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Biomedical subjects

J Leisti

Publications and source records attributed to J Leisti.

At least 19 recordsLinked to original sources
PubMed1995

Improved carrier testing for multiple endocrine neoplasia, type 1, using new microsatellite-type DNA markers.

Familial multiple endocrine neoplasia, type 1 (FMEN1), is an autosomal dominant trait generated by hyperfunction of various endocrine glands. The gene for MEN1 has been mapped to chromosome 11q13 by genetic linkage and deletion mapping in tumors. Eight Finnish families, including 46 individuals carrying the risk haplotype, have been typed for four polymorphic microsatellite DNA markers spanning the MEN1 chromosomal region. Three of the loci concerned, D11S913, D11S987, and D11S1337, displayed maximum lod scores (Zmax) 6.70, 9.88, and 2.54, respectively, with no recombinations with the disease gene, whereas a Zmax of 8.43 was obtained for D11S971 at a recombination fraction of 0.03. Our results indicate that the use of this set of markers considerably improves the diagnostic value of genotyping patients at risk of developing MEN1.

Alleles↗
PubMed1995

A molecular and cytogenetic study in Finnish Prader-Willi patients.

The Prader-Willi syndrome (PWS) is a developmental disorder caused by a deficiency of paternal contributions, arising from differently sized deletions, uniparental disomy or rare imprinting mutations, in the chromosome region 15q11-q13. We studied 41 patients with suspected PWS and their parents using cytogenetic and molecular techniques. Of the 27 clinically typical PWS patients, 23 (85%) had a molecular deletion that could be classified into four size categories. Only 15 of them (71%) could be detected cytogenetically. Maternal uniparental heterodisomy was observed in four cases. The rest of the patients showed no molecular defects including rare imprinting mutations. In our experience, the use of the methylation test with the probe PW71 (D15S63), together with the probe hN4HS (SNRPN), which distinguishes between a deletion and uniparental disomy, is the method of choice for the diagnosis of PWS.

Chromosome Deletion↗
PubMed1995

Familial fetal akinesia deformation sequence with a skeletal muscle maturation defect.

Two female siblings with the fetal akinesia deformation sequence (FADS) are described. Both showed facial anomalies, arthrogrypotic extremities, hypoplastic lungs, and fetal growth retardation. The central nervous system of the second sibling, including the spinal cord, was normal. The skeletal muscle was studied by immunohistochemistry for the expression of several myosin heavy chain isoforms, M-band proteins and intermediate filament proteins. The skeletal muscle was immature and atypical muscle spindles containing up to 31 intrafusal fibers were found. These findings suggest that a lethal FADS phenotype may involve a maturation defect of the skeletal muscle, and, in this family, may be inherited in a recessive fashion.

Adenosine Triphosphatases↗
PubMed1995

Northern epilepsy syndrome: clinical course and the effect of medication on seizures.

We describe the clinical course and treatment of 19 patients with the Northern epilepsy syndrome, an autosomal recessively inherited epilepsy with associated mental deterioration. The clinical course could be divided into three successive stages. The first stage continued from the onset of epilepsy until puberty. Seizures began at a mean age of 6.6 years and consisted predominantly of generalized tonic-clonic convulsions (GTC) and, transiently, also of complex partial seizures (CPS). Until puberty, seizure frequency increased in most patients from one attack in 1-2 months to one to two attacks weekly. Seizures did not respond to phenytoin (PHT) or carbamazepine (CBZ), were transiently controlled by valproate (VPA) and phenobarbital (PB), but were effectively treated only by clonazepam (CZP). Mental deterioration began 2-5 years after the onset of epilepsy and was most rapid before adulthood, a time when the seizures were also most frequent. The second stage is marked by fewer seizures, further mental deterioration, and less rapid progression. All patients were demented (I.Q. < 70) by age of 30 years. The first signs of motor clumsiness also appeared then. The third stage was one of permanent disability and usually began in middle age. Seizures were few, but the patients were clumsy and had marked equilibrium difficulties.

Adolescent↗
PubMed1995

Lethal congenital contracture syndrome (LCCS), a fetal anterior horn cell disease, is not linked to the SMA 5q locus.

The lethal congenital contracture syndrome (LCCS) is an autosomal recessive syndrome (McKusick 253310) leading to perinatal death owing to early onset degeneration of the anterior horn motor neurones of the spinal cord. The neuropathological findings in the LCCS closely resemble those of spinal muscular atrophy (SMA). Since all the three types of SMA have been localised to the same gene locus on the long arm of chromosome 5, we analysed samples from seven families with 10 LCCS fetuses with the microsatellite markers assigned to the SMA 5q region. Linkage analyses between the SMA linked DNA markers and the disease allele in the LCCS families excluded the critical chromosomal region around the SMA locus as the critical chromosomal region for the LCCS locus.

Anterior Horn Cells↗
PubMed1995

A patient with Wolf-Hirschhorn syndrome originating from translocation t(4;8) (p16.3;q24.3)pat.

We present here a 7 year old girl with the clinical signs of Wolf-Hirschhorn syndrome (WHS). Only on high resolution banding was a deletion of 4p16.3 suspected in both the proband and the father. Further studies using simultaneous R banding and FISH, with cosmid probe pc847.351 containing the mildly repetitive fragment 847-EC, confirmed the diagnosis and showed a paternal balanced translocation t(4;8)(p16.3;q24.3).

Abnormalities, Multiple↗
PubMed1994

The gene for a recessively inherited human childhood progressive epilepsy with mental retardation maps to the distal short arm of chromosome 8.

A recently delineated childhood epilepsy has hitherto been observed only in a small geographic region in northern Finland, where, with the exception of one, both parents of all of the 11 sibships with affected individuals descend from one or two founding couples. The disease is characterized by generalized tonic-clonic seizures with onset at 5-10 years and progressive, severe mental retardation with onset 2-5 years after the first seizures. In this study the gene locus is assigned to the telomeric region of chromosome 8p by linkage. Analyses of recombinations place the locus in the 7-centimorgan interval between AFM185xb2 and D8S262 in which three markers, D8S504, D8S264, and AFM077yg5, show no recombinations with the phenotype. Haplotypes comprising alleles at the above five loci support the hypothesis of a single founding mutation for all affected chromosomes except the one belonging to the unrelated parent, who has a very different haplotype, suggesting another mutation or a very old ancestry of a single mutation. This study raises to three the number of heritable epilepsies whose gene loci have been mapped and provides a starting point for the cloning of the gene. It also suggests the possibility that the disease might not be limited to the northern Finnish population.

Adult↗
PubMed1994

Diagnosis of fragile X syndrome by direct mutation analysis.

A total of 27 fragile X pedigrees consisting of over 100 nuclear families were analyzed by Southern blotting methods and probes StB12.3 and StB12.3xx to detect the expansion of the (CGG)n repeat within the FMR-1 gene and the abnormal methylation pattern of the adjacent DNA region responsible for the fragile X syndrome. Clinical expression was found to be associated with the presence of a full mutation (delta > 500 bp, associated with abnormal methylation) in all the males and 50% of the females studied, whereas individuals carrying a premutation (delta = 100-700 bp) were normal. A preferential size increase in the enlarged (CGG)n repeat was detected in successive generations, the instability being stronger when transmitted from a female than from a male. No expansion of the premutation to the full mutation occurred in the paternal transmissions, and the size increase was significantly smaller than in the maternal transmissions. This could partly explain the stability of the premutation through several generations in families with transmitting males. In the maternal transmissions, the risk of expansion of a premutation to a full mutation appeared to depend on its size. The critical maternal premutation size leading invariably to the full mutation was between delta = 175-200 bp. This is important for genetic counseling and also explains the commonly observed clustering of affected individuals in fragile X families.

Blotting, Southern↗
PubMed1994

The fragile X syndrome in Finland: demonstration of a founder effect by analysis of microsatellite haplotypes.

Microsatellite markers RS46 (DXS548) and FRAXAC2 flanking the fragile X mutation, an expansion of a (CGG)n repeat within the FMR-1 gene, were typed in 60 unrelated northern and eastern Finnish fragile X families and in a control population from the same geographical region. A significant difference was found in allelic and haplotypic distributions between the normal X and fragile X chromosomes. Evidence for a strong founder effect was detected, with the haplotype 196-153 being present on 80% of the fragile X chromosomes, but on only 8% of the normal X chromosomes. In addition to this major haplotype, four minor haplotypes were found on the fragile X chromosomes. These results suggest that the majority of present-day fragile X mutations in Finland may have a common initial ancestor, probably from the 16th century.

DNA, Satellite↗
PubMed1994

Lethal arthrogryposis in Finland--a clinico-pathological study of 83 cases during thirteen years.

Eighty-three cases of multiple congenital joint contractures, i.e., arthrogryposis, which were related with either a stillborn fetus, a termination of pregnancy following prenatal diagnosis or death within 28 days postnatally, were studied. Sixty-seven cases were neurogenic in origin, including forty-one with the lethal congenital contracture syndrome (LCCS, McKusick 253310), fifteen with milder anterior horn cell involvement, and ten with dysgenesis and degeneration of the CNS. Congenital muscular dystrophy was seen in two cases and nemaline myopathy in one case. A non-neuromuscular basis was established in ten cases, and the cause remained obscure in three cases. Apart from the autosomal recessive LCCS, the fifteen cases with anterior horn cell involvement made up a uniform clinico-pathological entity. In two families this disease recurred twice, and autosomal recessive inheritance is therefore likely. Recurrence was also seen twice in a family with central nervous system degeneration and in another with the oligohydramnios sequence. There are apparently several recessively inherited entities among the arthrogryposis phenotype. A careful clinical study and a neuropathological examination are essential for estimating the recurrence risk.

Arthrogryposis↗
PubMed1994

Northern epilepsy syndrome: an inherited childhood onset epilepsy with associated mental deterioration.

A new autosomal recessively inherited disease of the central nervous system involving childhood epilepsy and mental deterioration is described. Twenty three patients (11 males and 12 females) belonging to 11 families from northern Finland have been identified. A common ancestor has been found for nine families. The mean age of onset of epilepsy was 6.7 years (range 5-10 years) and the epilepsy was characterised by generalised tonic-clonic seizures increasing in frequency up to puberty. One third of the patients also had complex partial seizures during childhood. During young adulthood the epileptic activity began to decrease, but complete remission did not occur. Electroencephalography showed progressive slowing of the background activity with relatively scanty epileptiform activity. Out of four ictal recordings the paroxysmal activity was initiated focally in two cases. Clonazepam and sodium valproate had some antiepileptic effect, clonazepam being the more beneficial of the two. Mental development, which was originally normal, began to deteriorate two to five years after the onset of epilepsy, and the deterioration continued during adulthood in spite of good epilepsy control, leading to mental retardation by middle age. The pathogenesis of the disorder, called the Northern epilepsy syndrome, is unknown. Linkage analysis using DNA markers linked to the EPM1 gene for progressive myoclonus epilepsy of Unverricht-Lundborg type showed that the Northern epilepsy syndrome is not allelic to EPM1.

Adolescent↗
PubMed1992

Unstable DNA may be responsible for the incomplete penetrance of the myotonic dystrophy phenotype.

Myotonic dystrophy (DM) is associated with the expansion and instability of a trinucleotide (CTG) repeat in a sequence encoding a cAMP-dependent protein kinase. The normal copy number of 5-35 repeats is exceeded in DM patients, with the size of the expansion broadly correlating with the severity of symptoms experienced. In most families reported, the unstable DNA sequence has increased in size on transmission to affected offspring, thereby providing a molecular explanation for the phenomenon of anticipation in DM, i.e. an increase in the severity of symptoms associated with an earlier age at onset of the disease in successive generations of a family. Here we present the first reported case of a family where the transmission of the affected chromosome from father to son is accompanied by a reduction in the size of the triplet expansion, such that it falls within the normal range. As the son remains asymptomatic, this type of molecular event may provide an explanation for the incomplete penetrance of the disease phenotype reported for this disorder. The implications for genetic counselling of DM families and the mechanistic considerations of the trinucleotide instability are discussed.

Adult↗
PubMed1992

Identification of a common mutation in Finnish patients with nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (NKH) is an autosomal recessive metabolic disorder caused by the defects in the glycine cleavage system (GCS; EC 2.1.2.10), a multienzyme system that consists of four individual components. NKH is a rare disorder in many countries, but with a very high incidence in northern Finland. To understand the genetic background of this high incidence, we examined the GCS in a typical case of NKH at the molecular level. The activity of P protein, a component of the GCS, was not detected in the lymphoblasts of the patient, while P protein mRNA of a normal size and level was present in the cells. Structural analysis of P protein mRNA from the patient revealed a single nucleotide substitution from G to T in the protein coding region, which resulted in an amino acid alteration from Ser564 to Ile564. No P protein activity was detected when the mutant P protein with this amino acid substitution was expressed in COS 7 cells. The patient was homozygous for this mutation. Furthermore, this mutation was present in 70% (14 of 20) of P protein gene alleles in Finnish patients with NKH, whereas it was not found in 20 alleles of non-Finnish patients. The results suggest that this mutation is responsible for the high incidence of NKH in Finland.

Amino Acid Metabolism, Inborn Errors↗
PubMed1992

Fumarase deficiency: two siblings with enlarged cerebral ventricles and polyhydramnios in utero.

A family having two boys with progressive encephalomyopathy and fumaric aciduria due to fumarase deficiency is described. Both patients initially presented with polyhydramnios and enlarged cerebral ventricles in utero, with subsequent cerebral atrophy, severe developmental delay, infantile spasms, and hypsarythmia on electroencephalogram. Fumarase activity in blood mononuclear cells and in the mitochondrial and cytosolic fractions of cultured skin fibroblasts was less than 0.5% of the control mean or undetectable. The older boy died at the age of 5 years and 4 months and the younger one is now 2 years and 10 months. The unrelated parents are symptomless and the other three children in the family are clinically healthy. Fumarase activities in the blood mononuclear cells of the father, mother, sister, and two brothers were 59%, 52%, 52%, 120%, and 44% of the control mean, respectively. The results strongly support autosomal recessive inheritance of fumarase deficiency and suggest its consideration in children with congenital hydrocephalus, progressive brain atrophy, and infantile spasms.

Cells, Cultured↗
PubMed1991

Uridine enhances expression of the fragile X chromosome in human lymphocytes.

We have studied the effect of uridine on the expression of fragile X (fra[X]) in lymphocyte cultures established in the folate and thymidine deficient medium TC199. The results indicate that uridine enhances the expression of fra(X) and gives a higher mitotic rate. The excess of uridine during DNA synthesis might further promote the previously suggested cycle of misincorporation and removal of deoxyuridine monophosphate when the pool of deoxythymidine triphosphate is continuously depleted.

Culture Media↗