RESUMEN

UNLABELLED: The first 23 patients diagnosed with Salla disease in Sweden are presented. A high incidence of the "Finnish" R39C mutation, together with genealogical data, indicates that a large proportion of the mutations are of Finnish origin. All patients had pathologically high levels of free sialic acid in urine and in fibroblasts. The clinical picture confirms what has already been reported from Finland, with early psychomotor retardation, ataxia and speech problems. One-third of the patients had epilepsy. CONCLUSIONS: Salla disease is more common in Sweden than supposed. A large proportion of the mutated alleles seem to be of Finnish origin. The clinical picture is the same as that reported from Finland.

Asunto(s)

Enfermedad por Almacenamiento de Ácido Siálico/epidemiología , Femenino , Fibroblastos/química , Humanos , Masculino , Mutación , Ácido N-Acetilneuramínico/análisis , Prevalencia , Estudios Seroepidemiológicos , Enfermedad por Almacenamiento de Ácido Siálico/diagnóstico , Enfermedad por Almacenamiento de Ácido Siálico/genética , Suecia/epidemiología

RESUMEN

Sialic acid storage disorders, Salla disease (SD) and a severe infantile form of disease (ISSD), are recessively inherited allelic lysosomal storage disorders due to impaired egress of free sialic acid from lysosomes. Fourteen pregnancies at risk of adult-type free sialic acid storage disease, SD, were monitored by sialic acid assays, genetic linkage or mutation detection analyses using chorionic villus samples. Three affected and 12 unaffected fetuses were identified. The first studies were based on the sialic acid assays alone, but the location of the gene enabled the use of genetic linkage analysis and, more recently, the identification of the SLC17A5 gene and disease-causing mutations added yet another possibility for prenatal studies. A missense mutation 115C-->T (R39C) is present in 95% of all Finnish SD alleles, providing an easy and reliable means of diagnostic studies. Both molecular and biochemical (sialic acid assay) studies can be used for prenatal diagnosis of free sialic acid storage diseases.

Asunto(s)

Errores Innatos del Metabolismo de los Carbohidratos/diagnóstico , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/diagnóstico , Ácido N-Acetilneuramínico/genética , Adulto , Alelos , Errores Innatos del Metabolismo de los Carbohidratos/genética , Errores Innatos del Metabolismo de los Carbohidratos/metabolismo , Muestra de la Vellosidad Coriónica , Mapeo Cromosómico , ADN/análisis , Análisis Mutacional de ADN , Femenino , Finlandia , Ligamiento Genético , Haplotipos , Humanos , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/metabolismo , Masculino , Repeticiones de Microsatélite , Mutación Missense , Ácido N-Acetilneuramínico/metabolismo , Linaje , Reacción en Cadena de la Polimerasa , Embarazo

RESUMEN

Lysosomal free sialic acid-storage diseases include the allelic disorders Salla disease (SD) and infantile sialic acid-storage disease (ISSD). The defective gene, SLC17A5, coding for the lysosomal free sialic acid transporter was recently isolated by positional cloning. In the present study, we have identified a large number of mutations in SLC17A5 in patients presenting with either Salla disease or the ISSD phenotype. We also report for the first time the exon-intron boundaries of SLC17A5. All Finnish patients with SD (n=80) had a missense mutation changing a highly conserved arginine to cysteine (R39C); 91% of them were homozygotes for this old founder mutation. The compound-heterozygote patients, with the founder mutation in only one allele, presented with a more severe phenotype than did the homozygote patients. The same R39C mutation was also found both in most of the Swedish patients with SD and in a heterozygous form in five patients from central Europe who presented with an unusually severe (intermediate) SD phenotype. Ten different mutations, including deletions, insertions, and missense and nonsense mutations, were identified in patients with the most severe ISSD phenotype, most of whom were compound heterozygotes. Our results indicate some genotype-phenotype correlation in free sialic acid-storage diseases, suggesting that the phenotype associated with the homozygote R39C mutation is milder than that associated with other mutations.

Asunto(s)

Enfermedades por Almacenamiento Lisosomal/genética , Enfermedades por Almacenamiento Lisosomal/metabolismo , Proteínas de Transporte de Membrana/genética , Mutación/genética , Ácido N-Acetilneuramínico/metabolismo , Transportadores de Anión Orgánico , Simportadores , Edad de Inicio , Alelos , Sustitución de Aminoácidos/genética , Secuencia de Bases , Análisis Mutacional de ADN , Exones/genética , Finlandia/epidemiología , Efecto Fundador , Frecuencia de los Genes/genética , Pruebas Genéticas , Heterocigoto , Humanos , Lactante , Recién Nacido , Intrones/genética , Enfermedades por Almacenamiento Lisosomal/epidemiología , Enfermedades por Almacenamiento Lisosomal/fisiopatología , Proteínas de Transporte de Membrana/química , Fenotipo , Reacción en Cadena de la Polimerasa , Conformación Proteica , ARN Mensajero/análisis , ARN Mensajero/genética , Suecia/epidemiología

RESUMEN

OBJECTIVE: To evaluate the degree of possible peripheral nervous system (PNS) involvement in addition to CNS manifestations in Salla disease, a free sialic acid storage disorder leading to severe mental retardation with a wide clinical variation. BACKGROUND: Salla disease is a lysosomal storage disorder that affects the white matter of the CNS. MRI findings and recent 1H MRS study results provide evidence for delayed central myelination, but there is no previous evidence for PNS involvement in this disease. The gene coding for a presumptive sialic acid transport protein has recently been identified, and the first disease-causing mutations have been characterized. METHODS: Nerve conduction studies; evoked potentials to visual (VEP), brainstem auditory (BAEP), and somatosensory stimuli (SEP); and EEG were carried out on 22 patients (age range 2 months to 57 years) with biochemically and genetically confirmed Salla disease. Brain MRI were available on 14 patients. RESULTS: Nerve conduction studies revealed abnormalities in nearly half of the patients (10/21). The four severely disabled patients and the oldest patient had greatly reduced nerve conduction velocities and prolonged distal latencies compatible with demyelinating polyneuropathy. In addition, SEP was abnormal in the majority of the patients, but VEP and BAEP in only a few cases. PNS involvement was clearly associated with both the phenotypic severity and MRI findings. CONCLUSIONS: The results indicate that dysmyelination in Salla disease occurs not only in the CNS but also in the peripheral nervous system, contributing to the phenotypic variation, which can now be correlated with the molecular basis of the disease.

Asunto(s)

Sistema Nervioso Central/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Mucolipidosis/patología , Sistema Nervioso Periférico/patología , Adolescente , Adulto , Sistema Nervioso Central/fisiopatología , Niño , Preescolar , Electroencefalografía , Potenciales Evocados/fisiología , Femenino , Genotipo , Humanos , Lactante , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mucolipidosis/genética , Mucolipidosis/fisiopatología , Conducción Nerviosa/fisiología , Sistema Nervioso Periférico/fisiopatología , Fenotipo

RESUMEN

Lysinuric protein intolerance (LPI; MIM 222700) is an autosomal recessive disorder characterized by defective transport of the cationic amino acids lysine, arginine and ornithine at the basolateral membrane of the polar epithelial cells in the intestine and renal tubules, and by hyperammonemia after high-protein meals. LPI is caused by mutations in the SLC7A7 (solute carrier family 7, member 7) gene encoding y(+)LAT-1 (y(+)L amino acid transporter-1), which co-induces together with 4F2 heavy chain (4F2hc) system y(+)L in Xenopus oocytes. All Finnish LPI patients share the same founder mutation 1181-2A-->T (LPI(Fin)) not found in LPI patients elsewhere. Mutation screening of 20 non-Finnish LPI patients revealed 10 novel mutations: four deletions, two missense mutations, two nonsense mutations, a splice site mutation and a tandem duplication. Five LPI mutations (L334R, G54V, 1291delCTTT, 1548delC and LPI(Fin)) were studied functionally. All mutant proteins failed to co-induce amino acid transport activity when expressed with 4F2hc in Xenopus oocytes. Immunostaining experiments revealed that frameshift mutants 1291delCTTT, 1548delC and LPI(Fin)remained intracellular on expression with 4F2hc. In contrast, the missense mutants L334R and G54V reached the oocyte plasma membrane when co-expressed with 4F2hc, demonstrating that they are transport-inactivating mutations. This finding, together with the strong degree of conservation among all members of this family of amino acid transporters, indicates that residues L334 and G54 play a crucial role in the function of the y(+)LAT-1 transporter.

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos/genética , Aminoácidos/metabolismo , Proteínas Portadoras/genética , Proteínas de la Membrana/genética , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos , Sistemas de Transporte de Aminoácidos Básicos , Animales , Transporte Biológico , Proteínas Portadoras/metabolismo , Mapeo Cromosómico , Cromosomas Humanos Par 14 , Análisis Mutacional de ADN , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Proteínas de la Membrana/metabolismo , Microscopía Confocal , Oocitos/citología , Reacción en Cadena de la Polimerasa , Estructura Secundaria de Proteína , Xenopus

RESUMEN

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.

Asunto(s)

Aspartilglucosaminuria , Tamización de Portadores Genéticos , Enfermedades por Almacenamiento Lisosomal/psicología , Adolescente , Asparagina/metabolismo , Niño , Preescolar , Demografía , Femenino , Asesoramiento Genético , Glicopéptidos/metabolismo , Conocimientos, Actitudes y Práctica en Salud , Humanos , Lactante , Enfermedades por Almacenamiento Lisosomal/diagnóstico , Masculino , Estudios Retrospectivos , Sociología Médica

RESUMEN

Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid is impaired in lysosomal membranes from Salla and ISSD patients. The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14-q15 in a linkage study using Finnish families. Salla disease and ISSD were further shown to be allelic disorders. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.

Asunto(s)

Proteínas Portadoras/genética , Transporte Iónico/genética , Mutación , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Ácidos Siálicos/metabolismo , Adulto , Secuencia de Aminoácidos , Proteínas de Transporte de Anión , Secuencia de Bases , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Cartilla de ADN/genética , Femenino , Expresión Génica , Genes Recesivos , Humanos , Lactante , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido , Distribución Tisular

RESUMEN

Lysinuric protein intolerance is a recessively inherited metabolic disease characterized by defective efflux of cationic amino acids at the basolateral membrane of the intestinal and renal tubular epithelium. Linkage analysis and further linkage disequilibrium in Finnish LPI families have earlier assigned LPI gene locus within or in close vicinity of T-cell receptor alpha/delta gene cluster on chromosome site 14q11. In the present work we have characterized the linkage defined LPI region using RH-mapping and fiber-FISH and searched the LPI gene from the reported sequence of the T-cell receptor gene.

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos/genética , Cromosomas Humanos Par 14 , Lisina/metabolismo , Familia de Multigenes , Receptores de Antígenos de Linfocitos T/genética , Mapeo Cromosómico , Humanos , Hibridación Fluorescente in Situ , Lisina/orina

RESUMEN

Y chromosomal polymorphisms were studied in 502 males from 16 Eurasian ethnic groups including the Finns, Saami (Inari Lake area and Skolt Saami), Karelians, Mari, Mokshas, Erzas, Hungarians (Budapest area and Csángós), Khanty, Mansi, Yakuts, Koryaks, Nivkhs, Mongolians, and Latvians. The samples were analysed for polymorphisms in the Y chromosome specific Alu insertion (YAP) and six microsatellites (DYS19, DYS389-I and II, DYS390, DYS392, DYS393). The populations were also screened for the recently described Tat polymorphism. The incidence of YAP+ type was highest in the Csángós and in other Hungarians (37.5% and 17.5%, respectively). In the Karelians and the Latvians it was present at approximately the same level as commonly found in other European populations, whilst absent in our further samples of Eurasian populations, including the Finns and the Saami. Aside from the Hungarians, the C allele of the Tat polymorphism was common in all the Finno-Ugric speaking populations (from 8.2% to 63.2%), with highest incidence in the Ob-Ugrian Khanty. The C allele was also found in the Latvians (29.4%). The haplotypes found associated with the Tat C allele showed consistently lower density than those associated with the T allele, indicating that the T allele is the original form. The computation of the age of the Tat C suggested that the mutation might be a relatively recent event giving a maximum likelihood estimate of 4440 years (95% confidence interval about 3140-6200 years). The distribution patterns of the 222 haplotypes found varied considerably among the populations. In the Finns a majority of the haplotypes could be assigned to two distinct groups, one of which harboured the C allele of the Tat polymorphism, indicating dichotomous primary source of genetic variation among Finnish males. The presence of a bottleneck or founding effect in the male lineages of some of the populations, namely in the Finns and the Saami, would appear to be one likely interpretation for these findings.

Asunto(s)

Etnicidad/genética , Efecto Fundador , Genética de Población , Polimorfismo Genético , Cromosoma Y/genética , Elementos Alu/genética , ADN/genética , Europa Oriental , Asia Oriental , Finlandia , Genes tat/genética , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite/genética

RESUMEN

OBJECTIVE: To determine whether N-acetylaspartate (NAA) is reduced in patients with Salla disease, a neurodegenerative disorder. BACKGROUND: 1H MRS allows the brain metabolism to be studied noninvasively in vivo. N-acetyl (NA) is composed primarily of NAA, which is regarded as a neuronal marker. The NA signal in 1H MRS is reduced in several neurodegenerative disorders. Increased NA signal has thus far only been found in Canavan's disease as a result of NAA accumulation in the brain tissue. In Salla disease, an autosomal recessive free sialic acid storage disorder, N-acetylneuraminic acid (NANA), accumulates in lysosomes of brain tissue. METHODS: The authors studied eight patients with Salla disease (age range, 6 to 44 years) and eight age-matched healthy volunteers using quantitative 1H MRS. The spectra were obtained from two selected 8-cm3 volumes of interest localized in the basal ganglia and in the parietal white matter using conventional 1.5-T MRI equipment. The spectral resonance lines of NA groups, creatine and phosphocreatine (Cr), and choline-containing compounds (Cho) were analyzed quantitatively. All MR images were evaluated to verify the state of myelination. RESULTS: 1H MRS from parietal white matter revealed 34% higher NA and 47% higher Cr concentrations, and a 35% lower Cho concentration in the patients with Salla disease compared with the age-matched control subjects. The patients had a 22% higher water content in their parietal white matter, whereas in the basal ganglia the water concentrations did not differ significantly. In the patients' basal ganglia the Cr concentration was 53% higher. CONCLUSIONS: NAA is considered to be a neuronal marker that, except for Canavan's disease, has been found or assumed to be either stable or reduced. However, in Salla disease the high NA signal may have a contribution from accumulated lysosomal NANA, which offsets the possible loss of NAA. The high Cr is in line with the increased glucose uptake found in our earlier 2-fluoro-2-deoxy-D-glucose-PET study, reflecting increased energy demand. It is worth noting that in a conventional 1H MRS ratio-based analysis these underlying abnormalities would have remained undetected. Our study thus emphasizes the importance of a quantitative assessment of metabolite concentrations in 1H MRS for detecting altered brain metabolism.

Asunto(s)

Encéfalo/metabolismo , Enfermedades por Almacenamiento Lisosomal/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Adolescente , Adulto , Encéfalo/patología , Niño , Humanos , Enfermedades por Almacenamiento Lisosomal/patología , Imagen por Resonancia Magnética , Protones

RESUMEN

Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the baso-lateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos/genética , Proteínas Portadoras/genética , Proteínas de la Membrana/genética , Eliminación de Secuencia , Adolescente , Secuencia de Aminoácidos , Sistemas de Transporte de Aminoácidos Básicos , Animales , Arginina/metabolismo , Transporte Biológico , Proteínas Portadoras/metabolismo , Desoxirribonucleasas de Localización Especificada Tipo II/genética , Femenino , Finlandia , Heterocigoto , Humanos , Intrones , Leucina/metabolismo , Lisina/orina , Masculino , Proteínas de la Membrana/metabolismo , Datos de Secuencia Molecular , Mutación , Oocitos/fisiología , Xenopus

RESUMEN

UNLABELLED: Salla disease is an autosomal recessive lysosomal free sialic acid storage disorder characterized by psychomotor retardation and ataxia. MRI studies have revealed evidence of dysmyelination, but the biological mechanism of the brain dysfunction is unknown. METHODS: Nine patients with Salla disease (age 2.5 mo-42 y) presenting the disease in varying degrees of severity were studied by PET using 2-fluoro-2-deoxy-D-glucose (FDG) as a tracer. Local cerebral metabolic rates for glucose (LCMRGlc) in individual brain regions were compared with controls. RESULTS: The FDG PET results showed significantly increased LCMRGlc values in the frontal and sensorimotor cortex and especially in the basal ganglia of the patients. Cerebellar hypometabolism was present in all seven patients with marked ataxia, whereas the less severely affected patients without obvious ataxia had normal or even high glucose uptake in the cerebellum. CONCLUSION: The increased cerebral glucose utilization is a constant finding in Salla disease and may reflect the basic defect of the sialic acid metabolism in this disorder. The FDG PET findings in the cerebellum suggest a correlation between glucose uptake and the severity of the clinical symptoms.

Asunto(s)

Encéfalo/metabolismo , Glucosa/metabolismo , Enfermedades por Almacenamiento Lisosomal/metabolismo , Ácidos Siálicos/metabolismo , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Niño , Preescolar , Fluorodesoxiglucosa F18 , Humanos , Lactante , Enfermedades por Almacenamiento Lisosomal/patología , Imagen por Resonancia Magnética , Radiofármacos , Tomografía Computarizada de Emisión

Asunto(s)

Mano/patología , Mucolipidosis/genética , Niño , Humanos , Masculino , Mucolipidosis/diagnóstico , Mucolipidosis/patología

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos Básicos/genética , Aminoácidos Básicos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/historia , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Historia del Siglo XX , Humanos

RESUMEN

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.

Asunto(s)

Acetilglucosamina/análogos & derivados , Enfermedades por Almacenamiento Lisosomal/genética , Mutación , Acetilglucosamina/orina , Alelos , Aspartilglucosaminuria , Aspartilglucosilaminasa/genética , Femenino , Finlandia , Haplotipos , Humanos , Enfermedades por Almacenamiento Lisosomal/enzimología , Masculino , Linaje

RESUMEN

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.

Asunto(s)

Actitud , Asesoramiento Genético , Diagnóstico Prenatal , Adolescente , Adulto , Anciano , Femenino , Finlandia , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo

RESUMEN

Our patient material included families and sporadic patients of Finnish origin with the diagnosis of Charcot-Marie-Tooth (CMT) disease types 1 and 2, Dejerine-Sottas syndrome (DSS), and hereditary neuropathy with liability to pressure palsies (HNPP). We screened for mutations in the peripheral myelin protein genes connexin 32 (Cx32), myelin protein zero (P0) and peripheral myelin protein 22 (PMP22) by direct sequencing. All patients chosen for mutation screening were negative for the 1.5 Mb duplication/deletion at 17p11.2-p12. Eleven Cx32 mutations were found in 12 families, six with a CMT2 diagnosis, three with a CMT1 diagnosis and three with unclassified CMT. The total number of patients in these 12 CMTX families was 61, giving a minimum prevalence of 1.2/100,000 for CMTX in Finland. Four of the mutations, Pro58Arg, Pro172Leu, Asn175Asp and Leu204Phe, have not been previously reported. One male patient with an early onset CMT had a double Cx32 mutation, Arg22Gln and Val63Ile. The double de novo mutation was found to be of maternal grandpaternal origin. In the P0 gene a Ser78Leu mutation was found in one family with severe CMT1 and a de novo Tyr82Cys mutation was found in one DSS patient. Both mutations have been previously reported in other CMT1 families. A novel PMP22 mutation, deletion of Phe84, was found in one sporadic DSS patient. Our mutation screening results show the necessity of molecular diagnosis, in addition to clinical and electrophysiological evaluation, for proper subtyping of the disease and for accurate genetic counseling.

Asunto(s)

Enfermedad de Charcot-Marie-Tooth/genética , Mutación , Enfermedades del Sistema Nervioso/genética , Enfermedad de Charcot-Marie-Tooth/complicaciones , Aberraciones Cromosómicas , Cromosomas Humanos Par 17 , Conexinas/genética , Femenino , Finlandia , Humanos , Masculino , Proteína P0 de la Mielina/genética , Proteínas de la Mielina/genética , Enfermedades del Sistema Nervioso/complicaciones , Linaje , Proteína beta1 de Unión Comunicante

RESUMEN

Lysinuric protein intolerance (LPI) is an autosomal recessive disorder in which transport of the cationic amino acids lysine, arginine and ornithine is defective at the basolateral membrane of the epithelial cells in the intestine and renal tubules. LPI is unusually common in Finland, but patients have been described on all continents. Linkage analysis in Finnish LPI families recently assigned the LPI gene locus to a 10 cM interval between markers D14S72 and MYH7 on the long arm of chromosome 14. In the present study linkage analysis of LPI families from six different non-Finnish populations strongly suggests genetic homogeneity in LPI. Peak lod scores were obtained at the chromosomal area between D14S72 and MYH7 with the same markers as in the Finnish families. The non-Finnish families showed no linkage disequilibrium except in an Italian family cluster, whereas strong allelic association in the Finnish families implies that LPI in Finland is caused by a founder mutation.

Asunto(s)

Errores Innatos del Metabolismo de los Aminoácidos/genética , Lisina/orina , Mapeo Cromosómico , Cromosomas Humanos Par 14 , Ligamiento Genético , Haplotipos , Humanos , Recombinación Genética

RESUMEN

The mitochondrial DNA (mtDNA) sequence variation of 24 Finnish Leber hereditary optic neuroretinopathy (LHON) probands was characterized by sequencing and restriction endonuclease analyses. All LHON-associated substitutions and Caucasoid haplogroup-specific mutations were screened in the families. Analysis of the mtDNAs revealed that the Finnish LHON families have two unique features: an absence of the ND6/14484 mutation and a high number of families (10/24) without the primary mutations ND1/3460 and ND4/11778. Furthermore, the LHON families showed considerable mtDNA heterogeneity: among 24 families 22 haplotypes were detected. Overall, the haplogrouping of LHON families was similar to other European populations. However, the frequency of ND4/11778-positive families in haplogroup J was high, which may indicate that background mutations in this haplogroup together with the ND4/11778 primary mutation promote the penetrance of LHON.

Asunto(s)

ADN Mitocondrial/genética , Haplotipos , Atrofias Ópticas Hereditarias/genética , Filogenia , Adolescente , Adulto , Niño , Femenino , Finlandia , Heterogeneidad Genética , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Atrofias Ópticas Hereditarias/fisiopatología , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Población Blanca/genética

RESUMEN

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.

Asunto(s)

Pruebas Genéticas/psicología , Aceptación de la Atención de Salud , Adolescente , Adulto , Factores de Edad , Anciano , Escolaridad , Femenino , Finlandia , Encuestas Epidemiológicas , Humanos , Masculino , Persona de Mediana Edad , Factores Sexuales