Abstract
Seven phenotypically homogeneous Mediterranean myoclonus families were studied using DNA markers from the genetically defined EPM1 region on chromosome 21. No recombinations between the disease phenotype and the markers studied were detected. Within the EPM1 region, the highest lod score value of 5.07 (at Θ = 0.00) was reached at locus PFKL. Significant allelic association (P = 0.02) between the disease mutation and PFKL was detected suggesting a founder effect in Mediterranean myoclonus. However, haplotype data using four marker loci residing within 300kb of each other and of EPM1 suggest the occurrence of more than one mutation. The data are compatible with Mediterranean myoclonus being caused by mutations in the EPM1 gene and strengthen the concept that a large subset of progressive myoclonus epilepsies conforms with Unverricht-Lundborg disease and that this subset is an etiologically homogeneous entity.
Similar content being viewed by others
References
Andermann F, Berkovic S, Carpenter S, Andermann E (1989) The Ramsay Hunt syndrome is no longer a useful diagnostic category. Mov Disord 4:13–17.
Avramopoulos D, Cox T, Kraus JP, Chakravarti A, Antonarakis SE (1993) Linkage mapping of the cystathionine β-synthase (CBS) gene on human chromosome 21 using a DNA polymorphism in the 3′ untranslated region. Hum Genet 90:566–568.
Berkovic SF, Andermann F, Carpenter S, Wolfe LS (1986) Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med 315:296–305.
Burmeister M, Kim S, Price ER, Lange T de, Tantravahi U, Myers RM, Cox DR (1991) A map of the distal region of the long arm of human chromosome 21 constructed by radiation hybrid mapping and pulsed-field gel electrophoresis. Genomics 9:19–30.
Eldridge R, Iivanainen M, Stern R, Koerber T, Wilder BJ (1983) “Baltic” myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin. Lancet II:838–842.
Genton P, Michelucci R, Tassinari CA, Roger J (1990) The Ramsay Hunt syndrome revisited: Mediterranean myoclonus versus mitochondrial encephalomyopathy with ragged-red fibers and Baltic myoclonus. Acta Neurol Scand 81:8–15.
Hästbacka J, Chapelle A de la, Kaitila I, Sistonen P, Weaver A, Lander E (1992) Linkage disequilibrium mapping in isolated populations: diastrophic dysplasia in Finland. Nature Genet 2:204–211.
Koskiniemi M (1974) Psychological findings in progressive myoclonus epilepsy without Lafora bodies. Epilepsia 15:537–545.
Koskiniemi M (1986) Baltic myoclonus. In: Fahn S, Marsden D, Woert M van (eds) Advances in Neurology. Raven, New York, pp 57–64.
Koskiniemi M, Donner M, Majuri H, Haltia M, Norio R (1974a) Progressive myoclonus epilepsy. A clinical and histopathological study. Acta Neurol Scand 50:307–332.
Koskiniemi M, Toivakka E, Donner M (1974b) Progressive myoclonus epilepsy. Electroencephalographical findings. Acta Neurol Scand 50:333–359.
Lander ES, Botstein D (1986) Mapping complex genetic traits in humans: new methods using a complete RFLP linkage map. Cold Spring Harb Symp Quant Biol 51:49–62.
Lathrop GM, Lalouel JM, Julier C, Ott J (1984) Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci USA 81:3443–3446.
Lehesjoki A-E, Koskiniemi M, Sistonen P, Miao J, Hästbacka J, Norio R, Chapelle A de la (1991) Localization of a gene for progressive myoclonus epilepsy to chromosome 21q22. Proc Natl Acad Sci USA 88:3696–3699.
Lehesjoki A-E, Koskiniemi M, Pandolfo M, Antonelli A, Kyllerman M, Wahlström J, Nergårdh A, Burmeister M, Sistonen P, Norio R, Chapelle A de la (1992) Linkage studies in progressive myoclonus epilepsy: Unverricht-Lundborg and Lafora's diseases. Neurology 42:1545–1550.
Lehesjoki A-E, Koskiniemi M, Norio R, Tirrito S, Sistonen P, Lander E, Chapelle A de la (1993a) Localization of a gene for progressive myoclonus epilepsy (EPM1) on chromosome 21:linkage disequilibrium allows high resolution mapping. Hum Mol Genet 2:1229–1234.
Lehesjoki A-E, Eldridge R, Eldridge J, Wilder J, Chapelle A de la (1993b) Progressive myoclonus epilepsy of Unverricht-Lundborg type: clinical and molecular genetic study of a family from the United States with four affected sibs. Neurology 3:2384–2386.
Malafosse A, Lehesjoki A-E, Genton P, Labauge P, Durand G, Tassinari CA, Dravet C, Michelucci R, Chapelle A de la (1992) Identical genetic locus for Baltic and Mediterranean myoclonus. Lancet 339:1080–1081.
Marsden CD, Obeso JA (1989) Viewpoints on the Ramsay Hunt syndrome. 1. The Ramsay Hunt syndrome is a useful clinical entity. Mov Disord 4:6–12.
Marseille Consensus Group (1990) Classification of progressive myoclonus epilepsies and related disorders. Ann Neurol 28:113–116.
McInnis MG, Chakravarti A, Blaschak J, Petersen MB, Sharma V, Avramopoulos D, Blouin J-L, König U, Brahe C, Cox T, Warren AC, Talbot Jr CC, Van Broeckhoven C, Litt M, Antonarakis SE (1993) A linkage map of human chromosome 21∶43 PCR markers at average intervals of 2.5 cM. Genomics 16:562–571.
Millington Ward A, Wassenaar ALM, Pearson PL (1985) Restriction fragment length polymorphic probes in the analysis of Down's syndrome. Cytogenet Cell Genet 40:699.
Petersen MB, Weber JL, Slaugenhaupt SA, Kwitek AE, McInnis MG, Chakravarti A, Antonarakis SE (1991) Linkage mapping of D21S171 to the distal long arm of human chromosome 21 using a polymorphic (AC)n dinucleotide repeat. Hum Genet 87:401–404.
Polymeropoulos MH, Rath DS, Xiao H, Merril CR (1991) Dinucleotide repeat polymorphism at the human liver-type 6-phosphofructokinase (PFKL) gene. Nucleic Acids Res 19:2517.
Roger J, Soulayrol R, Hassoun J (1968) La dyssynergie cerebelleuse myoclonique (syndrome de Ramsay Hunt). Rev Neurol 119:85–106.
Rouyer F, Chapelle A de la, Weissenbach J (1990) A polymorphic DNA sequence from the terminal part of chromosome 21q [D21S154]. Nucleic Acids Res 18:1663.
Stewart GD, Tanzi RE, Kishimoto TK, Buraczynska M, Haines JL, Drabkin H, Gusella JF, Springer TA, Kurnit DM, Van Keuren M (1988) The CD18 gene maps to distal chromosome 21q22.3: RFLPs create a highly informative terminal haplotype. Am J Hum Genet 43:160.
Tassinari CA, Bureau-Paillas M, Dalla Bernardina B, Grasso E, Roger J (1974) Etude electroencephalographique de la dyssynergie cerebelleuse myoclonique avec epilepsie (syndrome de Ramsay Hunt). Rev Electroencephalogr Neurophysiol Clin 4:407–428.
Tassinari CA, Michelucci R, Genton P, Pellissier JF, Roger J (1989) Dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome): a condition unrelated to mitochondrial encephalomyopathies. J Neurol Neurosurg Psychiatry 52:262–265.
Tassinari CA, Michelucci R, Forti A, Rubboli G, Plasmati R, Salvi F, Shoffner JM, Wallace DC (1991) Ramsay Hunt syndrome and MERRF: two unrelated conditions as demonstrated by mitochondrial DNA study. Neurology 141 (Suppl 1):281.
Warren AC, Groner Y, Antonarakis SE (1988) A DNA polymorphism with KpnI of the human liver-type phosphofructokinase (PFKL) gene. Nucleic Acids Res 16:9060.
Warren AC, McInnis MG, Blaschak J, Kaliatsidaki M, Petersen MB, Chakravarti A, Antonarakis SE (1992) Dinucleotide repeat (GT)n markers on chromosome 21. Genomics 14:818–819.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lehesjoki, AE., Tassinari, C.A., Avanzini, G. et al. PME of Unverricht-Lundborg type in the Mediterranean region: linkage and linkage disequilibrium confirm the assignment to the EPM1 locus. Hum Genet 93, 668–674 (1994). https://doi.org/10.1007/BF00201568
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00201568