Progeria

Progeria (Greek and means "prematurely old") also known as Hutchison-Gilford progeria syndrome (HGPS) is a rare genetic disorder producing rapid aging and premature death. There are different forms of progeria, and HGPS, the classical type was named after the physicians who first documented it in 1886, Dr. Jonathan Hutchinson and Dr. Hastings Gilford. The disorder with a low incidence of 1 per 8 million live births is a fatal condition where changes of human aging are mainfested at an unusually early age. The affected children experience severe growth failure with changes in many organs. The mean survival age is 13.4 years and the most common cause of death is myocardial infarction.

Pathogenesis

The nuclear envelope contains proteins of the A-type lamin family, which consists of two members, lamin A and lamin C, as the major components of a thin proteinaceous filamentous meshwork, the lamina, that underlies the inner nuclear membrane. The lamin A/C gene (LMNA) of chromosome 1 encodes lamin A and lamin C and recent genetic advances have identified de novo point mutations in LMNA gene in patients with HGPS. The mutation results in production of defective form of lamin A which makes the nucleus unstable. The cellular instability appears to lead to the process of accelerated aging in progeria. In addition to progeria, mutations to LMNA can cause various disorders like Emery-Dreifus muscular dystrophy, atypical Werner syndrome and Charcot-Marie-Tooth type 2B1.

Molecular pathogenesis



Progeria (HGPS): Cells The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). The LMNA mutation is the most commonly reported and almost 90 percent of individuals with HGPS had an identifiable LMNA mutaton. Lamin A is synthesised as a precursor molecule referred to as prelamin A. Prelamin A has 664 amino acids and a cysteine residue (CAAX, cysteine-aliphatic-aliphatic-any amino acid) at its carboxyl terminus. It is modified by farnesylation (the attachment of an isoprenoid to the C-terminal cysteine residue), methylation and cleavage to generate lamin A with 646 amino acids.
The most common HGPS mutation is single-base substitution located at codon 608, G608G (GGC to GGT). The substitution reveals a cryptic splice site within exon 11 of LMNA gene, causing an in-frame deletion of 50 amino acids in prelamin A (residues 607–656). The improper processing of prelamin A leads to accumulation of a defective protein which results in nuclear lamina abnormalities that can be observed in immunofluorescent studies of HGPS cells with antibodies directed against lamin A.

Clinical features

The appearance of a progeric is of an old person with wrinkled skin and hair loss. Patients with classical HGPS follow an autosomal dominant pattern of inheritance. It is characterized by extreme short stature, early loss of hair, head disproportionately large for face, prominent scalp veins, abnormal dentition, short dystrophic clavicles, low body weight and high-pitched voice and absence of sexual maturation. The skin and bone changes become apparent in the second year of life and include lipodystrophy, scleroderma, decreased joint mobility and osteolysis. Cognitive development is normal. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble the findings in elderly. Rapidly progressing atherosclerosis of coronary arteries can lead to myocardial infarcton and death in teens.

In atypical forms of progeria or non-classical progeria, growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non-classical progeria is most probably autosomal recessive.

Diagnosis

It is based on identification of clinical features and exclusion of other diseases with similar features like mandibulo-acral dysplasia and restrictive dermopathy. The children appear normal at birth and early infancy. By the first year of life, progressive loss of hair and subcutaneous fat occurs. Mean age at diagnosis in a clinical study was found to be 2.9 years.

Treatment

There is no cure or specific treatment for progeria. There are many studies being conducted on HGPS and scientisits hope for a breakthrough to translate them into treatments and cure.



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