Mortality Statistics and their Contribution to Improving the Knowledge of Rare Diseases Epidemiology: The Example of Hereditary Ataxia in Europe.

Official mortality statistics provide population-based data and serve to improve epidemiological knowledge of rare diseases (RDs), by helping with the description of the natural history of the disease. They are an important complement of registries and estimates of disease burden and costs. At the same time, they heighten both the visibility of these diseases and the interest in their study and the search for treatments that may increase survival. This chapter contains a European analysis of hereditary ataxia mortality, which considers the time trend in different countries and the geographical variability in risk of death. Despite the limitations of applying this data source to RDs, mortality statistics share criteria which facilitate international comparisons and are of great utility for obtaining sufficiently uniform and robust time series for analysis of low-prevalence diseases.

Epidemiology of hereditary ataxias in Spain: hospital discharge registry and population-based mortality study.

BACKGROUND: Hereditary ataxias (HA) comprise a group of genetically heterogeneous rare diseases. As important public health problems to be monitored, this study analyses the morbimortality of HA in Spain. METHODS: Data were extracted from the national death index (1981-2008), using the International Classification of Diseases (ICD) 9th revision code 334 until 1998, and 10th revision code G11 from 1999 onwards. ICD-9 codes were then selected from the national discharge dataset (1998-2007). Age-adjusted morbidity and mortality rates were obtained by gender and 5-year period. RESULTS: Of the 610 HA deaths from 1981 to 2008, 277 corresponded to Friedreich's ataxia (45.4%) and 333 (54.6%) to other and unspecified ataxias (non-Friedreich group). Both groups showed an increase in mortality trend, which was more pronounced in males from 1985-1989 to 1990-1994. Geographical distribution of mortality revealed higher risk for males, mainly in the north of Spain. A total of 5,341 HA hospitalisations were identified from 1998 to 2007. The average annual age-adjusted hospitalisation rate was 1.19 per 100,000 population, with a rising trend. CONCLUSION: This increase in morbidity and mortality, coupled with the slight interprovincial differences, indicate that more attention should be paid to these rare diseases by public authorities and society alike.

The natural history of degenerative ataxia: a retrospective study in 466 patients.

The aim of the present study was (i) to compare disease progression and survival in different types of degenerative ataxia, and (ii) to identify variables that may modify the rate of disease progression. We included patients suffering from Friedreich's ataxia (FRDA, n = 83), early onset cerebellar ataxia (EOCA, n = 30), autosomal dominant cerebellar ataxia (ADCA) type I (ADCA-I, n = 273), ADCA-III (n = 13) and multiple system atrophy (MSA, n = 67). Molecular genetic testing allowed us to assign 202 ADCA-I patients to one of the following subgroups: spinocerebellar ataxia type I (SCAI, n = 36), SCA2 (n = 56) and SCA3 (n = 110). To assess disease progression we defined the following disease stages: stage 0 = no gait difficulties; stage 1 = disease onset, as defined by onset of gait difficulties; stage 2 = loss of independent gait; stage 3 = confinement to wheelchair; stage 4 = death. Disease progression was most rapid in MSA, intermediate in FRDA, ADCA-I and ADCA-III and slowest in EOCA. The rate of progression was similar in SCA1, SCA2 and SCA3. The CAG repeat length was a significant risk factor for faster progression in SCA2 and SCA3, but not in SCA1. In FRDA, the time until confinement to wheelchair was shorter in patients with earlier disease onset, suggesting that patients with long GAA repeats and early disease onset have a poor prognosis. Female gender increased the risk of becoming dependent on walking aids or a wheelchair, but it did not influence survival in FRDA, SCA3 and MSA. In SCA2, female gender was associated with shortened survival. In MSA, later age of onset increased the risk of rapid progression and death.

Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion.

The gene for spinocerebellar ataxia 7 (SCA7) has been mapped to chromosome 3p12-13. By positional cloning, we have identified a new gene of unknown function containing a CAG repeat that is expanded in SCA7 patients. On mutated alleles, CAG repeat size is highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranges from 7 to 17 repeats. Gonadal instability in SCA7 is greater than that observed in any of the seven known neuro-degenerative diseases caused by translated CAG repeat expansions, and is markedly associated with paternal transmissions. SCA7 is the first such disorder in which the degenerative process also affects the retina.

Genetic fitness in Huntington's Disease and Spinocerebellar Ataxia 1: a population genetics model for CAG repeat expansions.

An analysis of genetic fitness was performed in Huntington's Disease (HD) and Spinocerebellar Ataxia 1 (SCA1) families. Two partially overlapping samples were used: clinically defined HD and SCA1 patients from families ascertained in definite geographical areas, and molecularly typed carriers of HD and SCA1 mutations (CAG trinucleotide expansions). In both cases, a control group of normal relatives was used. HD and SCA1 patients born before 1915-20 had more children than normal controls. Carriers of HD and SCA1 mutations, all in the low/medium expansion range (37-49 and 47-54 CAG repeats respectively), had a higher number of children than controls up to more recent times (1935-1950). The reproduction of heterozygotes for large expansions could be analysed only in subjects born after 1950 and provided indirect evidence of a lower than normal number of children. The above results fit a model based on a differential fitness according to the degree of expansion. Such a model predicts that 1) up to relatively recently the frequency of alleles in the low/medium range has been maintained or even increased by the increased fitness of their carriers, as well as by new mutations, and 2) the frequency of large expansions, part of which are lost at each generation, is maintained through further expansions of alleles in the low/medium expansion range. The implications of such a model on linkage disequilibrium and the possible spread of these diseases in future generations are discussed.

Reduced life expectancy in 40 cases of early onset cerebellar ataxia with retained tendon reflexes: a population-based study.

A survival analysis of 40 cases of early onset cerebellar ataxia (EOCA) with retained tendon reflexes was performed. They represent all cases of EOCA diagnosed between 1945 and 1990 among residents of a defined area of Northwestern Italy, followed up to December 31, 1990. The survival rates were respectively 92%, 87% and 77% at 10, 20 and 30-years, worse than expected in a disease which is usually considered benign. The relative death rate was 4 times higher than expected for the general population. Prognosis was significantly worse for males than for females, whereas the age of onset and the calendar year of onset did not affect survival.

[A multivariate analysis of prognostic factors of spinocerebellar degenerations].

To clarify the factors relating to the prognosis of spinocerebellar degenerations (SCD), we performed a follow-up study on the survival of patients with Friedreich disease, familial spastic paraparasis, sporadic olivopontocerebellar atrophy (OPCA), hereditary OPCA of Menzel type, sporadic late cortical cerebellar atrophy (LCCA), cerebellar atrophy of Holmes type, Shy-Drager syndrome, striatonigral degeneration, dentatorubropallidoluysian atrophy, or Joseph disease. One hundred and forty-eight patients admitted to the Nagoya University Hospital during the period of 1976 to 1990 were dealt with. They had been followed-up for 15 years at longest through the medical records, or through the direct informations from the patients or their family members or both. In order to find factors influencing the survival of the patients, Kaplan-Meier method was used as the 1st step to construct the survival curve for each factor. These were calculated by generalized Wilcoxon test. Employing Cox's proportional hazard model, a multivariate analysis was then performed based on the factors which were shown significant in the 1st step. The multivariate analysis showed that the following four factors are related to the prognosis of SCD patients, i.e., lack of hereditary trait, existence of orthostatic hypotension, lack of walking disorder at onset, and lack of nystagmus on admission. Of these factors, the lack of hereditary trait had the most intimate relation to their poor prognosis. Therefore, these four factors are statistically informative to predict prognosis of each patient with SCD.

Hereditary ataxias: epidemiological aspects.

Hereditary ataxias, hereditary spastic paraplegia and Charcot-Marie-Tooth syndrome (HA) are chronic progressive neurological diseases. Epidemiologic studies of these disorders are few. In a geographically well-defined Danish population, we present incidence rates, cumulated incidence rates and prevalence for patients with HA based on modern continuous-time survival analysis techniques. From these, prevalence has been estimated to be 6.06 per 10(5) in the 10 to 50-year-old population. Combined risk of HA was found to be 0.16% for women and 0.20% for men up to their 51st birthday.

[Orthostatic hypotension and prognosis in spinocerebellar degeneration].

To study the prognosis, the patients with various types of spinocerebellar degeneration, examined as inpatients in Department of Neurology, University of Occupational and Environmental Health form 1979 to Oct., 1988, were followed up and classified into three groups, based on their medical records reviewed retrospectively. The survival or death was confirmed for each patient at the end of Oct., 1988. Group I included 11 patients who developed cerebellar ataxia after the symptom or/and sign of orthostatic hypotension. Group II included 13 patients who developed cerebellar ataxia followed by orthostatic hypotension. Group III included 18 patients who showed cerebellar ataxia without orthostatic hypotension. The percentages of the dead patients in groups I, II and III were 82 (9 out of 11), 62 (8 out of 13) and 17 (3 out of 18%), respectively. The median of the age at the onset of the initial symptom or sign of all the patients in each group and the median of the survival interval from the onset of the dead patients were similar among three groups. The median of the age at both the onset and death of the dead patients tended to be higher in group III than those in group I and II. The maximum blood pressure on standing and the difference of the maximum blood pressure between on lying and on standing were not statistically correlated with the survival interval after such blood pressure evaluation among the dead patients in both groups I and II.(ABSTRACT TRUNCATED AT 250 WORDS)

[Analysis of follow-up survey in spinocerebellar degeneration].

Spinocerebellar degeneration (SCD) is associated with other various degeneration of the nervous systems such as the optic tract, pyramidal pathway, extrapyramidal system, nuclei of the brain stem and autonomic nervous system as well as changes of heart. The clinical pattern, also have the great variability. We investigated the mode of progression of clinical symptoms and signs in 214 cases of SCD which were examined 2 times at intervals of about 10 years. 79 of 214 cases were reported to be died at the last examination. 135 alive cases included 3 with the Holmes type, 14 with late cortical cerebellar atrophy (LCCA) 10 with Menzel type, 18 with olive-ponto-cerebellar atrophy (OPCA), 33 with spinocerebellar form (SCF), 6 with Friedreich's ataxia, 18 with hereditary spastic paraparesis (HSP) and 33 with the other type. 79 dead cases included 0 with the Holmes type, 6 with LCCA, 5 with Menzel type, 32 with OPCA, 16 with SCF, 1 with Friedreich's ataxia, 4 with HSP and 15 with the other type. The disability of daily living in SCD revealed slower progression in the advanced stage than in the early stage. Every type of SCD had some different progression of disability each other. In the early stage, Friedreich's ataxia showed the highest progression of disability, but in the advanced stage, Holmes type and the OPCA did. Holmes type showed progression of ataxia without any remarkable change of other systems. LCCA showed increase of abnormality in the eye movements, pyramidal tract and autonomic nervous system in addition to the cerebellar system. OPCA involved multiple systems as ataxia worsening, but Menzel type had no remarkable changes of incidence in eye movement disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

[Epidemiology of spinocerebellar degeneration in Tottori prefecture].

1. A prevalence study of spinocerebellar degeneration (SCD) was carried out in Tottori prefecture. Seventy two patients were found and the prevalence rate was 11.6 per 100,000 population. When age adjusted to the country's population, the figure was 10.2. These rates was higher than those reported previously in Japan. The prevalence ratio for male and female was 1.4:1. 2. Twenty four cases of SCD who died were analysed for the study of long prognosis. The average age at death was 60.7 +/- 9.8 and the mean duration of illness was 5.3 +/- 2.8 years. The leading causes of death were bronchopneumonia in seven cases, feebleness in four cases, sudden death in four cases, malignant neoplasms in three cases and suffocation in two cases.

Patterns of mortality from hereditary ataxias in the United States, 1971 and 1973-1978.

Mortality rates for deaths 'due to' and 'with' hereditary ataxias are presented for the first time. Age-adjusted mortality rates were higher for whites than for nonwhites of either sex, and for men in both racial groups. Age-specific mortality rates for whites showed a peak for 'hereditary spinal ataxia' in the 20-29 age group. For the other types of ataxias they were low until age 40 and increased thereafter. Heart diseases were a frequent cause of death in people dying 'with' hereditary ataxias. The median survival (from birth) for hereditary spinal ataxia in whites was 35 years.