J7ournal of Neurology, Neurosurgery, and Psychiatry 1992;55:185-187 185 Gerstmann-Striaussler-Scheinker in an Alsatian family: clinical and genetic studies J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.3.185 on 1 March 1992. Downloaded from

C Tranchant, K Doh-ura, J M Warter, G Steinmetz, Y Chevalier, A Hanauer, T Kitamoto, J Tateishi

Abstract DNA was prepared from the frozen brain The clinical progression of Gerstmann- tissue of patient IV-28 and from leucocytes of Straussler-Scheinker disease in a family 47 living family members. The PrP coding of Alsatian origin is reported. The age of region was amplified by the polymerase chain onset and the duration of evolution were reaction (PCR) method, and the substitutions variable. The clinical picture became in codons 102, 117, 129, 178, and 200 were more complex over the generations: in the detected by dot-blot hybridisation and PvuII first generations, isolated dementia and in restriction mapping of the PCR-amplified later generations a triad of pyramidal, DNA.8 The results were compared with those pseudobulbar syndromes and dementia from 100 control patients: 20 patients from the associated with spinal cord and cerebeilar same town as the GSS family, half of whom features. gene analysis showed that had Alzheimers' disease, and 80 white subjects four surviving patients carry double mis- healthy or having other neurological . sense changes at codons 117 and 129, Genetic study-The family data were analysed identical to those found in one case at for genetic linkage with the linkage programs necropsy and 10 other healthy members of version 4 7 (R).'° We assumed that the disease the family. The missense changes were not followed a dominant mode of inheritance with found in 100 controls. No member of the penetrance depending non-linearly on age, family had modification of condons 102, from 0% at age 19 to 100% at 60 and over. 178, or 200. The lod score suggests linkage between the missense change at codon 117 and Gerstmann-Straussler-Scheinker Results disease in this family. The eight cases previously reported' and four new cases are summarised in table 1. In three cases (IV-3, IV-9, and IV-28) a cerebral biopsy In 1982, Warter et al' reported observations on specimen showed numerous multicentric or a family of Alsatian origin in which at least unicentric amyloid plaques' which were PrP eight members presented with Gerstmann- positive to immunohistochemical stains,5 Straussler-Scheinker (GSS) disease. This axonal degeneration at or surrounding the familial disease of autosomal dominant trans- plaques, neuronal degeneration, and a moder-

mission23 can sometimes be transmitted to ately intense spongiosis. Patient III-3, mother http://jnnp.bmj.com/ laboratory animals via intracerebral inocula- of IV-9, and hospitalised at present, began her tion of brain homogenates from GSS patients illness at 64 years of age, in 1984, with a right Service de Neurologie whose disease has incubated for periods of hemiparesis followed by a pseudobulbar syn- II, Universite Louis months to years. The infectious agent has not drome, a cerebellar syndrome, dementia, and Pasteur, Strasbourg, France as yet been indentified, but a protease-resistant an extrapyramidal syndrome. For the last 18 C Tranchant isoform of the prion protein,4" PrP, has been months, the patient has been bedridden and J M Warter found in these patients' brains. Molecular demented; she now has epileptic seizures.

G Steinmetz on October 3, 2021 by guest. Protected copyright. Y Chevalier genetic studies have recently detected a poly- Patient III-13 died aged 48 years after one PrP in in characterised a Department of morphism of the gene GSS families,6 year's progression by pseudo- Neuropathology, particular a missense variant at codon 102 bulbar syndrome, an asymmetrical pyramidal Neurological Institute, resulting in a substitution of leucine (leu 102) syndrome, and intellectual deterioration which Faculty of Medicine, for (pro Tateishi et al have in six months led to a bedridden state. There Kyushu University, proline 102).`-9 Fukuoka, Japan reported in one member of the Alsatian family, was no necropsy. Patient IV-25 became ill four K Doh-ura a missense PrP variant with an alanine (GCA) years ago at 33 years of age, starting with an T Kitamoto to valine (GTG) change at codon 117 and a asymmetrical pyramidal syndrome followed by J Tateishi methionine (ATG) to valine (GTG) change at extrapyramidal and pseudobulbar syndromes, Institut de Chimie Biologique, INSERM codon 129 on the same PrP allele. In this case, a state of dementia, and a cerebellar syndrome. U 184, Universit6 the attempts to transmit GSS to animals were For the past year he has been bedridden. Louis Pasteur, negative.' We summarise here the clinical and Finally, one year ago, at 57 years of age, patient Strasbourg, France genetic studies in this family (AND family). III-1 1, mother of IV-26 and IV-28, presented A Hanauer walking difficulties, dysarthria, and intellectual Correspondence to: ProfessorWarter, Service de deterioration. She has been bedridden and Neurologie II, C.H.U., 1 Subjects and methods demented for a few weeks. place de l'Hopital, 67091 Strasbourg Cedex, France. The family tree includes 76 subjects over six PrP gene analyses-No member of the family Received 12 April 1991 and generations. We have usable clinical and gen- had either insertion-deletion mutation or sub- in revised form 18 June etic data for 65 stitutional mutation at codons 102, 178, or 1991. (fig). Accepted 25 June 1991 PrP gene analyses-High molecular weight 200. Four patients still alive at present carried 186 Tranchant, Doh-ura, Warter, Steinmetz, Chevalier, Hanauer, Kitamoto, Tateishi J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.3.185 on 1 March 1992. Downloaded from

111 ;a 1 ~~1 2 3

III - 1 2

IV 0 2343 6 6 7

1 2 3 4 5 6 7 8 9 10I

VI 1 2

O Male DNA studied 0Deceased O Female GSS g3 DNA studied Figtre Alsatianl GSS famlily (ANrDfamlilJy

double missense changes at codons 117 and (p = 1 X i0-7) and Z = 2-023 (recombination 129 like patient IV-28, as well as 10 healthy fraction e = 0, p = 0 023). The confidence inter- members of the family between 11 and 38 val for the recombination fraction 9, approximat- years of age whose condition is not discussed ed by the lod score value Z-1, ranges from 0 to for reasons of confidentiality. The missense 0-28 for p = 107 and from 0 to 0-26 for change at codon 117 was not found in 100 p = 0-023 (table 2). control patients. The missense change at codon 129 was, however, found in the family and the controls. Of the 100 control subjects, 43 had Discussion the double allele methionine, 40 had alleles This family of vinmers and artisans has lived in methionine and valine, and 17 had double Alsace since at least 1795. Patient I-I's direct or allele valine. In the GSS family, the missense allied ascendants are now being studied. No change at codon 1 7 was always associated on conclusion is yet possible. The family disease is the same allele with the methionine to valine transmitted in the autosomal dominant mode. substitution at the codon 129. This methionine There are three sets of clinical signs: dementia to valine substitution was carried heterozy- alone in the first generations and, later, dementia gously by all the members of the family with followed by progressive hemiparesis which then the double one of the 10 became bilateral and was a missense, except accompanied by http://jnnp.bmj.com/ healthy members, who carried it homozygously. pseudobulbar syndrome. In the most recent Genetic analysis-According to these data, the generations, there is dementia, a pseudobulbar population frequency p for the missense change syndrome, and the appearance of more complex at codon 117 was estimated as having a 95% neurological signs associating a cerebellar syn- confidence interval between 0 to 0-015. The 99% drome, an extrapyramidal syndrome (fixed faces, confidence interval for p extends from 0 to 0-023. severely stooped posture, and hypertonia), motor As GSS is extremely rare (estimated one to 10 neuron signs with fasciculations and amyotrophy,

cases per 107) population frequency of q = 1 per spontaneous or provoked myoclonia, and gener- on October 3, 2021 by guest. Protected copyright. 107 was assumed for the GSS gene. The log alised tonic-clonic seizures. The age of onset, likehood ratio (lod score) varied between which at first appeared to be limited to the Z = 2-185 at a recombination fraction of = 0, interval between 30 and 45 years, is in fact much Table 1 Clinical characteristics offamily members with Gerstmann-Strdussler-Scheinker disease Disease devel- Pseudo bul- Family Onset age opment Codon 117 Progressive bar syn- Extra pyramidal Fascicula- Seizures of member (years) (years) Sex mutation Dementia hemiparesis drome Ataxia syndrome tions myoclonus I 1 44 3 M NA + II 2 43 3 F NA + II 4 40 3 M NA + III 7 26 5 M NA + + + + + III 9 43 3 M NA + + + IV 3 35* 2 M NA + + + + + IV 9 35* lit F + + + + + + + IV 28 20* 4 M + + + + + + + + III 3 64 6t F + + + + + + + III 13 47 1 F NA + + IV 25 33 4t M + + + + + + III I1 56 it F + + + NA: information not available. *From biopsy specimen. tPatient still living. Gerstmann-Striaussler-Scheinker disease in an Alsatian family: clinical and genetic studies 187

Table 2 Lod scores for several values ofp, the valine substitution frequency these clinical data. It is also too soon to know

whether the codons 117 and 129 variants in this J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.55.3.185 on 1 March 1992. Downloaded from P =o0 9=001e =005 e =01 =02 8=0-3 family or the codon 102 variant in other families 0-023 2-023 2-018 1-962 1-835 1-464 0-980 are a predisposing factor or the factor responsible 0-015 2-076 2-071 2-015 1-888 1-514 1-022 10-4 2-184 2-180 2-126 1-998 1-617 1-112 for the disease.'9 20 10 ' 2-185 2-181 2-127 1999 1-618 1-112 Continued clinical observation may give the e recombination fraction. answer. Follow up of the families with GSS patients, and above all of the now healthy carriers wider: 20 years at the youngest, 64 at the oldest. of a mutation of the prion gene, should suggest The duration of disease, three to five years in the the potential role of the prion in the induction of first cases, may vary from one year to at least 10 the disorder. If all the healthy carriers develop years in the case of one patient still alive. No GSS the mutation may be considered to be correlations could be established between onset sufficient for disease development; if not, it must age, sex, symptomatology, and generation. In be interpreted as necessary but not sufficient. several cases the disease started in the children before their parents (patients IV-28 and IV-25 before r-I 1 and patient IV-9 before IEI-3) and, among sisters and brothers, the older after the 1 Warter JM, Steinmetz G, Heldt N, et al. Demence pre-senile faniliale. Syndrome de Gerstmann-Straussler-Scheinker. younger. The histopathological lesions examined Rev Neurol (Paris) 1982;138:107-21. in three patients, on the other hand, are similar.' 2 Gerstmann J, Striussler E, Scheinker I. Uber eine eige- nartige hereditar-familiire Erkrankung des Zentralnerven- The AND family's clinical features lie between zystems Zugleich ein Bertrag zur Frage des vorzeingen the ataxic form58 1' and the dementing form of lokalen Alterns. Z Ges Neurol PIyhiat 1936;154:748-62. 3 Masters CL, Gaidusek DC, Gibbs CJ. Creutzfeldt-Jakob GSS.'2 Experimental of the disease disease virus isolations from the Gerstmann-Straussler- from patient IV-28 to mice was negative, as Scheinker syndrome.With an analysis of the various forms of amyloid plaque deposition in the virus-induced spongiform reported previously.5 The negative transmissions . Brain 1981;104:559-88. from this patient and other GSS patients contrast 4 Brown P, Coker-Vann M, Pomeroy K, a al. Diagnosis of Creutzfeldt-Jakob disease by Western blot identification of with the almost 100% positivity from sporadic marker protein in brain tissue. N EnglJ Med 1986; Creutzfeldt-Jakob disease patients.5 The low 314:547-51. 5 Tateishi J, Kitamoto T, Doh-ura K, et al. Inmunochemical, infectivity also contrasts with the high penetrance molecular genetic, and tansmiission studies on a case of of the disease in GSS families such as this one. Gerstmann-Straussler-Scheinker syndrome. Neurology 1990; 40:1578-81. The analysis of the PrP gene has shown a 6 Collinge J, Owen F, Lofthouse R, et al. Diagnosis of GCA-to-GTG mutation at codon 117. This Gerstmann-Straussler syndrome in familial dementia with prion protein gene analysis. Lancet 1989;2:15-7. missense mutation seems to be specific to this 7 Hsiao K, Baker HF, CrowTJ, et al. Linkage of a prion protein family; it has never been described in any other missnse vanant to Gerstmann-Straussler syndrome. Natu 1989;338:342-5. GSS family or any control subject. The loss ofthe 8 Doh-ura K, Tateishi J, Sasaki H, Kitamoto T, SakakiY Pro-> Pvul restriction site, probably by a silent GCA- Leu change at position 102 of prion protein is the most common but not the sole mutation related to Gersunann- to-GCG transition at the third base of codon 117 Striussler syndrome. Biochem Biopks Res Comm 1989; apparently represents a normal polymorphism of 163:974-9. 9 Goldgaber D, Goldfarb LG, Brown P, et al. Mutations in the gene which is found in 10% of white Familial Creutzfeldt-Jakob Disease and Gerstmann-Strauss- people.'3 The missense mutation at codon 117 ler-Scheins Syndrome. Exp Neurol 1989;106:204-6. 10 Lathrop GM, Lalouel JM. Efficient computations in multilocus reported here is presumably due to a C-to-T liikage analsis. Am J Human Genet 1988;42:498-505. transition at the CpG dinucleotide mutation hot 11 Rosenthal NP, Keesey J, Crandall B, Brown WJ. Familial neurological disease associated with spongiform encephalop- spot"4 of this GCG sequence at codon 117. The athy. Arch Neurol 1976;33:252-9. http://jnnp.bmj.com/ missense change at codon 129 was carried not 12 Nochlin D, Sumi SM, Bird TD, a al. Familial dementia with PrP-positive amyloid plaques: a variant of Gerstmann- only by the patients but also by over half (57) of Straussler syndrome. Neuroky 1989;39:910-8. controls, suggesting that it might be a normal 13 Wu Y, Brown WT, Robakis NK, et at. A Pvull RFLP detected in the human prion protein (PrP) gene. Nud Acids Res polymorphism of the gene. We have to take into 1987;15:3191. account, however, that the missense change at 14 Barker D, Schafer M, White R Restriction sites containing CpG show a higher frequency of polymorphism in human codon 117 was always combined with the change DNA. Cel 1984;36:131-8. at codon 129 in this family. The lod score 15 Carlson GA, Kingsbury DT, Goodman PA, et al. Linkage of prion protein and scrapie incubation time genes. Cell suggests a correlation between the valine change 1986;46:503-1 1. on October 3, 2021 by guest. Protected copyright. at codon 117 and the GSS disease gene in this 16 Westaway D, Goodman PA, Mirenda CA, McKinley MP, Carlson GA, Prusiner SB. Distinct prion proteins in short family. The value of 2-185 is certainly below the and long scrapie incubation period mice. Cel threshold of the Z = 3 value generally admitted 1987;51:651-62. 17 Lowenstein DH, Butler DA, Westaway D, McKinley MP, as significant, but in this extremely rare disease, DeArmond SJ, Prusier SB. Three hamster species with there can be difficulties about estimating the different scrapie incubation times and neuropathological features encode distinct prion proteins. Mol Cd Biol frequency of the PrP variant in the population. 1990;10: 1 153-63. The role ofthe PrP variant is unclear. In AND 18 Baker HF, Pbulter M, Crow TJ, Frith CD, Lopihouse R, Ridley RM. Aminoacid polymorphism in human prion family, it apparently influences neither the dura- protein and age at death in inhented prion disease. Lancet tion of incubation nor the progression of the 1991;337: 1286. 19 Prusiner SB. and neurodegenerative disease. N Engi Y disorder, unlike certain polymorphisms in animal Med 1987;317:1571-81. pathology.'17 Contrary to the suggestions of 20 Hsiao KK, Scott M, Foster D, Groth DF, DeArmond SJ, Prusiner SB. Spontaneous neurodegeneration in transgenic Baker et al 8 amino-acid polymorphism at codon mice with mutant prion protein. Scince 1990;250: 129 in the normal allele seems not to influence 1587-90.