A cerebellar ataxia locus identified by DNA pooling to search for linkage disequilibrium in an isolated population from the Cayman Islands

A non-progressive recessive cerebellar ataxia was identified in a highly inbred Cayman island population. Cayman cerebellar ataxia is characterized by marked psychomtor retardation, and prominent cerebellar dysfunction manifested by nystagmus, intention tremor, dysarthric speech, and an ataxic gait. In this study, we identify to chromosome 19p 13.3 using pooled DNA samples of affected individuals from an isolated population as PCR template for a genome wide screen with short tandem repeat markers. Our data demonstrate that the DNA pooling approach to identify disease gene loci is feasible using individuals from isolated populations in which kindred relationship are highly complex and exact relationships between all affected individuals are not known. Genetic fine mapping demonstrates that the genetic disease interval is approximately 9 cM, but contained within a small physical region. The existence of multiple individuals that are recombinant with flanking markers indicates that the disease interval can be further narrowed with additional markers. (AU)

Diabetic nephropathy is not preventable - abstract

Renal failure in diabeties mellitus is becoming the commonest cause of end-stage renal disease (ERSD) in developed and developing countries. While ERSD occurs in about 35 percent of patients with insulin-dependent diabetes mellitus (IDDM), it occurs generally in about 15-60 percent with non-insulin-dependent diabetes mellitus (NIDDM), depending on ethnicity. Since most of the diabetes are NIDDM, it follows that most of these patients developing renal failure and requiring dialysis are NIDDM. When significant proteinuria begins, usually after about 15-20 years of NIDDM or IDDM, renal function will fall steadily and the patient will require dialysis in 3-5 years or sooner. The proteinuric patients also have a 20-40-fold increase in cardiovascular mortality. About one-quarter of the patients who have negative routine urinary protein dipstick tests will have sub-clinical amounts of urinary albumin (30-300 mg/24 hr), so-called microalbuminuria (MA). This has recently been correlated with a very high incidence of microvascular disease. This MA predicts about a 20-fold chance of the patient developing clinical proteinuria and a high chance of ERSD. The accumulated evidence suggests that a common pathogenic mechanism may exist for microalbuminuria, diabetic nephropathy, atherosclerosis and obesity. Obesity seems to be related to all of these factors in that it has been associated with insulin resistance, hypertension and so dium retention, atherosclerosis and hyperlipidaemia (HL). NIDDM patients are almost always obese and they always have insulin resistance, which improves with weight loss. There is growing clinical evidence of hereditary influence in NIDDM, HL, and hypertension with the clustering of diabetic nephropathy in these high-risk families. These data show that genetic factors may well play a major role, and it is therefore understandable that we may have difficulty in altering the already genetically charted course of proteinuria, hypertension, HL, and NIDDM (AU)

Aetiology, treatment and prevention of diabetic nephropathy: an overview - abstract

In the studies of the aetiology, treatment and prevention of diabetic nephropathy, several end-points can be used, including death due to renal failure, uraemia, azotaemia, proteinuria, microalbuminuria and changes in glomerular and tubular functions. The two parameters commonly used, though not ideal, are glomerular filtration rate and protein excretion. Several factors contribute to the development and progression of diabetic nephropathy. These include hereditary factors, severity of hyperglycaemia, hypertension and hyperlipidaemia. Siblings of probands free of diabetic nephropathy have less evidence of renal disease than do siblings of probands with diabetic nephropathy. Several studies have also shown that individuals with high glycosylated haemoglobin concentrations (poor glycaemic control) are more likely to develop diabetic nephropathy. It is not clear, however, if this is a direct relationship (e.g. via glycosylation) or indirect (e.g. increased flux through the aldose reductase pathway, or alteration in vascular permeability). It is also unclear whether there is a direct relationship between glucose level and the development of diabetic nephropathy. The route of administration of insulin, e.g. into systemic circulation or into the portal system, may be important in the development of diabetic nephropathy. Specific inhibitors in the metabolic pathways (e.g. aldose reductase inhibitors, glycosylation inhibitors) may slow or prevent the development of diabetic nephropathy. Several studies have shown that increase in albumin excretion rate and decrease in glomerular filtration rate precede the development of hypertension and, once present, contribute to the rate of progression of diabetic nephropathy. Some, on the other hand, feel that hypertension reduces protein excretion, and a few studies have shown that it also preserves renal function and/or prevents azotaemia. It is also not clear at what level blood pressure should be treated, as urinary albumin excretion decreases when normotensive individuals are treated with angiotensin-converting enzyme inhibitors. Reduction of protein consumption in humans (to approximately 0.6 gm protein/kg body weight per day) can slow the rate of decline in glomerular filtration. Also influencing the rate of development of hyperlipidaemia, if necessary, with hypolipidaemic drugs is potentially beneficial in hypertensive diabetic patients. In summary, although definite data are lacking, an attempt should be made to optimize glycaemic control and hypertension should be treated early and vigorously. Hyperlipidaemia which persists in the presence of normoglycaemia should be treated with diet and hypolipidaemic drugs (AU)

A time-dependent logistic hazard function for modeling variable age of onset in analysis of familial diseases

This paper presents an extension of the regressive logistic model proposed by Bonney [Biometrics 42:611-625, 1986], to address the problems of variable age-of-onset and time-dependent covariates in analysis of familial diseases. The goal is achieved by using failure time data analysis methods, and partitioning the time of follow up in K mutually exclusive intervals. The conditional probability of being affected within the Kth interval (K=1...K) given not affected before represents the hazaard function in this discrete formulation. A logistic model is used to specify a regression relationship between this hazard function and a set of explanatory variables including genotype, phenotype of ancestors and other covariates which can be time independent. The probability that a given person either becomes affected within the Kth interval (ie. interval K includes age of onset of the person) or remains unaffected by the end of the Kth interval (ie. interval K includes age at examination of the person) are derived from the general result of failure time data analysis and used for the likelihood formulation. This proposed approach can be used in any genetic segregation and linkage analysis in which a penetrance function needs to be defined. Application of the method to familial leprosy data leads to results consistent with our previous analysis performed using the unified mixed model [Abel and Demenias, Am J Hum Genet 42:256-266, 1988], ie. the presence of a recessive major gene controlling susceptibility to leprosy. Furthermore, a simulation study shows the capability of the new method to detect major gene effects and to provide accurate parameter estimates in a situation of complete ascertainment. (AU)

Diabetes mellitus and risk factors in a French West Indian island - abstract

Diabetes mellitus is an important cause of morbidity and mortality in the Caribbean. In order to design and implement specific prevention programmes, it is necessary to estimate the prevalence of glycaemic disorders and study the risk factors involved. This paper presents the results of such a study from a representative sample of the adult population in Guadeloupe. The estimated total prevalence of glycaemic disorders was 13.2 per cent of the adult population over 18 years of age. Impaired glucose tolerance (IGT) appeared in 7.4 per cent of subjects. The prevalence of diabetes mellitus was 5.8 per cent (95 per cent confidence interval: 4.4-7.2). Insulin-dependent patients represent 14 per cent of all diabetics. The associated factors studied were sex, age, obesity, parental diabetes status and ethnicity. The relative risk (RR) for age in non-obese non-diabetic parent patients was 5.1. In older subjects, RR for diabetic parent without obesity was 3.2 and for obesity alone 1.8. For obesity and diabetic parent, RR was 5.0. In this case, there was additivity of these two factors. Except age, the individual predominant factor of Diabetes mellitus was the presence of a diabetic parent; this was more evident in the small and closed Indian group. In the Public Health approach, i.e. taking into account the prevalence of each risk factor in the population, obesity was the most important. It is also the one and only factor which could be reached directly by a prevention programme (AU)

A study of the integration of the genetic programme into the maternal and child health services of the Cayman Islands

The study of the integration of the Genetic Programme into the Maternal and Child Health Services of the Cayman Islands sought to ascertain the reactions opinions, attitudes and personal experience of the community health nurses, the staff-nurse midwives, and the mothers of affected children, as they relate to the Genetic Programme. Four community health nurses, seven staff-nurse midwives, and twenty-nine mothers with affected children were interviewed. The programme has provided role expansion for the nurse and a new challenge. They feel inadequate due to the lack of information in this new field. They expressed the feeling that the problems they are experiencing can be overcome with education and training, by in-service education and workshops. The mothers expressed great appreciation for the programme, stating that they are aware of exactly what is wrong with their children. Based on the findings of the study, the researcher has outlined several recommendations for strengthening the Genetic Programme and enhancing its contribution to the delivery of health care (AU)

Hereditary hypochromic anaemia with iron loading

An unusual case was reported in which a 24 year old Jamaican male was found to have a constitutional defect of iron metabolism involving the utilization of pyridoxine in hemoglobin formation. It was found that pharmacological doses of Vit B6 allowed a greater rate of haemoglobin formation without altering the fundamental defect which caused iron accummulation in the body (AU)

Huntington's chorea in Trinidad

This distressing and fatal hereditary condition is more prevalent in the Caribbean than is thought. Its hereditary associations are mental deficiency, aggressive psychopathy, alcoholism and other mental illnesses. There is a high fecundity rate and steps to prevent its spread should include eugenic advice and admission of advanced cases to hospital. Data on 3 family pedigrees is presented, one East Indian and the other two of mixed negro and white ancestry, showing an unbroken line of transmission, in 2 instances through 4 generations (AU)

Hereditary gingival fibromatosis associated with splenomegaly and skeletal and soft tissue abnormalities

Details of a family with this disorder are presented. It appears to be transmitted by means of an autosomal dominant gene. The changes include gingival hypertrophy, particularly in the maxilla, increase in the soft tissues of the palate, nose and ears, changes in the nails and digits, excessive joint mobility and pes cavus as well as splenomegaly (AU)

Acid mucopolysaccharide excretion in a family of patients with gargoylism

Gargoylism is a hereditary disorder of acid mucopolysaccharide metabolism and is associated with elevated urinary levels of total AMPS. This was confirmed in 9 of 40 members of a family, spread over three generations, in which there were three members with gargoylism. In other family with two children affected, the mother and 3 siblings were found to have elevated excretion of AMPS. Elevation in th excretion of AMPS in the direct ascendants and family of patients with gargoylism justified their qualification as heterozygous carriers of the gargoylism disease trait (AU)