M Savukoski

University of Helsinki, Helsinki, Province of Southern Finland, Finland

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Publications (13)103.41 Total impact

  • S Ranta, M Savukoski, P Santavuori, M Haltia
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    ABSTRACT: Finland and the Finns have been the subject of numerous genetic and genealogical studies, owing to enrichment of certain rare hereditary disorders in the Finnish population. Two types of NCL have so-far been found almost exclusively in Finland: Finnish variant late infantile NCL, vLINCL (CLN5), and the Northern epilepsy syndrome or Progressive epilepsy with mental retardation, EPMR (CLN8). The first symptoms of Finnish vLINCL are concentration problems or motor clumsiness by 3 to 6 years of age, followed by mental retardation, visual failure, ataxia, myoclonus, and epilepsy. Northern epilepsy, the newest member of the NCL family with the most protracted course, is characterized by the onset of generalized seizures between 5 and 10 years of age and subsequent progressive mental retardation. Visual problems are slight and late, while myoclonus has not been observed. Both the Finnish vLINCL and Northern epilepsy are pathologically characterized by intraneuronal cytoplasmic deposits of autofluorescent granules which are Luxol fast blue-, PAS-, and Sudan black B-positive in paraffin sections. In Northern epilepsy the intraneuronal storage process and neuronal destruction are generally of mild degree but highly selective and, in contrast to other forms of childhood onset NCL, the cerebellar cortex is relatively spared. By electron microscopy the storage bodies mainly contain rectilinear complex type and fingerprint profiles in Finnish vLINCL and structures resembling curvilinear profiles in Northern epilepsy. Mitochondrial ATP synthase subunit c is the main stored protein in both disorders. Both the DCLN5 and CLN8 genes encode putative membrane proteins with yet unknown functions. Furthermore, a well studied spontaneously occurring autosomal recessive mouse mutant, motor neuron degeneration (mnd) mouse, is a homolog for CLN8.
    Advances in genetics 02/2001; 45:123-40. · 4.85 Impact Factor
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    ABSTRACT: The authors analyzed the clinical phenotype, including MRI, of eight patients with Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCLFin; CLN5; MIM256731). Although the four known mutations, including one novel mutation identified in this study, have very different consequences for the predicted polypeptide, none of them results in an atypical phenotype, as has been reported in other forms of NCL. Thus, it seems likely that each mutation severely disturbs the normal function of the CLN5 protein.
    Neurology 09/2000; 55(4):579-81. · 8.30 Impact Factor
  • L Peltonen, M Savukoski, J Vesa
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    ABSTRACT: The neuronal ceroid lipofuscinoses (NCLs) are an intriguing group of inherited neurodegenerative disorders characterized by blindness, progressive psychomotor deterioration and death of neocortical neurons. Clinically, four major NCL groups have been identified: infantile, late infantile, juvenile and adult. In recent years, our understanding of the molecular basis of different NCLs has advanced significantly. The accumulation of autofluorescent material in patients' tissues has been shown to be caused by defects in either lysosomal enzymes or in novel membrane proteins of unknown function. Although the accumulated material is biochemically well defined and some of the causative mutations are known, a unifying hypothesis for the molecular basis of the NCLs remains elusive. Further work will be required to characterize the interactiving molecules and metabolic pathways involved in the pathogenesis of NCLs.
    Current Opinion in Genetics & Development 07/2000; 10(3):299-305. · 7.47 Impact Factor
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    ABSTRACT: Neuronal ceroid lipofuscinoses (NCLs) in children are progressive encephalopathies inherited as autosomal recessive traits. Progressive neuronal damage leads to psychomotor deterioration, visual failure, seizures, and finally to premature death. Based on the clinical course of the disease, the childhood forms can be divided into several subtypes. A variant form of the late infantile NCL (vLINCL), characterized by mental retardation, visual failure, ataxia, myoclonia, and death between the ages of 13 and 30 years, is prevalent in Finland. Information on ancient recombination events in disease alleles rising from this isolated population provided an efficient tool for refining the initial assignment of the CLN5 locus. Here we describe the steps resulting in the identification of the novel gene, defective in vLINCL.
    Molecular Genetics and Metabolism 05/1999; 66(4):324-8. · 2.83 Impact Factor
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    ABSTRACT: Our efforts to clone the CLN5 gene, mutated in a severe children's brain disease, variant late infantile neuronal ceroid lipofuscinosis (vLINCL, MIM256731), resulted in large-scale sequencing of genomic clones flanking the critical chromosomal region on 13q22. Computational and traditional transcript identification analyses of the resulting sequence were used to identify the disease gene. In addition to the identification of the CLN5 gene, this effort produced a large amount of genomic sequence data. Here, we report a transcription map of the 107 kb sequence in the CLN5 region, based on traditional and computational gene identification strategies. Several transcripts were identified in this sequence. Queries against the database of expressed sequence tags proved to be the most powerful tool for gene identification from large-scale sequence.
    Human Genetics 01/1999; 105(1-2):51-6. · 4.63 Impact Factor
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    ABSTRACT: A 13q isodisomy in a balanced karyotype: 45,XY,-13,-13, + i(13)(q10) was found in cultured amniocytes studied because of advanced maternal age. The isochromosome was monocentric and a new mutation as both parents had normal chromosomes. Fetal blood was studied to exclude 13-trisomy mosaicism. All (100) lymphocytes studied had the same karyotype with i(13)(q10) as the amniocytes. To determine the origin of the isochromosome, six microsatellite markers from 13q were analysed: D13S175, D13S166, D13S162, AC224, COLAC1 and D13S122. The results indicated that the i(13)(q10) was of paternal origin and isodisomic. The father had a risk of 1/20 for being a carrier for an autosomal recessive, progressive brain disorder, variant late infantile neuronal ceroid lipofuscinosis (CLN5). The risk for the fetus for this disorder of chromosome 13 was excluded by haplotype analysis. A healthy child was born at week 40 of pregnancy, supporting the idea that there are no paternally imprinted genes on chromosome 13q. Analysis of extra embryonal tissue (four samples studied) revealed the same balanced karyotype with the i(13)(q10)pat chromosome. According to the cytogenetic and molecular studies, the origin of the isochromosome 13 could be a transverse centromere cleavage at the paternal meiosis II or at an early mitosis.
    Prenatal Diagnosis 12/1998; 18(11):1169-73. · 2.68 Impact Factor
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    ABSTRACT: The neuronal ceroid lipofuscinoses (NCLs) represent a group of common recessive inherited neurodegenerative disorders of childhood, with an incidence of 1:12,500 live births. They are characterized by accumulation of autofluorescent lipopigments in various tissues. Several forms of NCLs have been identified, based on age at onset, progression of disease, neurophysiological and histopathological findings and separate genetic loci. All types of NCL cause progressive visual and mental decline, motor disturbance, epilepsy and behavioral changes, and lead to premature death. One of the subtypes, Finnish variant late infantile neuronal ceroid lipofuscinosis (vLINCL; MIM256731) affects children at 4-7 years of age. The first symptom is motor clumsiness, followed by progressive visual failure, mental and motor deterioration and later by myoclonia and seizures. We have previously reported linkage for vLINCL on chromosome 13 (ref. 5) and constructed a long-range physical map over the region. Here, we report the positional cloning of a novel gene, CLN5, underlying this severe neurological disorder. The gene encodes a putative transmembrane protein which shows no homology to previously reported proteins. Sequence analysis of DNA samples from patients with three different haplotypes revealed three mutations; one deletion, one nonsense and one missense mutation, suggesting that mutations in this gene are responsible for vLINCL.
    Nature Genetics 08/1998; 19(3):286-8. · 35.21 Impact Factor
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    ABSTRACT: The childhood neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative disorders characterised by progressive visual failure, neurodegeneration, epilepsy and the accumulation of an autofluorescent lipopigment in neurones and other cells. Three main subtypes have been identified according to age of onset, clinical features and ultrastructural morphology. These are infantile NCL (INCL; CLN1), classical late infantile NCL (LINCL; CLN2) and juvenile NCL (JNCL; CLN3). Several atypical forms of late infantile NCL (LINCL) have also been described including a Finnish variant LINCL (CLN5). The CLN2 gene has been excluded from the CLN1, CLN3 and CLN5 loci. A genome search was initiated using a homozygosity mapping strategy in five classical LINCL and two variant LINCL consanguineous families. A common region of homozygosity was identified on chromosome 11p15 in two of the classical families. Analysis of a further 33 classical LINCL families supported linkage in this region (Zmax = 3.07 at theta = 0.06 at D11S1338). A common region of homozygosity was also observed on chromosome 15q21-23 in the two variant LINCL families. Extension of the analysis to include a further seven families of identical ultrastructural phenotype established linkage to this region (Zmax = 6.00 at theta = 0.00 at D15S1020).
    Human Molecular Genetics 05/1997; 6(4):591-5. · 7.69 Impact Factor
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    ABSTRACT: The variant form of late infantile neuronal ceroid lipofuscinosis (vLINCL, locus definition CLN5) represents a progressive brain disease with autosomal recessive inheritance. We have previously assigned the CLN5 locus to chromosome 13q21.1-q32 between markers D13S160 and D13S162 by linkage analysis in Finnish families. The information on ancient recombination events obtained from linkage disequilibrium provided an efficient tool for further refining the assignment of the CLN5 locus. Isolation of two novel (CA)n markers, COLAC1 and AC224, resulted in a dramatic restriction of the critical DNA region. We utilized the Fiber-FISH technique to orient and order the large DNA clones isolated by STSs and were able to eliminate almost totally the restriction digestion and PFGE step in the construction of the long-range DNA contig. Both linkage disequilibrium data and Fiber-FISH analyses assigned the CLN5 locus to a well-defined 200-kb region. Here we report a complete physical map of about 350 kb covering the critical chromosomal region of CLN5, which will facilitate the final isolation of the CLN5 gene.
    Genomics 08/1996; 35(1):71-8. · 3.01 Impact Factor
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    ABSTRACT: Variant late infantile neuronal ceroid lipofuscinosis (vLINCL) is an autosomal recessive progressive encephalopathy of childhood enriched in the western part of Finland, with a local incidence of 1 in 1500. We recently assigned the locus for vLINCL, CLN5, to 13q21.1-q32. In the present study, the haplotype analysis of Finnish CLN5 chromosomes provides evidence that one single mutation causes vLINCL in the Finnish population. Eight microsatellite markers closely linked to the CLN5 gene on chromosome 13q were analyzed, to study identity by descent by shared haplotype analysis. One single haplotype formed by flanking markers D13S160 and D13S162 in strong linkage disequilibrium (P < .0001) was present in 81% of disease-bearing chromosomes. Allele 4 at the marker locus D13S162 was detected in 94% of disease-bearing chromosomes. To evaluate the age of the CLN5 mutation by virtue of its restricted geographical distribution, church records were used to identify the common ancestors for 18 vLINCL families diagnosed in Finland. The pedigrees of the vLINCL ancestors merged on many occasions, which also supports a single founder mutation that obviously happened 20 to 30 generations ago (i.e., approximately 500 years ago) in this isolated population. Linkage disequilibrium was detected with seven markers covering an extended genetic distance of 11 cM, which further supports the young age of the CLN5 mutation. When the results of genealogical and linkage disequilibrium studies were combined, the CLN5 gene was predicted to lie approximately 200 - 400 kb (total range 30 - 1360 kb) from the closest marker D13S162.
    The American Journal of Human Genetics 03/1996; 58(3):506-12. · 11.20 Impact Factor
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    ABSTRACT: The neuronal ceroid-lipofuscinoses (NCL) are a group of neurodegenerative disorders with an autosomal-recessive pattern of inheritance. There are 3 main categories of childhood NCL, namely, infantile, late-infantile, and juvenile NCL. These can be distinguished on the basis of age of onset, clinical course, and histopathology. A number of variant forms of NCL have also been described, and these show symptoms intermediary between the main classical forms. The genes for both the infantile and juvenile forms of NCL have previously been mapped to chromosome areas 1p32 and 16p12, respectively. The gene for late-infantile NCL (LINCL), CLN2, has been excluded from both these loci, but its location is as yet unknown. Recently, CLN5, the gene for the Finnish variant form of LINCL, was mapped to 13q21.1-32. Using the 3 microsatellite markers which were most tightly linked to CLN5, we have excluded CLN2 from this region using a subset of 17 families. Thus, CLN2 represents a fourth distinct genetic locus involved in the pathogenesis of NCL.
    American Journal of Medical Genetics 07/1995; 57(2):348-9.
  • European Journal of HumanGenetics 02/1995; 3(5):326-8. · 4.32 Impact Factor
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    ABSTRACT: We demonstrate here that at least four genetically separate loci are involved in the pathogenesis of human neuronal ceroid lipofuscinoses (NCLs), fatal brain disorders of children. Earlier the assignments of the infantile and juvenile subtypes of NCL to 1p32 and 16p12 had revealed two loci; and here a variant subtype of the late-infantile form of NCL is mapped to a well-defined region on 13q21.1-q32, whereas the clinically similar, classical form of late-infantile NCL was found to represent the fourth, yet-unidentified NCL locus. The linkage disequilibrium was crucial for locus assignment in our highly limited family material, and the data exemplify the significance of this phenomenon in the random mapping of rare human diseases.
    The American Journal of Human Genetics 11/1994; 55(4):695-701. · 11.20 Impact Factor