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).[
Although there may not be any successful treatments for progeria itself, there are treatments for the problems it causes, such as arthritic, respiratory, and cardiovascular problems.

Refferences
1.    http://www.ncbi.nlm.nih.gov/books/NBK1121
2.    http://www.answers.com/topic/progeria
3.    http://www.cags.org.ae/pdf/176670.pdf