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Medical Genetics - Disease Topic Overview

Medical genetics is the specialty that studies the heredity and genetic causes of disease. Increased knowledge of genetics, medical genetics in particular, has been particularly important in recent years. The human population is not homogenous in terms of risk of disease, every human being has a uniquely defined risk based on their genetic constitution and the environmental characteristics.¹

Using ovarian cancer as an example, a genetic predisposition is found in 10% of confirmed cases.2 Mutations of the BRCA genes are responsible for a large proportion of hereditary cases. The identification of predisposing genes, and the development of molecular diagnosis of the genetic risk, has permitted effective screening and disease prevention.²

The term genetic medicine is now used to encompass rapidly developing areas such as predictive medicine, personalised medicine and gene therapy. The goal of research in medical genetics is not only to identify specific genes that influence the risk of developing a disease, but also to determine the predicted response to treatment.¹ In breast cancer, HER2 overexpression initially has to be reported as a prognostic factor before it is considered as a main parameter to predict treatment efficacy. HER2 determination is considered as a revolutionary therapeutic strategy in about 20% of patients.³

Moreover, within the population, different rates of drug metabolism exist. This is caused by variations in genes encoding drug metabolizing enzymes. Variations in their genetic make-up can cause some people metabolize drugs at a slower rate; as a result, a drug may accumulate in the body, causing toxicity.⁴ Genotype assessment must become a clinical priority as a routine part of drug evaluation.⁵

Research in genetic medicine allows for a newer and clearer understanding of disease mechanisms. It helps to build links between genetic diseases and new treatments for many diseases, in order to develop a more individualised therapy.¹

1. Risch N. et al. Categorization of humans in biomedical research: genes, race and disease. Genome Biology. 2002 ; 3 (7) : comment2007. : 1-12.
2. Uhrhammer N. et al. What place do BRCA1 and BRCA2 have in the hereditary risk of ovarian cancer ? Oncologie. 2005 ; 7 (7) : 526-530.
3. Maroun P. et al. Impact of HER2 status to define prognosis and to predict treatment efficacy in adenocarcinomas. Bio Tribune Magazine. October 2010 ; 36 (1) : 30--35.
4. Beers M.H. et al. The Merck manual of medical information. Merck research laboratories. Second home edition. 2003 ; 73-78.
5. Wilson J.F. et al. Population genetic structure of variable drug response. Nature Genetics. November 2001 ; 29 (3) : 265-9.

Cystic Fibrosis
Cystic Fibrosis (CF) is caused by a defect in a gene known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene makes a protein that controls the movement of ions, such as chloride, and water, across cell membranes.^1,2

CF is caused by hundreds of different gene mutations. The most common mutation is delta F508, usually written as ΔF508.³

Thick, sticky mucus causes most of the symptoms of CF. The most common symptoms of CF include:⁴
- Persistent cough, often with phlegm
- Frequent lung infections
- Wheezing or shortness of breath
- Very salty-tasting skin
- Poor growth or weight gain despite a good appetite
- Greasy, bulky, foul-smelling stools Stomach pain and discomfort caused by too much gas in the intestines
- Dehydration
Because CF is a multisystem disease, treatment must be multidisciplinary, with a team of healthcare professionals providing comprehensive management of the patient.

Current therapy for CF is targeted at prevention and treatment of exacerbations. Care at the CF center includes inpatient as well as outpatient clinical care.⁵

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What's in the Cystic Fibrosis Knowledge Centre?
References

1. Boucher RC. Cystic Fibrosis. In: Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL et al., editors. Harrison's Internal Medicine. 16th ed. New York: McGraw-Hill; 2005. p. 1-9.
2. Aitken M, Fiel SB, Stern RC. Cystic Fibrosis: Respiratory Manifestations. In: Taussig LM, Landau LI, editors. Pediatric Respiratory Medicine. 1st ed. St. Louis: Mosby, Inc.; 1999. p. 1-47.
3. Farrell PM, Kosorok MR, Rock MJ, et al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. PEDIATRICS 2001;107:1-13.
4. National Heart Lung and Blood Institute. What Is Cystic Fibrosis. US Department of Health and Human Services National institute of Health 2005;1.
5. Smyth RL. Diagnosis and management of cystic fibrosis. Arch Dis Child Ed Pract 2005;90:1-6.

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Patients with Cystic Fibrosis (CF) develop a wide range of clinical consequences and experience varying degrees of disease severity. Regardless of its clinical presentation, the basic problem of the disease is the same - an abnormality in the glands that produce or secrete sweat and mucus.

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Lysosomal Storage Disorders
Lysosomal storage disorders (LSDs) are a group of progressive and often fatal genetic diseases that are caused by an inborn error of metabolism. This genetic defect results in the deficiency of a specific enzyme, which causes accumulation of substrate resulting in irreversible organ damage. As a group, lysosomal storage disorders affect nearly every part of the body in people of all ages and races.

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Lysosomal storage disorders (LSDs) are a group of progressive and often fatal genetic diseases that are caused by an inborn error of metabolism. This genetic defect results in the deficiency of a specific enzyme, which causes accumulation of substrate resulting in irreversible organ damage. As a group, lysosomal storage disorders affect nearly every part of the body in people of all ages and races. Currently, more than 45 LSDs are known and all together, they occur in approximately 1 in 5000 live births making this a disease group likely to be encountered in many medical practices.

Lysosomal storage disorders include Gaucher disease, MPS1 disease, Fabry disease and Pompe disease.

Skeletal pathology is highly prevalent among patients with lysosomal storage disorders however, due to the wide variability of symptom presentation and lack of disease awareness many of these patients remain undiagnosed for years or even decades.

If diagnosed late or left untreated, patients with a lysosomal storage disorder are at risk of developing significant, irreversible organ damage, loss of body functions, and life-threatening complications. An increasing number of lysosomal storage disorders are now treatable, therefore early diagnosis and intervention is critical.

Individuals with undiagnosed lysosomal storage disorders may be referred to a rheumatologist presenting with a wide range of musculoskeletal complaints that resemble, but do not quite fit, those of several rheumatologic disorders.

Due to the multi-systemic and heterogeneous nature of these diseases, early recognition of key symptoms is a challenge. Accurate identification requires skillful evaluation.

Treatment options vary across the lysosomal storage disorders and patients often undergo a variety of therapies and care. Various relief and support options (such as dialysis, surgery or physical therapy) can be helpful with managing symptoms. However, these are all palliative and do not prevent disease progression.

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Niemann-Pick type C
Niemann-Pick type C disease is a rare genetic lysosomal storage disorder that causes severe, progressive neurological symptoms. It is a very serious, life-threatening condition that can affect infants, children and adults. NP-C is characterized by cellular accumulation of lipids, in particular unesterified cholesterol and glycosphingolipids, in many parts of the body including brain, liver and spleen.

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Niemann-Pick type C disease is a rare genetic lysosomal storage disorder that causes severe, progressive neurological symptoms. It is a very serious, life-threatening condition that can affect infants, children and adults. NP-C is characterized by cellular accumulation of lipids, in particular unesterified cholesterol and glycosphingolipids, in many parts of the body including brain, liver and spleen.

The variability of NPC presentations provides a wide range of life expectancy. In general, early-onset patients tend to die during childhood or early adolescence, while patients with later-onset disease who appear to be less drastically affected can live into late adulthood.

Accurate diagnosis of NPC requires awareness of many clinical phenotypes, narrowing of differential diagnosis by ancillary testing and final confirmation by biochemical testing – the current mainstay of primary diagnosis in NPC.

The prevalence of NPC has undoubtedly been underestimated in the past due to a mixture of factors including confusing terminology, prior lack of specific biochemical or genetic tests, varied pathology, and the many variant clinical manifestations of the disease.

Current, non-specific treatments for NPC focus mainly on supportive care, aimed toward managing the symptoms of the disease. As such, these treatments have no effect on disease progression or long-term outcomes.

Specific therapies for the intended treatment of NPC are based on targeting known pathophysiological and/or biochemical defects involved in the pathogenesis of the disease. While earlier attempts proved largely ineffective, more recent efforts indicate possible hope for the future.

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Latest Multi Media

An Introduction to Genetics and Genetic Testing

Medical Genetics Drug Data - A-Z English

Latest Drug News

FDA accepts new drug application from Pfizer for tafamidis for TTR-FAP - 16-02-2012

After a Refusal to File notification from the FDA for tafamidis from Pfizer, the FDA has now accepted the new drug application for Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP) a rare, progressive fatal neurodegenerative disease, which affects about 8,000 patients worldwide.The drug is approved as Vyndaqel in the EU.

FDA approves Kalydeco (Vertex Pharma) for Cystic Fibrosis - 31-01-2012

The FDA has approved Kalydeco(ivacaftor)from Vertex Pharma, the first medicine to treat the underlying cause of Cystic Fibrosis (CF), a rare, genetic disease. Kalydeco is approved for people with CF ages 6 and older who have at least one copy of the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approximately 1,200 people in the United States , or 4 percent of those with CF, are believed to have this mutation. The company has established a financial assistance and patient support program to help get Kalydeco to eligible patients for whom it is prescribed. Kalydeco was discovered as part of a collaboration with Cystic Fibrosis Foundation Therapeutics, Inc. , the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation.Kalydeco is filed for approval in the EU.

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Latest Journal Publications

Cancer Letters

Early detection of lung cancer provides the highest potential for saving lives. To date, no routine screening method enabling early detection is available, which is a key factor in the disease’s high mortality rate. Copy number changes and DNA methylation alterations are good indicators of carcinogenesis and cancer prognosis. In this study, we attempted to combine profiles of DNA copy number and methylation patterns in 20 paired cancerous and noncancerous tissue samples from non-small cell lung cancer (NSCLC) patients, and we detected several clinically important genes with genetic and epigenetic relationships. Using array comparative genomic hybridization (aCGH), statistically significant differences were observed across the histological subtypes for gains at 1p31.1, 3q26.1, and 3q26.31–3q29 as well as for losses at 1p21.1, 2q33.3, 2q37.3, 3p12.3, 4q35.2, and 13q34 in squamous cell carcinoma (SQ) patients, and losses at 12q24.33 were measured in adenocarcinoma (AD) patients (p < 0.05). In an analysis of DNA methylation at 1505 autosomal CpG loci that are associated with 807 cancer-related genes, we identified six and nine loci with higher and lower DNA methylation levels, respectively, in tumor tissue compared to non-tumor lung tissues from AD patients. In addition, three loci with higher and seven loci with lower DNA methylation levels were identified in tumor tissue from SQ patients compared to non-tumor lung tissue. Subsequently, we searched for regions exhibiting concomitant hypermethylation and genomic loss in both ADs and SQs. One clone representing 7p15.2 (which includes candidate genes such as HOXA9 and HOXA11) and one target ID representing HOXA9_E252_R were detected. Quantitative real-time PCR identified the potential candidate gene HOXA9 as being down-regulated in the majority of NSCLC patients. Moreover, following HOXA9 over-expression, the invasion of representative cell lines, A549 and HCC95, were significantly inhibited. Taken together, our results show that the combined profiling analysis technique is a useful tool for identifying biomarkers in lung cancer and that HOXA9 might be a potential candidate gene for the pathogenesis and diagnosis of NSCLC patients.

International Journal of Molecular Medicine

Adult T-cell leukemia/lymphoma (ATL) is one of the peripheral T-cell malignant neoplasms strongly associated with human T-cell leukemia virus type-I (HTLV-I). Although the viral transactivator protein Tax has been proposed to play a critical role in leukemogeneis, additional cellular events are required for the development of ATL. One of the genetic events of the disease is inactivation of tumor suppressor genes. The CDKN2A locus on chromosome 9p encodes 2 cell cycle regulatory proteins, p14ARF and p16INK4a, which share exon 2 using different reading frames. The p14ARF and p16INK4a genes have been implicated as tumor suppressor genes by their frequent mutation, deletion or promoter hypermethylation in a variety of human tumors. In this report, we describe the expression status of p14ARF and p16INK4a in 9 ATL cell lines (MT1, MT2, OKM3T, F6T, K3T, Oh13T, S1T, Su9T01 and HUT102). By reverse transcription polymerase chain reaction (RT-PCR), expression of p14ARF was not detected in one cell line (OKM3T), while expression of p16INK4a was not detected in 6 cell lines (OKM3T, MT1, MT2, Oh13T, S1T and Su9T01). In the OKM3T cell line, the shared exon 2 of the p14ARF/p16INK4a gene was deleted; however, the p16INK4a gene, was epigenetically inactivated in 5 other cells lines. In primary tumor cells obtained from ATL patients, p14ARF expression was absent in 6 of the 11 samples. We confirmed the methylation of the p16INK4a gene in MT1 and MT2 cells using the methylation-specific PCR (MSP) method. Treatment with 2.0 µM of Azacitidine (AZA), a demethylating agent, for 72 h restored p16INK4a transcript expression and induced growth inhibition in MT2 cells. Our results demonstrate that p16INK4a is epigenetically silenced in ATL. AZA offers a potential new therapeutic approach to improve the poor outcomes associated with ATL.

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