Calculating predictive values for the large repeat alleles at the SCA8 locus in patients with ataxia.
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Alleles↗
Biomedical subjects
M Hietala
Publications and source records attributed to M Hietala.
MECP2 gene analysis in classical Rett syndrome and in patients with Rett-like features.
OBJECTIVE: To discuss the diagnostic criteria for Rett syndrome based on mutational screening of the methyl-CpG-binding protein 2 gene ( MECP2 ) in patients with classic Rett syndrome and patients with Rett-like features. METHODS: Thirty-nine patients with classical Rett syndrome, one with preserved speech variant (PSV), and 12 patients with developmental delay and some features of Rett syndrome were recruited for sequence analysis of the MECP2 gene coding region. The phenotype of the patients was correlated with the presence and type of the mutation as well as the X-chromosome inactivation (XCI) pattern. RESULTS: found in 100% of the patients with classical Rett syndrome originating from Finland. One novel mutation, P127L, was detected in a patient with PSV. No mutations were found in other cases. The XCI status was found to be random in 72% of the patients with classical Rett syndrome, including the patient with PSV and all patients with developmental delay informative for the analysis. CONCLUSIONS: An MECP2 mutation can be found in almost every patient with classical Rett syndrome. More patients need to be analyzed in order to clarify the mutation prevalence in patients with atypical Rett syndrome and in patients with mental retardation.
Adolescent↗
Familial cutaneous leiomyomatosis is a two-hit condition associated with renal cell cancer of characteristic histopathology.
Little has been known about the molecular background of familial multiple cutaneous leiomyomatosis (MCL). We report here a clinical, histopathological, and molecular study of a multiple cutaneous leiomyomatosis kindred with seven affected members. This detailed study revealed strong features of a recently described cancer predisposition syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC). The family was compatible with linkage to the HLRCC locus in 1q. Also, all seven cutaneous leiomyomas derived from the proband and analyzed for loss of heterozygosity displayed loss of the wild-type allele, confirming the association with a susceptibility gene in chromosome 1q. One individual had had renal cell cancer at the age of 35 years. This tumor displayed a rare papillary histopathology, which appears to be characteristic for HLRCC. The derived linkage, loss of heterozygosity, and clinical data suggest that MCL and HLRCC are a single disease with a variable phenotype. The possibility that members of leiomyomatosis families are predisposed to renal cell cancer should be taken into account.
Adult↗
A retrospective study of long-term psychosocial consequences and satisfaction after carrier testing in childhood in an autosomal recessive disease: aspartylglucosaminuria.
Genetic carrier testing of children is usually not recommended. However, there are no data concerning long-term psychological consequences, experience, and satisfaction of those tested as well as their recall of the test results. We evaluated these items retrospectively 10-24 years after carrier testing performed in childhood. Study material comprised 25 families with aspatylglucosaminuria (AGU), an autosomal recessive disorder, with 35 healthy sibs from all parts of Finland tested for carriership during childhood between 1973 and 1987. Of these sibs, 25 participated in our study. The questionnaire comprised multiple-choice and open-ended questions. The psychosocial well-being of the study subjects measured by the RAND 36 item Health Survey 1.0 (RAND) was, in general, at least as good as that of controls, and showed no significant differences between carriers and non-carriers (p > 0.154). All tested individuals were satisfied with the fact that they had been tested and stated that the decision to perform carrier testing on a child can be made by the parents. Of the 25 tested, 23 knew and understood their test result correctly at the time of our study. Most of the tested individuals (60%) stated that the best time for carrier testing would be in the childhood or in the teen years. This study indicates that carrier testing in childhood for an autosomal recessive disorder (AGU) had caused no measurable disturbance of quality of life in adulthood, and those tested reported being satisfied. However, we do not recommend testing in childhood, as the result is not needed prior to the time for reproductive decisions.
Adolescent↗
Clinical and genetic findings in Finnish ataxia patients with the spinocerebellar ataxia 8 repeat expansion.
Spinocerebellar ataxia 8 (SCA8) is caused by a CTG repeat expansion in an untranslated region of a recently cloned gene on 13q21. The pathogenic role of this trinucleotide repeat was evaluated by examining 154 Finnish ataxia patients and 448 controls. Expansions ranging from 100 to 675 repeats were present in 9 (6%) unrelated patients and in 13 (3%) controls. There was a threefold excess of shorter expansions (<204 repeats) in the ataxia series, and the expansions tended to cluster in patients with a family history for the disease. Clinical and genetic data were subsequently collected from 15 patients. Common initial symptoms included gait instability, dysarthria, and tremor. A marked cerebellar atrophy in magnetic resonance imaging or computed tomography was found in all patients. Pyramidal affection was often seen, and various kinds of cognitive impairment were evident in 40% of patients. Disease progression was slow, and fluctuation of symptoms was commonly observed. A maternal penetrance bias was not seen, nor was there any clear-cut negative correlation between age of onset and repeat number. Meiotic but not mitotic instability of the repeat expansion was evident. Haplotype analysis suggests multiple origins for the Finnish spinocerebellar ataxia 8 repeat expansions.
Adolescent↗
Bone marrow transplantation in aspartylglucosaminuria--histopathological and MRI study.
This study comprised two patients with aspartylglucosaminuria (AGU), who were followed up for 4 and 7 years. The patients underwent allogeneic bone marrow transplantation (BMT) at the ages of 2 and 2.6 years. Both patients had abnormal speech development and gross motor clumsiness. At the time of the BMT, they were mentally retarded. We report on follow-up data of these patients obtained by MRI, in addition to the histopathological, biochemical and clinical investigations. MR images of six non-transplanted patients and seven healthy children served as controls. In the non-transplanted patients, MRI revealed evident delay of myelination in contrast to the two transplanted patients showing fair or evident grey- vs. white matter differentiation on T2-weighted images. The aspartylglucosaminidase (AGA) activity in blood leukocytes reached a heterozygous level. Urinary excretion of aspartylglucosamine and glycoasparagines slowly decreased but remained about a third of the pre-BMT level 5 years after BMT. Storage lysosomes in electron microscopic investigations were not decreased 6 months after BMT, but after 1.5-2 years, rectal mucosa samples showed a decrease in the storage vacuoles of different cells. Three years after BMT, no cells with storage vacuoles were present. Allogeneic BMT slowly normalises the pathological, biochemical and MRI findings in patients with AGU.
Aspartylglucosaminuria↗
Origin of Finnish mutations causing aspartylglucosaminuria.
Aspartylglucosaminuria (AGU) is an autosomal recessive lysosomal storage disease highly enriched in Finland where one mutation AGUFin major is responsible for 98% of the AGUFin alleles. Another mutation AGUFin minor has been identified in eight compound heterozygote patients who have AGUFin major mutation in their other allele. In addition four compound heterozygote patients have AGUFin major in one allele and unknown AGUFin mutation in the other allele. To study the origin of these mutations the haplotype analysis was performed on six patients with AGUFin minor mutation and four patients with unknown AGUFin mutation using nine microsatellite markers on the 7.6 cM chromosome region on 4q28-4qter. The haplotype data suggest that one founder mutation is responsible of all AGUFin minor alleles. Allelic association was also observed in AGUFin major chromosomes. Patients with unknown mutation did not share a common haplotype and therefore most likely have different origin.
Acetylglucosamine↗
Attitudes towards genetic testing: analysis of contradictions.
A survey study was conducted among 1169 people to evaluate attitudes towards genetic testing in Finland. Here we present an analysis of the contradictions detected in people's attitudes towards genetic testing. This analysis focuses on the approval of genetic testing as an individual choice and on the confidence in control of the process of genetic testing and its implications. Our analysis indicated that some of the respondents have contradictory attitudes towards genetic testing. It is proposed that contradictory attitudes towards genetic testing should be given greater significance both in scientific studies on attitudes towards genetic testing as well as in the health care context, e.g. in genetic counselling.
Adolescent↗
Two novel mutations in a Canadian family with aspartylglucosaminuria and early outcome post bone marrow transplantation.
Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by deficiency of aspartylglucosaminidase. The disease is overrepresented in the Finnish population, in which one missense mutation (Cys163Ser) is responsible for 98% of the disease alleles. The few non-Finnish cases of AGU which have been analyzed at molecular level have revealed a spectrum of different mutations. Here, we report two new missense mutations causing AGU in two Canadian siblings. The patients were compound heterozygotes with a G299-->A transition causing a Gly100-->Gln substitution and a T404-->C transition resulting in a Phe135-->Ser change in the cDNA coding for aspartylglucosaminidase. The younger patient recently underwent bone marrow transplantation.
Acetylglucosamine↗
[Attitudes toward genetic testing in Finland].
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Acetylglucosamine↗
DNA-based carrier screening in primary healthcare: screening for aspartylglucosaminuria mutations in maternity health offices.
Large-scale genetic screening programs are complex enterprises in which ethical, technical, medical, and socioeconomic aspects have to be handled with professional expertise. Establishment of automated, relatively robust, and inexpensive laboratory techniques is one step of this path. Here a pilot carrier-screening program for the mutations causing aspartylglucosaminuria was carried out for pregnant women in primary care maternity health offices. Women (1975) were tested before their 12th week of pregnancy, and 31 heterozygotes were detected. The sampling was based on dried blood strips, facilitating convenient handling and inexpensive mailing to the laboratory. The mutation detection technique, solid-phase mini-sequencing simplified by the use of scintillation microplates and automated equipment, proved to be rapid, simple, inexpensive, and reliable, with a low repeat rate (2.5%). In conclusion, we found that good collaboration between the primary healthcare unit, the laboratory, and counseling experts, combined with modern laboratory technology, facilitate reliable low-cost genetic testing.
Acetylglucosamine↗
Identification of a novel mutation causing aspartylglucosaminuria reveals a mutation hotspot region in the aspartylglucosaminidase gene.
Aspartylglucosaminuria (AGU) is a recessively inherited metabolic disorder caused by the deficiency of a lysosomal enzyme, aspartylglucosaminidase. The worldwide most common mutation causing the disease is the AGUFin, enriched in Finland; all the other known AGU mutations are family-specific. We developed exon-specific primers to facilitate mutation search directly from the genomic DNA and identified a novel mutation, designated AGUFin minor, in seven Finnish AGUFin compound heterozygote patients. This deletion/frameshift mutation creates a premature translational termination codon and was shown to result in severely reduced transcript levels as quantified by the solid-phase minisequenching method. Genealogical data on this novel mutation suggest its relatively recent introduction into the population. The AGU mutations identified so far have been reported to be evenly distributed throughout the 1 kb coding region of the AGA cDNA. We identified a mutation hotspot region of 40 bp within the 12.5 kb AGA gene containing two previously identified mutations and the novel AGUFin minor mutation characterized in this study.
Acetylglucosamine↗
Attitudes toward genetic testing among the general population and relatives of patients with a severe genetic disease: a survey from Finland.
In the present study we explore the attitudes of the Finnish population toward genetic testing by conducting a questionnaire study of a stratified sample of the population as well as of family members of patients with a severe hereditary disease, aspartylglucosaminuria (AGU). The questionnaire evaluated attitudes toward gene tests in general and also respondents' preparedness to undergo gene tests for predictive testing, carrier detection, prenatal diagnosis, and selective abortion, in theoretical situations. The results of the study indicate that both the Finnish population in general and family members of AGU patients have a favorable attitude toward genetic testing. However, a commonly expressed reason against testing was that test results might lead to discrimination in employment or insurance policies. Based on the responses, we predict that future genetic testing programs will most probably be met with a high acceptance rate by the Finnish population.
Adolescent↗
Prospects of carrier screening of aspartylglucosaminuria in Finland.
The frequency of carriers of the AGUFin mutation, the predominant mutation causing aspartylglucosaminuria in Finland, was determined in a population sample comprising 553 newborns from a delivery hospital in southern Finland, and 607 from a hospital in northern Finland. The AGUFin point mutation was identified from cord blood samples using the PCR-based, solid-phase minisequencing method. Nineteen carriers of the AGUFin mutation were detected, 8 (1:69) in the sample from the southern and 11 (1:55) from the northern population, respectively. The solid-phase minisequencing method proved to be rapid and convenient for the detection of the AGUFin mutation, and can readily be applied in large-scale carrier screening at the population level.
Amino Acid Metabolism, Inborn Errors↗
Acceptance of genetic testing in a general population: age, education and gender differences.
The aim of the study was to analyze effects of age, education and gender on acceptance of genetic testing. Subjects, n = 1967 aged 15-69, were a stratified random sample of the Finnish population. One thousand, one hundred and sixty nine subjects, 530 men and 639 women, returned the questionnaire. The majority of the respondents approved of the availability of genetic testing. Young, aged 15-24, were more favourable towards testing and more willing to undergo suggested tests, but they were also more worried than others about the misuse of test results. Men aged 45-69 with only basic education were more in favour of mandatory genetic testing than other respondents. Respondents with university education were more critical towards genetic testing and expressed their worry about eugenics more often than other education groups. In conclusion, there are age, education and gender related differences in acceptance of genetic testing which need to be taken into account when considering screening programmes and informing the public.
Adolescent↗