DISEASES

 

The telomeropathies are a newly described group of human diseases based on the genetics and molecular biology of telomeres, the ends of chromosomes. Along with the rare dyskeratosis congenita, the telomeropathies include some cases of the blood disorder aplastic anemia and, idiopathic pulmonary fibrosis, etc. Chromosome instability is a result of critical shortening of telomeres.

Telomeropathies are rare diseases with incidence ranging between 1:100,000 and 1:1,000,000 people.

WERNER SYNDROME

Is a premature aging disease that begins in adolescence or early adulthood and results in the appearance of old age by 30-40 years of age. Its physical characteristics may include short stature (common from childhood on) and other features usually developing during adulthood: wrinkled skin, baldness, cataracts, muscular atrophy and a tendency to diabetes mellitus, among others.

 

The disorder is inherited and transmitted as an autosomal recessive trait. Cells from WS patients have a shorter lifespan in culture than do normal cells. The gene for Werner disease (WRN) was mapped to chromosome 8 and cloned: by comparing its sequence to existing sequences in GenBank, it is a predicted helicase belonging to the RecQ family. However, it has yet to be shown to have real helicase activity (as a DNA unwinder important for DNA replication). The molecular role of WRN in Werner syndrome therefore remains to be proven, as does any role it might have in the aging process in general.

 

 

A yeast protein similar to the human WRN protein, called SGS1, has been found. Mutations in SGS1 cause yeast to have a shorter lifespan than yeast cells without the mutation, and shown other signs typical of aging in yeast, such as an enlarged and fragmented nucleolus. Using yeast as a model for human aging in general, may give insight into the mechanisms of Werner syndrome and related diseases.

IDIOPATHIC PULMONARY FIBROSIS

Pulmonary fibrosis is a condition in which tissue deep in your lungs becomes thick and stiff, or scarred, over time. The development of the scarred tissue is called fibrosis.

 As the lung tissue becomes thicker, your lungs lose their ability to move oxygen into your bloodstream. As a result, your brain and other organs don’t get the oxygen they need. In some cases, doctors can find out what’s causing the fibrosis. But in most cases, they can’t find a cause. They call these cases idiopathic pulmonary fibrosis.

 IPF is a serious condition that usually affects middle-aged and older adults. IPF varies from person to person. In some people, the lung tissue quickly becomes thick and stiff. In others, the process is much slower. In some people, the condition stays the same for years.

 IPF has no cure yet. Many people live only about 3 to 5 years after diagnosis. The most common cause of death related to IPF is respiratory failure. Other causes include:
• Pulmonary hypertension
• Heart failure
• Pulmonary embolism
• Pneumonia
• Lung cancer
Some people may be more likely to develop IPF because of their genes (the basic units of heredity). If more than one member of your family has IPF, the condition is called familial idiopathic pulmonary fibrosis.

 Today, scientists are beginning to understand more about what causes IPF, and they can diagnose it more quickly. They also are studying several medicines that may slow the progress of the disease. These efforts should improve the lifespan and quality of life for people who have IPF.

APLASTIC ANEMIA

Aplastic anemia (A-A) is a condition that occurs when bone marrow slowing or shutting down the production of new blood cells. The patient has pancytopenia (anemia, neutropenia and thrombocytopenia) resulting in decrease of all three blood cell types: red blood cells, white blood cells, and platelets.

Findings from several retrospective studies suggest that the incidence is 0.6-6.1: 1,000,000 people. The annual incidence of A-A in Europe, as detailed in large epidemiologic studies, is 2: 1,000,000 people. A-A is thought to be more common in Asia than in the West. The incidence was accurately determined to be 14 cases per million population in Japan, based on prospective studies.

Treatments for aplastic anemia may include observation for mild cases, blood transfusions and medications for more serious cases, and, in severe cases, bone marrow transplantation. 5%-10% of A-A cases has heterozygous mutations in genes encoding the telomerase components TERT or TERC.

ROTHMUND-THOMSON SYNDROME

 

Rothmund-Thomson syndrome (RTS) is a genodermatosis characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism.

RTS is a very rare disease and reliable data on its prevalence are not available. To date, approximately 300 patients have been recorded in the medical literature.

RTS is transmitted in an autosomal recessive manner and is genetically heterogeneous: RTS2 is caused by homozygous or compound heterozygous mutations in the RECQL4 helicase gene (8q24.3; detected in 60-65% of RTS patients), whereas the etiology in RTS1 remains unknown.

DYSKERATOSIS CONGENITA

Dyskeratosis congenita (DC), also called Zinsser-Cole-Engman syndrome, is a rare progressive disease which results in what in some ways resembles premature aging (similar to progeria). The disease mainly affects the integumentary system, the organ system that protects the body from damage, with a major consequence being anomalies of the bone marrow. Immune failure (90%) and cancer (10%) are the leading causes of death. Life expectancy of these patients ranges between 14 and 16 years old.
Clinical diagnosis is well established, based on a triad of symptoms: dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. Once the disease has developed, other symptoms are increased risk of progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors, and pulmonary fibrosis. Actually there is no cure or treatment for this disease. Hematopoietic cell transplantation can cure bone marrow failure, but they don’t cure other problems caused by DC, like problems with the digestive system and lungs.

There are three different forms of DC, all of them caused by low telomerase activity, different forms mainly correspond to mutations in different telomerase subunits. To date, nine genes have been found to cause DC: DKC1, TERC, TERT, TINF2, NHP2, NOP10, WRAP53, CTC1 and RTEL1.

All individuals with DC have abnormally short telomeres for their age, unstable chromosomes and accelerated aging of different tissues.

ATAXIA-TELANGIECTASIA

 

 

Ataxia-telangiectasia (A-T) is a rare human autosomal recessive disease characterized by cerebellar degeneration, immunodeficiency, infertility, cancer predisposition, and sensitivity to ionizing radiation (IR) and agents that induce double strand breaks (DSBs) in DNA.
A-T is reported in all regions of the world. The probable incidence of A-T is about 1 case in 100,000 births. A-T occurs equally among males and females. Death typically occurs in early or middle adolescence, usually from bronchopulmonary infection, less frequently from malignancy, or from a combination of both. The median age at death is reported to be approximately 20 years.

 

 

There is no cure for A-T, and current treatments are therefore directed toward alleviating symptoms.

 

 

The responsible gene, ATM (ataxia–telangiectasia mutated), has been identified and is found on the long arm of chromosome 11 at 11q22-23. It controls the production of a phosphatidylinositol-3-kinase-like enzyme involved in cellular responses to stress, DNA damage and cell cycle control.

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