Non-inherited Forms Research Articles

Amyotrophic Lateral Sclerosis – A Comprehensive Review

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, generally said to affect people with an age between 50 years and 70 years. Signs of upper motor neuron and lower motor neuron damage, which are not explained by any other disease process, and are the reasons behind ALS. It attacks the neurons in the brain and spinal cord. These neurons transmit messages from brain and spinal cord to the voluntary muscles. At first, it causes mild muscle problems. Some people show symptoms like difficulty in walking, running, writing and speech. Eventually, the patient may lose the strength and cannot move. Due to the depletion of neuronal transmission to muscles in the chest, the patient may report difficulty to breath. The loss of lower motor neurons leads to flaccid paralysis, decreased muscle tone, decreased reflexes, muscle weakness, muscle atrophy. The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. There are small eosinophilic, hyaline intra-cytoplasmic inclusions that stain positive for cystatin and transferring and are present in 70–100% of cases. Environmental and lifestyle factors play a major role in the development of ALS, but no conclusive evidence is available to support making specific changes to decrease the risk of the disease, Genetic mutations can lead to inherited ALS, which appears nearly identical to the non-inherited form. Patients with ALS generally have higher levels of glutamate in the brain, around the nerve cells in their spinal fluid. ALS patients may experience pain involving more than one type, no rigid treatment program that involves the sole use of a single agent should be employed to treat ALS-associated pain conditions. Opioids have proven to be effective in providing pain relief in advanced disease. Nevertheless, these therapies lack the ability to induce long-term lasting effects without constant administration. Over the last decade awareness of ALS has significantly increased, diagnosis is being achieved in a more timely fashion, and overall care is better. This review gives a comprehensive information about the symptoms, pathophysiology common causes, drugs currently used in the treatment.

Anemia in Pregnancy: Screening and Clinical Management Strategies.

Screening recommendations for anemia during pregnancy, etiologies of inherited and noninherited forms of anemia, their impact on maternal-fetal outcomes, and the clinical management of pregnant patients presenting with these conditions are reviewed. Anemia during pregnancy can cause adverse perinatal outcomes including preterm labor, premature rupture of membranes, and increased maternal and fetal mortality. Physiologic (dilutional) anemia and iron deficiency anemia are the two most common noninherited forms of anemia, and some cases may be the result of an underlying comorbidity such as diabetes or lupus. Aplastic anemia and autoimmune hemolytic anemia are uncommon forms of noninherited anemias that also merit discussion. Inherited forms of anemia include sickle cell disease, alpha-thalassemia, and beta-thalassemia. Timely diagnosis and treatment of anemia during pregnancy, whether inherited or noninherited, is imperative to protect mother and baby from potential adverse outcomes associated with these conditions.

11.2 HARNESSING AN ASD GENOMIC REVOLUTION IN THE HERE AND NOW: PERSONALIZED MEDICINE, RISK-BASED COUNSELING, AND WHAT TO DO ABOUT POLYGENIC RISK

A large share of the population-attributable risk of ASD is traceable to complex polygenic inheritance. The ability to clinically distinguish inherited from noninherited forms of ASD has significant public health implications and underscores the opportunity to complement the discovery of gene-based therapeutic targets with that of: 1) early phenotypic targets that index polygenic liability; and 2) common “comorbidities” that exacerbate the severity of impairment in ASD.

Hypothesis: Etiologic and Molecular Mechanistic Leads for Sporadic Neurodegenerative Diseases Based on Experience With Western Pacific ALS/PDC.

Seventy years of research on Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia Complex (ALS/PDC) have provided invaluable data on the etiology, molecular pathogenesis and latency of this disappearing, largely environmental neurodegenerative disease. ALS/PDC is linked to genotoxic chemicals (notably methylazoxymethanol, MAM) derived from seed of the cycad plant (Cycas spp.) that were used as a traditional food and/or medicine in all three disease-affected Western Pacific populations. MAM, nitrosamines and hydrazines generate methyl free radicals that damage DNA (in the form of O6-methylguanine lesions) that can induce mutations in cycling cells and degenerative changes in post-mitotic cells, notably neurons. This paper explores exposures to naturally occurring and manmade sources of nitrosamines and hydrazines in association with sporadic forms of ALS (with or without frontotemporal degeneration), progressive supranuclear palsy, and Alzheimer disease. Research approaches are suggested to examine whether these associations might have etiological significance.Lay SummaryUnknown environmental exposures are thought to be risk factors for non-inherited forms of certain progressive brain diseases, such as sporadic forms of amyotrophic lateral sclerosis (sALS), progressive supranuclear palsy (sPSP), and Alzheimer's disease (sAD). Related progressive and fatal brain disorders coalesce in a single neurodegenerative disease of largely environmental origin (ALS-Parkinsonism-dementia Complex) that has affected three genetically distinct populations residing in islands of the Western Pacific region. Prolonged study of this prototypical neurodegenerative disease has provided invaluable information on the probable environmental cause (specific chemical genotoxins) and molecular mechanisms (unrepaired nerve cell DNA-damage) by which brain degeneration begins, evolves and, years or decades later, clinical signs appear, and progress. This information is used as a foundation to explore whether chemically related genotoxins (nitrosamines, hydrazines) are possible risk factors for sALS, sPSP, and sAD. Methods to test this hypothesis in the field and laboratory are proposed.

The Promoter Regions of Intellectual Disability-Associated Genes Are Uniquely Enriched in LTR Sequences of the MER41 Primate-Specific Endogenous Retrovirus: An Evolutionary Connection Between Immunity and Cognition.

Social behavior and neuronal connectivity in rodents have been shown to be shaped by the prototypical T lymphocyte-derived pro-inflammatory cytokine Interferon-gamma (IFNγ). It has also been demonstrated that STAT1 (Signal Transducer And Activator Of Transcription 1), a transcription factor (TF) crucially involved in the IFNγ pathway, binds consensus sequences that, in humans, are located with a high frequency in the LTRs (Long Terminal Repeats) of the MER41 family of primate-specific HERVs (Human Endogenous Retroviruses). However, the putative role of an IFNγ/STAT1/MER41 pathway in human cognition and/or behavior is still poorly documented. Here, we present evidence that the promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 HERVs. This observation is specific to MER41 among more than 130 HERVs examined. Moreover, we have not found such a significant enrichment in the promoter regions of genes that associate with autism spectrum disorder (ASD) or schizophrenia. Interestingly, ID-associated genes exhibit promoter-localized MER41 LTRs that harbor TF binding sites (TFBSs) for not only STAT1 but also other immune TFs such as, in particular, NFKB1 (Nuclear Factor Kappa B Subunit 1) and STAT3 (Signal Transducer And Activator Of Transcription 3). Moreover, IL-6 (Interleukin 6) rather than IFNγ, is identified as the main candidate cytokine regulating such an immune/MER41/cognition pathway. Of note, differences between humans and chimpanzees are observed regarding the insertion sites of MER41 LTRs in the promoter regions of ID-associated genes. Finally, a survey of the human proteome has allowed us to map a protein-protein network which links the identified immune/MER41/cognition pathway to FOXP2 (Forkhead Box P2), a key TF involved in the emergence of human speech. Our work suggests that together with the evolution of immune genes, the stepped self-domestication of MER41 in the genomes of primates could have contributed to cognitive evolution. We further propose that non-inherited forms of ID might result from the untimely or quantitatively inappropriate expression of immune signals, notably IL-6, that putatively regulate cognition-associated genes via promoter-localized MER41 LTRs.

Understanding the Amyloid Hypothesis in Alzheimer's Disease.

The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.

Current Infection Control Recommendations for Prion Disease; A Difficult Problem for the Deployed Personnel of the Armed Forces

Background: Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia are a group of transmissible, progressive, and ultimately lethal neurodegenerative disorders caused by prion diseases. Prion disease may present in sporadic, inherited, and acquired forms. Fewer new cases of CJD are presenting themselves compared to the 1990’s when a surge of cases was recognized after an extended incubation period following dura mater and growth hormones replacement up to 25 years before. Currently, prion disease affects approximately 1 - 2 persons per million worldwide annually. In recent years, however, variant CJD has been associated with transfusions, making the possibility of transmission through operative procedures, blood, and tissue donations a real concern. Since the emergence of variant CJD, prion disease has become a considerable public health threat, not only because of their mysterious pathogenesis, but the lack of treatment options, limited diagnostic availability, and emerging transmission routes. Active surveillance of human prion diseases is critical for disease control and prevention considering the limited options for therapeutic and prophylactic interventions. Due to the risk to public health, CJD surveillance systems are now established in many countries; especially developing countries and deployed military units where healthcare is poor and infection control measures in the field are difficult to maintain. Several long-term multinational cooperative projects are on-going as well as reporting systems which protect military families from purchasing bovine in endemic countries. Objective: This paper reviews the epidemiological characteristics of various human prion diseases, infection control issues, current disinfection processes as well as recommended processes, and active surveillance systems in different countries. Conclusions: Prion disease represents a continued public health concern due to its insidious nature. Current practice continues to advance finding better ways at diagnosing earlier. Treatment options are still far from being anything but palliative. Prevention remains the primary component to neutralizing the spread of non-inherited forms of prion disease.

Aged dominant negative p38α MAPK mice are resistant to age-dependent decline in adult-neurogenesis and context discrimination fear conditioning

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38αAF/+) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38αAF/+) and kinase activity. As a result, aged DN-p38αAF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates.Aging is the major risk factor for non-inherited forms of Alzheimer’s disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual’s relative risk. In the present study, we evaluated aged DN-p38αAF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38αAF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38αAF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38αAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38αAF/+ mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD.

Diffuse normolipemic plane xanthoma associated with monoclonal gammopathy

Diffuse normolipemic plane xanthoma (DNPX) was first described by Altman and Winkelmann in 1962. It is a rare and non-inherited form of xanthomatosis. Clinically, the dermatosis is characterized by the presence of symmetric yellowish-orange plaques that favor the neck, upper trunk, flexural folds and periorbital region. It has been recognized to be associated with hematological diseases, especially with multiple myeloma and monoclonal gammopathy. We present a patient with diffuse plane xanthoma, normal lipid level, and monoclonal gammopathy.

Sex differences in cardiomyopathies

Cardiomyopathies are a heterogeneous group of heart muscle diseases with a variety of specific phenotypes. According to the contemporary European Society of Cardiology classification, they are classified into hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), restrictive (RCM), and unclassified cardiomyopathies. Each class is aetiologically further categorized into inherited (familial) and non-inherited (non-familial) forms. There is substantial evidence that biological sex is a strong modulator of the clinical manifestation of these cardiomyopathies, and sex-specific characteristics are detectable in all classes. For the clinician, it is important to know the sex-specific aspects of clinical disease expression and the potential modes of inheritance or the hereditary influences underlying the development of cardiomyopathies, since these may aid in diagnosing such diseases in both sexes.

Genetic diagnosis of hyperkinetic movement disorders

People with hyperkinetic movements have always attracted the attention of the public and professionals. Alert colleagues noticed families in which a disease passed from generation to generation around Lake Maracaibo in Venezuela. This study led in 1993 to the localization of the gene for Huntington disease on chromosome 4. The genetic basis of many other familial and sporadic diseases has been identified on human DNA. The clinical presentation of hyperkinesias remains the starting point for diagnosis, but differential diagnosis is a long, difficult process, the first step being to differentiate between inherited and non-inherited forms. The need to know the diagnosis is of major importance for patient and family. Knowledge about the cause limits the number of extra diagnostics. This review of the literature presents the most frequently occurring genetically-determined forms of hyperkinesias, mainly chorea and dystonia and tries to give some practical guidelines. The final part of the review will offer some thoughts and views for future development in a world which probably has more knowledge than we can handle. The drive to find a diagnosis is rewarded by the patient but one also needs to reflect on the use of medical care.

New developments in steroid-resistant nephrotic syndrome

Nephrotic syndrome is a disorder of the glomerular filtration barrier, a highly specialised tri-layer structure with unique functional properties. Recent advances emanating from the field of molecular genetics have revealed the podocyte as probably the central player in the control of glomerular filtration. More specifically, the cell-cell junction between adjacent podocyte foot processes, namely, the slit diaphragm, has been revealed to be made up of a sophisticated multi-protein complex which dynamically controls foot process architecture via signalling to the actin cytoskeleton. Key genes that have been identified from the study of inherited nephrotic syndromes include those encoding nephrin, podocin, TRPC6 (transient receptor potential canonical channel-6) and α-actinin-4, and more remain to be found. It is now possible to identify genetic causes underlying a proportion of nephrotic syndromes presenting at any age. The next big challenge for clinicians and researchers is to translate the molecular information learnt into the understanding of acquired, non-inherited forms of the disease and to guide therapeutic options. In this regard several exciting advances have been made, both in understanding the molecular mechanisms of current therapies and in revealing circulating plasma factors and the molecular pathways they trigger in the podocyte, that could be targeted by novel therapies.

Abstract 226: Transcriptional control of the BRCA1 expression by a metabolic switch

Abstract Deletion or loss of BRCA1 function is the major cause of most familial forms of breast cancer, decreased expression of non-mutated BRCA1 alleles is often found in sporadic breast cancer, suggesting that alterations in BRCA1 transcriptional regulation may contribute to non-inherited forms of breast cancer. BRCA1 plays a central role in maintenance of genome stability and cell cycle control and therefore, often recognized as both a “care taker” and “gate keeper” of the genome. In this study, we show that BRCA1 expression is controlled by a tightly regulated dynamic balance between the association of transcriptional co-activators and co-repressors that regulate histone acetylation and chromatin accessibility at the BRCA1 promoter during the transcriptional response to estrogen stimulation. A central regulatory step in the control of the BRCA1 promoter is the eviction of the co-repressor and metabolic sensor C-terminal-binding protein1 (CtBP1). Loss of CtBP1 from the BRCA1 promoter either by estrogen induction, CtBP1 RNAi depletion or increasing NAD+/NADH ratio results in elevated histone acetylation, HDAC1 dismissal from the BRCA1 promoter and increased BRCA1 transcription. These findings indicate that BRCA1 expression is controlled by a metabolic switch that dynamically influences the localized deposition of epigenetic marks and chromatin structure at the BRCA1 promoter and suggests that caloric intake may influence the levels of this critical tumor suppressor in mammary tissues. Strikingly extended observation of other DNA damage response genes indicate that they are also under direct regulation by CtBP and CtBP complex. These data suggest a global molecular linkage between cellular metabolic status and the capacity to maintaining the genome free from damage or mistakes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 226. doi:10.1158/1538-7445.AM2011-226

Abstract 1116: Epigenetic control of the BRCA1 expression by a metabolic switch

Abstract Though deletion or loss of BRCA1 function is the major cause of most familial forms of breast cancer, decreased expression of non-mutated BRCA1 alleles is often found in sporadic breast cancer, suggesting that alterations in BRCA1 transcriptional regulation may contribute to non-inherited forms of breast cancer. In this study, we show that BRCA1 expression is controlled by a tightly regulated dynamic balance between the association of transcriptional co-activators and co-repressors that regulate histone acetylation and chromatin accessibility at the BRCA1 bi-directional promoter to enforce unidirectional transcriptional activation in response to estrogen stimulation. A central regulatory step in the control of the BRCA1 promoter is the eviction of the co-repressor and metabolic sensor C-terminal-binding protein1 (CtBP1). Loss of CtBP1 from the BRCA1 promoter induced by estrogen, CtBP1 RNAi depletion or increasing NAD+/NADH ratio results in elevated histone acetylation, HDAC1 dismissal from the BRCA1 promoter and increased BRCA1 transcription. Notably this level of regulation is lost in the absence of physiological chromatin structure at the BRCA1 promoter. These findings indicate that BRCA1 expression is controlled by a metabolic switch that dynamically influences the localized deposition of epigenetic marks and chromatin structure at the BRCA1 promoter and suggests that caloric intake may influence the levels of tumor suppressor function in mammary tissues. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1116.

Clinical Uses of Microsatellite Instability Testing in Colorectal Cancer: An Ongoing Challenge

Clinical Uses of Microsatellite Instability Testing in Colorectal Cancer: An Ongoing Challenge

BRCA1 Promoter Methylation in Sporadic Breast Cancer Is Associated with Reduced BRCA1 Copy Number and Chromosome 17 Aneusomy

To explore the molecular mechanisms for the similarities between inherited and noninherited forms of breast cancer, we tested the hypothesis that inactivation of BRCA1 by promoter hypermethylation is associated with reduced gene copy number and chromosome 17 aneusomy as observed in tumors from BRCA1 mutation carriers. Using a combination of methylation-specific PCR analysis and fluorescence in situ hybridization, we observed varying degrees of promoter methylation in 39 of 131 (29.8%) primary tumors. Despite significant tumor heterogeneity, mean copy numbers of BRCA1 and CEP17 per cell were lower in methylated cases compared with unmethylated cases [1.78 versus 2.30 (P = 0.001) and 1.85 versus 2.29 (P = 0.005), respectively]. Methylation was more frequently observed in younger women (P = 0.05) with high-grade (P = 0.001), estrogen receptor-negative (P = 0.04), and progesterone receptor-negative (P = 0.01) tumors. Moreover, methylation was associated with reduced or absent BRCA1 transcripts, which was reversible in the heavily BRCA1-methylated cell line UACC3199 following treatment with 5-aza-2'-deoxycytidine and trichostatin A. We identified five CpGs at positions -533, -355, -173, -21, and +44 as critical in the reexpression of BRCA1. We conclude that BRCA1 methylation contributes to a subset of sporadic breast cancers with the resulting molecular and clinicopathologic phenotype similar to that of hereditary BRCA1-associated breast cancers. Our data support a model of carcinogenesis in which BRCA1 promoter methylation may serve as a "first hit," much like an inherited germ line mutation, and promote tumor progression down a restricted set of molecular pathways.

Microbiology. Noninherited resistance to antibiotics.

Why is it that the rate of mortality of bacteria exposed to bactericidal antibiotics declines with time but sensitive cells survive for hours or even days of exposure? The mechanisms responsible for this persistence have perplexed microbiologists for decades. In his Perspective, Levin discusses a pair of recent studies ( Balaban et al., Miller et al.) that shed light on the mechanisms responsible for this phenomenon and the way in which these bacterial persisters emerge. Levin also considers the potential clinical implications of this non-inherited form of resistance to antibiotics.

Tumor necrosis factor-alpha production from mononuclear cells in nephrotic syndrome.

Tumor necrosis factor-alpha (TNF-alpha) levels in supernatant fluid from cultured peripheral blood mononuclear cells (PBMC) were measured by ELISA in 54 children with active non-inherited forms of primary nephrotic syndrome (PNS), 10 nephrotics in remission, and 10 healthy controls. Children with active PNS included 21 patients with steroid-sensitive (SS) minimal change nephrotic syndrome (MCNS), 5 patients with steroid-resistant (SR) MCNS, 11 with SR focal segmental glomerulosclerosis (FSGS), 6 patients with SS diffuse mesangial proliferation (DMP), 5 patients with SR DMP, and 6 patients with mesangiocapillary glomerulonephritis (MCGN). Patients with active PNS had elevated TNF-alpha production compared with controls. Remission was associated with normalization of TNF-alpha production. There was a positive correlation between TNF-alpha production and the degree of proteinuria ( r=0.34, P=0.013), mesangial hypercellularity ( r=0.42, P=0.028), and glomerulosclerosis ( r=0.46, P=0.001). By using ROC curve, TNF-alpha production greater or equal to a cut-off point of 50 pg/ml could be used to predict resistance to steroid therapy (predictability 93.2%). By discriminate analysis, TNF-alpha production could be used to discriminate between patients with SR MCNS, SR FSGS, and SR DMP (predictability 100%). In conclusion, TNF-alpha from cultured PBMC might be involved in the pathogenesis of proteinuria as well as the pathological changes that occur in non-inherited forms of PNS. TNF-alpha levels in PBMC culture could be used to predict the pathological type of PNS and the response of these patients to steroid therapy.

Treating Genetic Disease

Colon cancer, specifically hereditary nonpolyposis colorectal cancer, and breast cancer are malignant diseases that show some degree of genetic inheritance, as do cystic fibrosis, Duchenne muscular dystrophy, and neurofibromatosis. In fact, humans are afflicted by nearly 4000 genetic diseases, and the possibility exists that knowledge of a person’s genetic code could allow us to prevent or cure some of them. Cancers arise from a multistep process involving the interplay of multiple changes, or mutations, in several different genes, in combination with environmental factors such as diet or lifestyle. In the most common, noninherited forms of cancer, the genetic changes are acquired after birth. But people who have a hereditary risk for cancer are born with one or more altered genes — in other words, they are one step along the road to cancer from birth. Women in general have a 10% risk of breast cancer and a 2% to 3% chance of ovarian cancer sometime in their lifetime. With regard to breast cancer, mutations in the BRCA-1 and BRCA-2 genes are present in only a small portion (5% to 10%) of all cases, but carriers of mutations in these genes have a greater risk of cancer, especially before menopause. Similarly, in hereditary nonpolyposis colorectal cancer, children who inherit an altered gene from either parent face a 70% to 80% chance of developing this disease, usually at an early age. In treating a genetic disease, the first question that must be answered is, Which altered gene causes the disease? Two related questions are, What protein does this gene normally produce? and Can the altered protein or gene be fixed or replaced? Determining the answer to the first question is often difficult, because few clues exist as to where, on any of the 23 pairs of chromosomes, the altered gene resides. However, as a result of the Human Genome Project, the altered genes for many genetic diseases have now been identified. These discoveries offer a preview of how the Human Genome Project is likely to transform medicine by opening up new approaches to prevention. The earliest beneficiaries will be individuals and families who face a very high risk of cancer. First, for those who choose to take it, will come a simple blood test to determine if they carry the altered gene or genes. In the case of hereditary nonpolyposis colorectal cancer, individuals found to carry an altered gene would likely receive counselling to adopt a high-fibre, low-fat diet in the hope of preventing the cancer. They would also be advised to undergo yearly colon examinations starting at about age 30. Such exams should help to detect any Treating Genetic Disease

Pure red cell aplasia.

Pure red cell aplasia.