The load of genetic and partially genetic disease in man. IV. Severe visual handicaps and profound childhood deafness in Hungarian school-age children

In Hungary, the school-age prevalences of severe visual handicaps and of profound childhood deafness have been estimated to be about 6/10⁴ and 10/10⁴, respectively. Most of these conditions have onset at birth or in early childhood and are aetiologically heterogeneous.

Severe visual handicaps are grouped under 11 aetiological categories, their relative contributions to the prevalence being: perinatal damage syndrome (20%; half of this is due to retinopathy of premature infants), cataracts (15%), choroidoretinal degenerations (15%), congenital abnormalities of the eye (15%), syndromes (10%), high myopia ± retinal detachment (7%), postnatal causes (5%), nystagmus (5%), optic atrophy (4%), bilateral retinoblastoma (2%) and prenatal causes (2%). Overall, Mendelian conditions (included under many of the above) account for about 50% with relatively more autosomal dominant than autosomal recessive and sex-linked entities, and acquired causes account for about 40% of the cases studied. No actiology could be assigned in 10% of the cases.

For profound childhood deafness, the rank order of the aetiological categories is: autosomal recessive entities (34%), postnatal causes (22%), perinatal causes (19%), autosomal dominant entities (17%), prenatal causes (5%) and unknown causes (3%).

Severe childhood visual handicaps are responsible for about 60 years of loss of life per 10⁴ live births and about 400 years of impaired life per 10⁴ live births. Genetic causes account for one-quarter of lost life years and three-quarters of impaired life years. The comparable estimates for profound childhood deafness are: about 240 years of life loss per 10⁴ live births (again, about one-quarter due to genetic causes) and about 640 years of impaired life per 10⁴ live births (about one-half due to genetic causes). In all these calculations, it has been assumed that the average life expectancy at birth for an individual in the population is 70 years.     

The load of genetic and partially genetic diseases in man. II. Some selected common multifactorial diseases: estimates of population prevalence and of detriment in terms of years of lost and impaired life

This paper presents epidemiological data on the prevalence of 26 common (i.e., having a lifetime prevalence of more than 1 per 10(4) individuals in the population) multifactorial diseases in Hungary and estimates of detriment associated with them. The detriment is expressed using 3 indicators, namely years of lost life (LL), potentially impaired life (PIL) and actually impaired life (AIL). The total prevalence of these diseases in Hungary has been estimated to be about 6500 per 10(4) individuals in the population. This estimate is in agreement with published data for other parts of the world. On the basis of clinical severity, these diseases have been split into 3 groups, namely (1) very severe (schizophrenia, multiple sclerosis, epilepsy, acute myocardial infarction and related conditions, and systemic lupus erythematosus); (2) moderately severe and/or episodal or seasonal (15 entities including Graves' disease, diabetes mellitus, gout, affective psychoses, essential hypertension, peptic ulcers, asthma, etc.); and (3) less severe than those in the first 2 groups (varicose veins, allergic rhinitis, atopic dermatitis, Scheuermann disease and adolescent idiopathic scoliosis). The essential clinical and genetic aspects of these diseases are briefly discussed. With the exception of epilepsy, none of the diseases included in our list causes mortality between ages 0 and 19. However, they are among the leading causes of death between ages 20 and 69 and thereafter. A sizeable proportion of those with essential hypertension, diabetes mellitus, rheumatoid arthritis, etc. survive to 70 years and beyond, as do those with gout, glaucoma, allergic rhinitis, psoriasis, etc. Overall, about 16% of all deaths that occur in Hungary every year (all age groups) can be attributed to these diseases. The mean number of years of PIL covers a wide range (about 20-40, 12-70 and 40-60 for groups 1, 2 and 3, respectively), the overall mean being about 24 years. However, the nature and degree of impairment and the impact on the life quality of those afflicted differ for the different diseases. Likewise, the mean number of years of AIL (for which the interval between the mean age at premature retirement and mean age at death was used as a rough index) also spans a wide range from 16 to 45, and the overall mean is about 20 years. At the population level, the diseases considered in this paper cause about 2700 years of LL, 96,000 years of PIL and about 5800 years of AIL per 10(4) individuals in the population. Relative to Mendelian diseases as a whole, these multifactorial diseases are associated with much greater detriment (LL: 1.4 X; PIL: 30 X and AIL: 3.9 X).     

Years of Life Lost Due to External Causes of Death in the Lodz Province,Poland

Background

The aim of the study is the analysis of years of life lost due to external causes of death, particularly due to traffic accidents and suicides.

Materials and Methods

The study material includes a database containing information gathered from 376,281 death certificates of inhabitants of the Lodz province who died between 1999 and 2010. The Lodz province is characterized by the highest mortality rates in Poland. The SEYLL_p (Standard Expected Years of Life Lost per living person) and the SEYLL_d (per death) indices were used to determine years of life lost. Joinpoint models were used to analyze time trends.

Results

In 2010, deaths due to external causes constituted 6.0% of the total number of deaths. The standardized death rate (SDR) due to external causes was 110.0 per 100,000 males and was five times higher than for females (22.0 per 100,000 females). In 2010, the SEYLL_p due to external causes was 3746 per 100,000 males and 721 per 100,000 females. Among males, suicides and traffic accidents were the most common causes of death (the values of the SEYLL_p were: 1098 years and 887 years per 100,000 people, respectively). Among females, the SEYLL_p values were 183 years due to traffic accidents and 143 years due to suicides (per 100,000 people).

Conclusions

A decrease in the number of years of life lost due to external causes is much higher among females. The authors observe that a growing number of suicides contribute to an increase in the value of the SEYLL_p index. This directly contributes to over-mortality of males due to external causes. The analysis of the years of life lost focuses on the social and economic aspects of premature mortality due to external causes.     

Martin-Bell phenotype in males with acquired central nervous system lesions. 15 males diagnosed during a systematic etiological study of 274 mentally retarded males

Martin-Bell phenotype in males with acquired central nervous system lesions. 15 males diagnosed during a systematic etiological study of 274 mentally retarded males: After a brief survey of the etiological findings in 274 moderately mentally retarded adult males, we present data on the phenotypic features in the group of 65 patients with a acquired (pre-, peri- or postnatal) cause of their handicap. In 15 of them "Martin-Bell stigmata" were observed i.e. they had 3 or more symptoms as found in fra(X) positive "Martin-Bell" males. These data are a further indication for a disregulation of the cortico-hypothalamico-hypophyseal axis in the fra(X) syndrome.     

The relative risks and etiologic fractions of different causes of death and disease attributable to alcohol,tobacco and illicit drug use in Canada

BACKGROUND: In 1996 the number of deaths and admissions to hospital in Canada that could be attributed to the use of alcohol, tobacco and illicit drugs were estimated from 1992 data. In this paper we update these estimates to the year 1995. METHODS: On the basis of pooled estimates of relative risk, etiologic fractions were calculated by age, sex and province for 90 causes of disease or death attributable to alcohol, tobacco or illicit drugs; the etiologic fractions were then applied to national mortality and morbidity data for 1995 to estimate the number of deaths and admissions to hospital attributable to substance abuse. RESULTS: In 1995, 6507 deaths and 82,014 admissions to hospital were attributed to alcohol, 34,728 deaths and 194,072 admissions to hospital were attributed to tobacco, and 805 deaths and 6940 admissions to hospital were due to illicit drugs. INTERPRETATION: The use and misuse of alcohol, tobacco and illicit drugs accounted for 20.0% of deaths, 22.2% of years of potential life lost and 9.4% of admissions to hospital in Canada in 1995.     

Ionizing radiation and genetic risks. I. Epidemiological, population genetic, biochemical and molecular aspects of Mendelian diseases

This paper reviews the currently available information on naturally occurring Mendelian diseases in man; it is aimed at providing a background and framework for discussion of experimental data on radiation-induced mutations (papers II and III) and for the estimation of the risk of Mendelian disease in human populations exposed to ionizing radiation (paper IV). Current consensus estimates indicate that a total of about 125 per 10(4) livebirths are directly affected by one or another naturally occurring Mendelian disease (autosomal dominants, 95/10(4); X-linked ones, 5/10(4); and autosomal recessives, 25/10(4). These estimates are conservative and take into account conditions which are very rare and for which prevalence estimates are unavailable. Most, although not all, of the recognized "common" dominants have onset in adult ages while most sex-linked and autosomal recessives have onset at birth or in childhood. Autosomal dominant and X-linked diseases (i.e., the responsible mutant alleles) presumed to be maintained in the population due to a balance between mutation and selection are the ones which may be expected to increase in frequency as a result of radiation exposures. Viewed from this standpoint, the above assumption seems safe only for a small proportion of such diseases; for the remainder, there is no easy way to discriminate between different mechanisms that may be responsible or to rigorously exclude some in favor of some others. Mutations in genes that code for enzymic proteins are more often recessive in contrast to those that code for non-enzymic proteins, which are more often dominant. At the molecular level, with recessives, a wide variety of changes is possible and these include specific types of point mutations, small and large intragenic deletions, multilocus deletions and rearrangements. In the case of dominants, however, the kinds of recoverable point mutations and deletion-type changes are less extensive because of functional constraints. The mutational potential of genes varies, depending on the gene, its size, sequence content and arrangement, location and its normal functions, and can be grouped into three groups: those in which only point mutations have been found to occur, those in which only deletions or other gross changes have been recovered and those in which both kinds of changes are known. Molecular data are available for about 75 Mendelian conditions and these suggest that in approximately 50% of them, the changes categorized to date are point mutations and in the remainder, intragenic deletions or other gross changes; there does not seem to be any fundamental difference between dominants and recessives with respect to the underlying molecular defect.(ABSTRACT TRUNCATED AT 400 WORDS)     

On the nosology of moderate mental retardation with special attention to X-linked mental retardation. A diagnostic genetic survey of 274 institutionalized moderately mentally retarded men

In this paper we report the results of a genetic-diagnostic survey of 274 institutionalized moderately mentally retarded adult males and compare these data with those from our previous studies in the severely mentally retarded and from a comparable population of 262 institutionalized moderately mentally retarded males and females (The Borgenstein experience). Special attention is paid to the nosology of X-linked mental retardation and familial mental retardation in general.     

Curing mental retardation: searching for balance

Mental retardation (MR) occurs in 2 to 3 % of the general population and is still not therapeutically addressed. Milder forms of MR result from deficient synaptogenesis and/or impaired synaptic plasticity during childhood. These alterations would result from disequilibrium in signalling pathways regulating the balance between long term potentiation (LTP) and long term depression (LTD) in certain neurons such as hippocampus neurons. To provide mentally retarded children with increased cognitive abilities, novel experimental approaches are currently being developed to characterize signalling status associated with MR and to identify therapeutic targets that would restore lost equilibrium. Several studies also highlighted the major role played by molecular switches like kinases, phosphatases, small G proteins and their regulators in the coordination and integration of signalling pathways associated with synaptic plasticity. These proteins may therefore constitute promising therapeutic targets for a number of cognitive deficiencies.     

Dendritic pathology in mental retardation: from molecular genetics to neurobiology

Mental retardation (MR) is a developmental brain disorder characterized by impaired cognitive performance and adaptive skills that affects 1–2% of the population. During the last decade, a large number of genes have been cloned that cause MR upon mutation in humans. The causal role of these genes provides an excellent starting point to investigate the cellular, neurobiological and behavioral alterations and mechanisms responsible for the cognitive impairment in mentally retarded persons. However, studies on Down syndrome (DS) reveal that overexpression of a cluster of genes and various forms of MR that are caused by single-gene mutations, such as fragile X (FraX), Rett, Coffin-Lowry, Rubinstein–Taybi syndrome and non-syndromic forms of MR, causes similar phenotypes. In spite of the many differences in the manifestation of these forms of MR, evidence converges on the proposal that MR is primarily due to deficiencies in neuronal network connectivity in the major cognitive centers in the brain, which secondarily results in impaired information processing. Although MR has been largely regarded as a brain disorder that cannot be cured, our increased understanding of the abnormalities and mechanisms underlying MR may provide an avenue for the development of therapies for MR. In this review, we discuss the neurobiology underlying MR, with a focus on FraX and DS     

The prevalence of minor physical anomalies in mentally retarded children

The prevalence of minor physical anomalies was examined in a sample of 109 children with idiopathic mental retardation (65 boys and 44 girls). Control group consisted of 246 healthy schoolchildren (123 boys and 123 girls) aged 8 to 12 years. A comparison was made between number of found minor anomalies per child (W1) and their Waldrop weight scores (W2) in healthy and mentally retarded (MR) children. The MR children were found to have a higher number of minor anomalies per child. In their group predominated those with four or more anomalies (56.9%), whereas among healthy children only 7.7% had four anomalies or more. In contrast to the high weighted score value (W2) of five or greater in 36.7% of MR children, it was absent in all control group subjects. There were highly significant differences between the MR and healthy children in the average value of the number of minor anomalies per child (W1) and in the average weighted score (W2). The average number of minor anomalies per child (W1) in MR and well children was 3.65 and 1.7, respectively. In MR children the average weighted score (W2) was 3.82, being 1.46 in healthy children. Our results suggest that common etiological factors, which had led to a physical and mental disorder, were active early in the development of MR children. The finding of high incidence of multiple minor anomalies in MR children indicates that genetic factors may play an important role in the etiology of the underlying disorder in the child group studied.     

Years of life lost due to Huntington disease.

Many genetic diseases shorten the lives of people who have them. Hence, it makes sense to speak of years of life lost due to cystic fibrosis or sickle-cell anemia or numerous other genetic disorders. In conventional practice, years of life lost is calculated for causes of death only, but a genetic disease is better understood as a risk-altering state or condition: it acts not at the time of death only but from birth onwards. Therefore, we must reformulate the concept of years of life lost before applying it to genetic conditions. This has already been done for congenital genetic diseases. This paper extends the reformulation to diseases with delayed onset. Huntington disease (HD) is used as an example.     

Costs associated with gunshot wounds in Canada in 1991.

OBJECTIVE: To estimate the costs (in 1993 dollars) associated with gunshot wounds in Canada in 1991. DESIGN: Cost analysis using separate estimates of gunshot incidence rates and costs per incident for victims who died, those who survived and were admitted to hospital and those who survived and were treated and released from emergency departments. Estimates were based on costs for medical care, mental health care, public services (i.e., police investigation), productivity losses, funeral expenses, and individual and family pain, suffering and lost quality of life. SETTING: Canada. OUTCOME MEASURES: Costs per case, costs by type of incident (e.g., assault, suicide or unintentional shooting) and costs per capita. RESULTS: The total estimated cost associated with gunshot wounds was $6.6 billion. Of this, approximately $63 million was spent on medical and mental health care and $10 million on public services. Productivity losses exceeded $1.5 billion. The remaining cost represented the value attributed to pain, suffering and lost quality of life. Suicides and attempted suicides accounted for the bulk of the costs ($4.7 billion); homicides and assaults were the next most costly ($1.1 billion). The cost per survivor admitted to hospital was approximately $300,000; this amount included just over $29,000 for medical and mental health care. CONCLUSION: Costs associated with gunshot wounds were $235 per capita in Canada in 1991, as compared with $595 in the United States in 1992. The differences in these costs may be due to differences in gun availability in the two countries. This suggests that increased gun control may reduce Canada''s costs, especially those related to suicide.     

Combined 10pter-->p11 and 18pter-->q11 trisomy in a 7-year-old child.

We report a severely mentally retarded, dysmorphic girl aged 7 years with a 47,XX, +der(18), t(10;18)(p11.2;q11.2)mat. The phenotype of our patient is compared with 6 cases of trisomy 10p and 10 cases of trisomy 18q- from the literature. The short trisomic segment 10pter-10p11 appears to affect more the phenotype than the trisomic segment 18qter-q11.     

Trisomy 10p, due to an unusual translocation

A mentally retarded boy with short stature, craniofacial dysmorphia, clubfeet, hypertonia and several other congenital anomalies is described. Chromosome analysis revealed a trisomy 10p, due to a peculiar t(10 ; 14) (p11 ; p12) translocation.     

Cytogenetic investigations in mentally retarded and normal males from 14 families with the fragile site at Xq28

Summary Lymphocyte cultures from 27 mentally retarded males aged 1 year to 77 years, and from 11 normal brothers from a total of 14 families with the fragile X segregating have been examined cytogenetically employing three different culture methods including methods for induction of fra(X) by FUdR (fluorodeoxyuridine) or MTX (methotrexate). All mentally retarded males showed unequivocal fra(X) expression. No statistically significant correlation between fra(X) expression and age could be demonstrated. No enhancement with FUdR was observed. Fibroblast cultures from 10 retarded males expressed fra(X) in a dose-response relationship to increasing concentrations of FUdR. None of the normal males showed fra(X). In vivo folic acid treatment of seven mentally retarded males resulted in marked reduction in fra(X) expression in lymphocyte cultures grown in medium 199. However, reinduction was achieved by FUdR or MTX, except in one case who temporarily received very high doses of folic acid.     

Mortality from unintentional injuries in California, 1985.

In 1985 unintentional injuries were the fourth leading cause of death among California residents, causing 10,380 deaths. They were the leading cause of potential life lost, accounting for 278,109 years lost. This was more than twice the number of years lost due to heart disease and 1 1/2 times the number lost due to cancer. Motor vehicle traffic accidents were the leading cause of unintentional injury deaths, accounting for half (5,158) the deaths. The next two leading causes were poisoning (especially for men aged 25 to 44 years) and falls (especially among persons aged 75 and older). Drowning was second to motor vehicle accidents as a cause of death in children aged 1 to 14 years. California''s age-adjusted injury mortality rates in 1985 were lower in coastal and urban counties than in inland and rural counties, and these rates were generally lower in counties having organized systems of trauma care.     

Human chromosome hot points

Summary A chromosome hot point, 3p14, in healthy peasants, mentally retarded patients (MR), and epileptic patients (EP) was studied. The frequency of the hot point, 3p14 break, was significantly higher in EP. It may be caused by folic acid reduction in patients' serum induced by the antiepileptic drugs. The difference between hot point and fragile site is discussed.     

Social class differences in years of potential life lost: size,trends, and principal causes.

British social class differences in mortality are examined in terms of years of potential life lost, a measure that gives more weight to deaths that take place at younger ages. It shows wider class differences during the years of working life than those found when mortality is expressed in terms of standardised mortality ratios. Examination of the change in class differences between 1971 and 1981 for all causes of death combined and for the three categories of death which during these ages make a major contribution to total years of potential life lost shows complex changes. Inequalities in years of potential life lost have increased between 1971 and 1981, during which all the principal causes of death have shown stationary or rising rates among the manual classes. The use of years of potential life lost as a measure of population health trends focuses attention on the major contribution of violent death, which occurs mainly in younger men, to widening class differences in mortality.     

Screening for fragile X syndrome among Brazilian mentally retarded male patients using PCR from buccal cell DNA

Fragile X syndrome is one of the most frequent causes of mental retardation. Since the phenotype in this syndrome is quite variable, clinical diagnosis is not easy and molecular laboratory diagnosis is necessary. Usually DNA from blood cells is used in molecular tests to detect the fragile X mutation which is characterized by an unstable expansion of a CGG repeat in the fragile X mental retardation gene (FMR1). In the present study, blood and buccal cells of 53 mentally retarded patients were molecularly analyzed for FMR1 mutation by PCR. Our data revealed that DNA extraction from buccal cells is a useful noninvasive alternative in the screening of the FMR1 mutation among mentally retarded males.     

Solvent encephalopathy.

Nineteen children aged 8-14 years were admitted over a six-year period with an acute encephalopathy due to toluene intoxication. Seven had a history of euphoria and hallucinations. The remainder presented with coma (4), ataxia (3), convulsions (3), and behaviour disturbance with diplopia (2), A history of glue sniffing was elicited in 14, but in the remainder toluene assay confirmed the diagnosis. Thirteen children recovered completely; five still had psychological impairment and personality change on discharge from hospital but were lost to follow-up, and one has a persistent cerebellar ataxia one year after the acute episode, despite absence of further exposure. Toluene inhalation is an important cause of encephalopathy in children and may lead to permanent neurological damage. Diagnosis is most important if further damage due to continued abuse is to be prevented, and toluene assay is a valuable aid to diagnosis.