Disease clustering: the example of ALS, PD, dementia and hereditary ataxias in Italy
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Disease clustering: the example of ALS, PD,
dementia and hereditary ataxias in Italy
Andrea Malaspina*,** cupational hazards) in public health management (1,2).
Dario Alimonti* Geographical epidemiology has become a distinct
Tino Emanuele Poloni*** branch of epidemiology, with increasing attention being
Mauro Ceroni*,*** devoted to describing the health status of small, geo-
graphically-circumscribed populations (3).
*Laboratory of Experimental Neurobiology, IRCCS C. In medical terms, a cluster is a “mini-epidemic” distribu-
Mondino Institute of Neurology, University of Pavia, Italy, tion of a pathological condition within a well-defined re-
**Division of Neuroscience and Psychological Medicine, gion, where it accounts for a higher-than-expected dis-
Imperial College School of Medicine, University of London, ease prevalence (i.e., above the estimated national
UK, prevalence). When, in some families, more “disease
***Department of Neurology, “Policlinico di Monza” cases” occur than would be expected on the basis of
Hospital, Monza, Italy the occurrence rate in the general population, we also
talk of familial clustering. The identification of a cluster
Reprint requests to: Prof. Mauro Ceroni, depends on the precise evaluation of several factors,
including the expected prevalence of the disease in the
IRCCS C. Mondino Institute of Neurology
given area and the geographical distribution of the pa-
Via Palestro 3, 27100 Pavia, Italy
tients under investigation. However, it can be argued
E-mail: mceroni@unipv.it
that an “aggregation” of patients may also occur by
chance or as a consequence of a statistical bias in the
process of patient selection (2).
Accepted for publication: November 14, 2002
A genetic mutation with a recessive or dominant pattern
of inheritance is often responsible for the appearance of
a disease cluster, within a family or a geographical
Summary area. Exposure to environmental factors is another im-
portant cause of disease clustering. As postulated in
The “mini-epidemic” distribution of rare conditions (ei- Parkinson’s disease (PD), when the disease is not
ther sporadic, inherited or due to a transmissible agent) clearly related to a single gene mutation (4), the com-
is frequently described as a cluster. Genetic abnormali- bined action of several genes together with exposure to
ties and environmental factors are usually investigated environmental factors may be important pathogenically.
to explain the presence of a disease cluster. We have re- In a situation where there is genetic predisposition to
ported a cluster of amyotrophic lateral sclerosis (ALS) the disease and exposure to environmental precipitat-
cases in a small area of central Italy, where an identical ing factors (for members of some families but not for
SOD1 gene mutation was found both in familial ALS members of other families), a monogenic inheritance
(FALS) cases and in one apparently sporadic ALS indi- may be mimicked (5).
viduals. Along with this cluster of ALS patients, we re- The importance of identifying disease clusters is in-
view important clusters of neurological disorders in Italy creasingly debated. Systematic surveillance systems
and discuss the importance of an accurate estimation of have been developed to identify foci of increased dis-
their regional/local prevalence. This approach is likely to ease occurrence (together with possible risk factors),
facilitate molecular investigations, the search for envi- but despite this, their reliability remains a matter of dis-
ronmental agents and the analysis of gene-environment cussion (6).
interaction in disease presentation and development.
Social and cultural background can also play a part in
The organisation of national registers that record, in par-
the uneven distribution of several medical conditions (2).
ticular, the geographical distribution of neurological dis-
In addition to the aetiological factors, such as genetic
orders, might represent a good research strategy.
abnormalities and/or environmental factors, socio-cultur-
KEY WORDS: Cluster, environmental factors, Italy, mutations, neuro - al habits and traditions appear to contribute to regional
logical disorders. differences in general health status and in the develop-
ment of several pathological disorders. A strong associ-
ation between a population’s health status and social
and economic characteristics has been shown by many
methodological approaches, such as the “deprivation in-
Introduction dices” developed in the United Kingdom (7). A signifi-
cant association between antibodies against CMV and
Epidemiological studies constitute a powerful tool for specific socio-demographic/geographical factors has al-
the identification of clues to disease aetiology and for so been found. The prevalence of these antibodies was
the evaluation of risk factors (e.g., environmental or oc- significantly higher in females and in subjects residing in
Functional Neurology 2002; 17(4): 177-182 177A. Malaspina et al.
the South of Italy (8). CMV infection may be a critical same environmental agent. A total of nine cases of con-
determinant for the appearance of neurological disor- jugal ALS have been previously described (12), two of
ders, particularly in immune-compromised patients. these from Italy (southern Italy and Sardinia). All these
To emphasise the importance of identifying regionally- couples, including our family, originated from small, in-
confined clusters of patients suffering from a neurologi- bred rural communities.
cal condition, we describe our experience with a cluster The presence of a significant number of individuals shar-
of patients suffering from ALS. We have studied both ing the same rare molecular abnormality in a small isolat-
the genetic and the environmental factors that may ed population may suggest a common founder for the
have played a role in the high occurrence of ALS in the SOD1 gene mutation and a high level of inbreeding with-
area studied (9). The major clusters of neurological dis- in the population in the area. The presence of ALS cases
orders in Italy are also reviewed, paying particular at- bearing a SOD1 gene mutation increased the total num-
tention to analysis of genetic mutations, environmental ber of affected individuals in the area, and ultimately, the
hazards and gene-environment interaction. We discuss local disease prevalence to 7.8/100,000. The prevalence
the importance of studying the geographical distribution of sporadic ALS in the area was 4.8/100,000, which is
of patients affected by a specific neurological disorder within national estimated range. In this small population
and the possible use of disease registers that would al- the SOD1 gene mutation spreads vertically through ap-
low collection of and easy access to all the information parently distant lineages and distinct family pedigrees.
regarding a patient population. Environmental factors were also investigated in search of
other elements explaining the “apparently” high occur-
rence of ALS cases in this area. A putative external
Amyotrophic lateral sclerosis agent was unlikely to explain the appearance of the dis-
ease in subsequent generations (transmitted in an auto-
A 41-year-old man presenting with rapidly progressive somal dominant fashion). Therefore, if an exogenous
weakness of the lower limbs was admitted to our clinic. agent had been responsible for the occurrence of the
The patient had a family history of ALS, and detailed in - disease throughout the generations, a “subtle” element,
vestigation of the pedigree led to the identification of a perhaps linked to a well-established local practice, could
large kindred with an autosomal dominant inheritance be postulated. We discovered that shoe manufacturing
for ALS (FALS). The proband’s mother died of ALS at spread rapidly within a well-defined period in the area
36 after 4 years of illness and his grandfather died at 55 and that many individuals, including our FALS cases,
after a 12-year disease course. In this particular family, were employed in this activity (whereas in the past, agri-
we identified a total of 13 cases spanning back 6 gener- culture had been the most important form of occupation
ations to the beginning of the 19th century. Data were for the area’s population). Nevertheless, no evidence of
collected from interviews with family members, medical increased exposure to toxicants in these individuals or in
records, and church/civic records of births and deaths. the general population of the area emerged. Further-
With the cooperation of local general practitioners (GPs), more, analysis of local aqueduct water did not reveal
we also analysed the distribution of other ALS cases in high concentrations of manganese or magnesium, as re-
the area where the proband was identified: an area of ported in the previous investigations on environmental
approximately 400 km2 located in the north of the central hazards in ALS (13,14). Finally, we were unable to find
Italian province of Ascoli Piceno, including the valleys environmental factors that could explain the trend of gen-
around Fermo (the area). A total of 12 different ALS cas- erational anticipation that was present in these families.
es (2 familial and 10 sporadic) were identified in a popu- Few other studies of the regional distribution of the dis-
lation numbering 166,451 people (1997). The prevalence ease are available in the literature. As for other neuro-
of the disease according to our findings was 7.8/100,000, logical disorders, Sardinia has been a focus of epidemi-
higher than the national frequency (which ranges be- ological studies because it is isolated from foreign influ-
tween 1.56 (10) and 5.4 (11) per 100,000). ence and has communities, throughout the island, that
The SOD1 gene molecular analysis of the FALS cases have maintained close kinship ties. Giagheddu et al.
(including our proband) yielded a missense point muta- (15) analysed the occurrence of ALS cases in various
tion causing the substitution of Leucine with Phenylala- areas of the island, and noted a significantly heteroge-
nine in exon 4 (L84F). We extended the molecular in- neous distribution of the disease.
vestigation to the sporadic ALS cases and to those Maurelli et al. (16) reported 3 families in the province of
members of the pedigrees at risk of inheriting the dis- Pavia, an area in northern Italy. Reconstruction of the
ease. The L84F SOD1 gene mutation was also detect- pedigree was difficult and the SOD1 gene analysis was
ed in a 60-year-old sporadic ALS patient with unknown not carried out. Prior to our study, only one family har-
father and with clinical features that overlapped those bouring a SOD1 gene mutation had been reported in
of the FALS cases. Furthermore, the L84F mutation Italy (17), while more recently, six other mutations have
was also found in a 65-year-old unaffected woman be- been identified in seven ALS families (18). The authors
longing to the proband’s family. do not comment on the pattern of territorial distribution
One of the two new FALS patients was linked to the of these families.
family lineage of our proband. In this pedigree a case of
conjugal ALS was present in a previous generation, but
no subject homozygous for the L84F mutation was de- Parkinson’s disease (PD)
tected. Due to the low population prevalence of ALS,
this event may suggest that the disease had been in- Unlike ALS, Parkinson’s disease (PD) shows a much
herited by two apparently unrelated individuals in a higher prevalence, varying in Italy from 74 to 257 cases
small community or that they had been exposed to the per 100,000 members of the population (19). The crude
178 Functional Neurology 2002; 17(4): 177-182Disease clustering: ALS, PD, dementia and hereditary ataxias in Italy
prevalence of idiopathic PD in Italy varies considerably, some 14 (31). These pedigrees also contained cases of
depending on the method of study utilised (20-22). An early-onset FAD and were finally merged into two larger
important “aggregation” of PD cases was detected in kindreds through an extensive epidemiological and ge-
Sicily, where a door-to-door method of investigation nealogical reconstruction.The molecular analysis identi-
was adopted (23). fied a Met 146 Leu missense mutation in the presenilin
Despite the presence in the southern Italian Campania 1 (PS-1) gene.
and Molise regions (including the Salerno province) of Migration from southern Italy to other Italian regions or
an overall prevalence that is comparable to that of other abroad explains the molecular findings of other families
western populations, a large kindred of autosomal dom- with early-onset FAD harbouring the same genetic mu-
inant PD was found in a small village in the Salerno tations. A large South American pedigree from Argenti-
province (24). The procedures for identification and na with early-onset FAD was recently found to bear the
characterisation of the families living in this area were presenilin 1 gene mutation (32), but no clear genealogi-
similar to those used in our study on the ALS familial cal link with the above Calabrian families could be iden-
cluster. Initially, two large kindreds were found in the tified. In Turin (northern Italy), a pedigree with autoso-
village of Contursi (Salerno province) where the rate of mal dominant early-onset FAD was found to contain
occurrence of the illness was significantly high. The dis- 1,950 members, spanning eight generations with at
ease in the two kindreds showed a phenotypic homo- least thirty living affected individuals (33). The ances-
geneity. Further investigation revealed a common origin tors of the proband were from Calabria (southern Italy)
of the two families and an autosomal dominant pattern from where they had emigrated to the northern part of
of inheritance of the disease. Molecular studies con- Italy, France and United States. The “Turin family”
firmed the presence of a mutation in exon 4 in the α- shows several genealogical and clinical similarities with
synuclein gene with Ala to Thr substitution at position other large FAD pedigrees originating from Calabria.
53 (25,26). As in our experience with the ALS cluster, An association of apolipoprotein E (ApoE) epsilon 4 al-
molecular investigations confirmed a genetic mutation lele (chromosome 19) with late-onset familial and spo-
to be responsible for the significant increase in the radic AD was also sought in a number of Italian pa-
number of PD cases in the above PD familial cluster. tients, but a geographical clustering of AD cases and of
Prior to the publication of these results, De Michele et this allele was not identified (34).
al. analysed PD-related environmental and genetic risk Several foci of high incidence of Creutzfeldt-Jacob dis-
factors in these regions of southern Italy. Family history ease (CJD) have been reported in France, Chile, Slova-
was found to be the major risk factor for the disease, kia, Israel and among Libyan Jews (3,35,36). All of
with 33% of the patients having had at least one affect- these resulted from high incidence of familial CJD in a
ed relative (27). No environmental risk factor has been restricted area. In Italy, a large familial cluster of CJD
reported to act on the genetic background described in was found in the Calabria region, where, as mentioned
the Contursi families. The search for an external toxic above, the prevalence of dementia-related disorders
agent in PD has focused in the past on the study of (including the prevalence of early-onset FAD) linked to
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), different genetic mutations, has been found to be signif-
which shows a selective toxicity for the neurones of the icantly high. The CJD cluster in this region was later
substantia nigra (28). However, no PD clusters caused found to bear the E200K Prp gene mutation (37,38).
by MPTP-related environmental toxins have, to date,
been described (29). Several studies have also
analysed susceptibility markers within important meta- Autosomal dominant spinocerebellar ataxias
bolic pathways, to identify genetic polymorphisms (ADCAs)
which might aggregate with the disease. Of these, the
“pharmacogenetic” marker P4502D6 debrisoquine 4- Autosomal dominant spinocerebellar ataxia type 1
hydroxylase (a cytochrome P450-dependent enzyme (ADCA1), the most common form of dominant ataxia,
which metabolises over 25 drugs) can be present in the is another inherited neurological condition described
“extensive” and “poor” metaboliser aplotype conforma- mainly in the southern part of Italy, particularly in Sicily
tions. No clear association between PD and any of (39). Genetic heterogeneity is a specific hallmark of
these allelic variants has been found (4). this condition where different loci have been found to
bear a pathological expansion of a trinucleotide repeat.
Molecular analysis in 51 families from these regions
Dementia harbouring this disorder identified an SCA2 expansion
in 30 families (39). In particular, molecular studies per-
Alzheimer’s disease (AD) is the most common of the formed in 12 of 15 families with ADCA type I originat-
various forms of dementia. In the last few years, large ing from mid-eastern Sicily identified the SCA2 muta-
Italian pedigrees harbouring different genetic abnormal- tion in 11 of them (91.6%) (40). Despite the lack of a
ities and showing a cluster-like distribution of early-on- clear analysis of the territorial distribution of these fam-
set familial AD (FAD) have been found in the southern ilies in this part of the island, the presence of a sub-
part of the Italian peninsula. Initially, two unrelated fami- stantial number of ADCA1 pedigrees with the same
lies from the Calabria region had been found to carry a molecular abnormality in a small territory would strong-
mutation in exon 17 of the amyloid precursor protein ly support the idea of a clustering distribution, where
gene (APP717) on chromosome 21, which segregates the disease and the mutation have spread through ap-
with an early-onset form of AD (30). The study of other parently unrelated families. Another pedigree with mu-
large pedigrees based in the same area has led to the tations in the SCA2 gene has been reported to have a
identification of another genetic abnormality on chromo- southern Italian ancestry (41).
Functional Neurology 2002; 17(4): 177-182 179A. Malaspina et al.
Concluding remarks Sicily and the southern part of the Italian peninsula show
an undoubtedly high prevalence of various neurological
We have emphasised the importance of an accurate disorders and a cluster-like distribution of some of these
analysis of the territorial distribution of patients afflicted conditions. In Sardinia, for example, diseases like myas-
by neurological disorders. For a number of reasons, in- thenia gravis, multiple sclerosis and insulin-dependent di-
cluding socio-cultural factors, historical traditions and abetes mellitus show frequencies up to 3-5 times higher
the particular regional/geographical conformation of the than those found in the rest of Italy (49). The social con-
country, the Italian peninsula emerges as an extraordi- text in these areas, characterised by large family groups
nary pool of inherited disorders. In certain regions of and people traditionally not inclined to emigrate, may
southern Italy, the rural populations are geographically have favoured the spread of gene aplotypes involved in
isolated, which explains the significantly increased the disease presentation and development. As we have
presence of several genetic disorders, most of them pointed out, subsequent migration from these areas with
neurological. These diseases can appear in familial high rates of inherited disorders has, as reported above
clusters and in some cases, a genetic abnormality has for AD and PD, resulted in the appearance of the same
been found to cause the illness. hereditary diseases (and possibly of associated genetic
Epidemiological searches in confined regions, where mutations) in other recipient regions and countries.
patients with a family history of a neurological disorder The relationship between genetic determinants and envi-
can be identified, appear to be of primary importance. ronmental factors is currently the focus of study through
The validity of this approach is confirmed by our experi- the project “Colombo 2000”, an analysis of the phenome-
ence with an ALS cluster in central Italy. In our study non of massive migration from Italy to Argentina. The pro-
we identified a concentration of familial and sporadic ject represents a “natural experiment” into gene-environ-
ALS patients confined within a restricted area, i.e., a ment interactions in disease pathogenesis. Data on inci-
cluster of the disease. Subsequent studies discovered dence, prevalence and mortality rates in the original and
an underlying genetic defect (a SOD1 gene mutation) in the migrant population (exposed to different environ-
causing the spread of the pathological condition within mental factors) may be compared to elucidate risk fac-
“apparently” non-related pedigrees (9). In a previous tors, as well as protective influences, for different neuro-
molecular investigation of several individuals suffering logical disorders. Preliminary data from this study have
from sporadic and familial ALS and originating from dif- shown differences in mortality rates for brain tumours,
ferent Italian regions, we failed to identify SOD1 gene Parkinson’s disease, Alzheimer’s disease, motor neuron
mutations (42). These findings support the idea that the diseases, stroke and alcohol-related diseases, between
evaluation of patients within well-characterised clusters Italy and Argentina (50,51).
may represent a priority in the quest to find either In conclusion, we suggest that the observations out-
known molecular defects or new aetiological clues. lined above underline the importance of careful analysis
Clusters of patients suffering from a specific neurological of the “territorial distribution” of patients afflicted by vari-
disorder may differ as regards the clinical features of the ous neurological disorders. The implementation of re-
illness and the severity of its evolution. In the reported gional and national disease registers, which report the
ALS pedigrees and in the clusters of familial CJD, indi- origins of cases, would greatly favour such investiga-
viduals carrying the same genetic mutation show ex- tions and represent a crucial step towards the elucida-
treme variability in age at onset and disease duration tion of the role of genetic mutations, environmental fac-
(3,9,26,35,43,44). A comparative study of these clusters tors and/or gene-environment interaction in the patho-
may provide further insight into genetic and/or environ- genesis of specific neurological disorders.
mental factors influencing the disease phenotype. The
geographical location of a disease cluster can also be
highly informative with regard to the role of toxic agents Acknowledgments
in the disease aetiology. To date, no significant relation-
ship between a specific neurological disorder and a well- We are grateful to the patients and their families who
defined neurotoxic element has been identified, with the kindly agreed to participate in the study. We wish to ac-
exception of some toxic polyneuropathies (45). An in- knowledge Prof. de Belleroche (Department of Neuro-
creased concentration of different elements, including muscular Diseases, Division of Neuroscience and Psy-
metals in certain areas of the CNS of patients affected by chological Medicine, ICSM), the UK Motor Neuron Dis-
different neurological disorders, has been suspected ease Association, the financial support of the “C.
(46,47). Studies of the basal ganglia, which included Mondino Institute of Neurology” Foundation (Pavia),
measurement of the levels of iron, potassium, silica, AISLA (the Italian Amyotrophic Lateral Sclerosis Asso-
sodium, sulphur, zinc and aluminium, as well as assess- ciation), the Hayward Foundation, Smith’s Charities and
ment of exposure to other environmental agents (particu- Charing Cross Hospital Trustees. Dr A. Malaspina is
larly pesticides, industrial solvents and MPTP), did not grateful for the support of the Riquier family, from whom
reveal any pathological accumulation (48). he received an award.
Single gene abnormalities or environmental factors may
cover the entire range of possible aetiologies of a neuro-
logical disorder. However, a complex interplay between References
various genes and environmental xenobiotics is likely to
explain, at least in some cases, both the heterogeneous 11. Wall S. Epidemiology for prevention. Int J Epidemiol
distribution of a neurological disorder and the occurrence 1995;24:655-664
of areas (i.e., clusters) with a higher-than-expected 12. Cobb N. Investigating cancer clusters. International Jour-
prevalence of the disorder. The islands of Sardinia and nal of Circumpolar Health 1998;571:27-30
180 Functional Neurology 2002; 17(4): 177-182Disease clustering: ALS, PD, dementia and hereditary ataxias in Italy
13. Goldfarb LG, Brown P, Mitrova E et al. Creutzfeldt-Jacob dis- General Pratictioner Study Group (IGPSG). The preva-
ease associated with the PRNP codon 200Lys mutation: an lence of parkinsonism in Italy: an epidemiological survey of
analysis of 45 families. Eur J Epidemiol 1991;7:477-486 the disease in general practice. Mov Disord 1994;9:403-
14. Landi MT, Ceroni M, Martignoni E, Bertazzi PA, Caporaso NE, 408
Nappi G. Gene-environment interaction in parkinson’s dis- 23. Morgante L, Rocca WA, Di Rosa AE et al. for the Sicilian
ease. CYP2D6 gene polymorphism. Adv Neurol 1996;69:61- Neuro-Epidemiologic Study (SNES) Group. Prevalence of
72 Parkinson’s disease and other types of parkinsonism: a
15. Borch-Johnsen K, Olsen JH, Sorensen TI. Genes and fam- door-to door survey in three Sicilian municipalities. Neurol-
ily environment in familial clustering of cancer. Theor Med ogy 1992;42:1901-1907
1994;15:377-386 24. Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A
16. Marchi M, Bianchi F. Surveillance in public health: the large kindred with autosomal dominant Parkinson’s dis-
methodological problems in identifying risk factors. Epi- ease. Ann Neurol 1990;27:276-282
demiol Prev 1992;14:49-54 25. Polymeropoulos MH, Lavedant C, Leroy E et al. Mutation
17. Carstairs V. Deprivation indices: their interpretation and in the α-synuclein gene identified in families with Parkin-
use in relation to health. J Epidemiol Community Health son’s disease. Science 1997;276:2045-2047
1995;49(Suppl 2):S3-8 26. Golbe LI, Di Iorio G, Sanges G et al. Clinical genetic analy-
18. de Mattia D, Stroffolini T, Arista S et al. Prevalence of cy- sis of Parkinson’s disease in the Contursi kindred. Ann
tomegalovirus infection in Italy. Epidemiol Infect 1991;107: Neurol 1996;40:767-775
421-427 27. De Michele G, Filla A, Volpe G et al. Environmental and
19. Ceroni M, Malaspina A, Poloni TE et al. Clustering of ALS genetic risk factors in Parkinson’s disease: a case-control
cases in central Italy due to the occurrence of the L84F study in southern Italy. Mov Disord 1996;11:17-23
SOD-1 gene mutation. Neurology 1999;53:1064-1071 28. Burns RS, LeWitt PA, Ebert MH, Pakkenberg H, Kopin IJ.
10. Rosati G, Pinna L, Granieri E et al. Studies on epidemio- The clinical syndrome of striatal dopamine deficiency.
logical, clinical and etiological aspects of ALS disease in Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-
Sardinia, southern Italy. Acta Neurol Scand 1997;55:231- tetrahydropyridine (MPTP). N Engl J Med 1985;312:1418-
244 1421
11. Guidetti D, Bondavalli M, Sabadini R et al. Epidemiological 29. Tanner MC, Goldman SM. Epidemiology of Parkinson’s
survey of amyotrophic lateral sclerosis in the province of disease. Neurol Clin 1996;14:317-335
Reggio Emilia, Italy: influence of environmental exposure 30. Sorbi S, Nacmias B, Mortilla M, Forleo P, Piacentini S,
to lead. Neuroepidemiology 1996;15:301-312 Amaducci L. Molecular genetics of Alzheimer’s disease in
12. Rachele MG, Mascia V, Tacconi P, Dessi N, Marrosu F, Italian families. Neurochem Int 1994;25:81-84
Giagheddu M. Conjugal amyotrophic lateral sclerosis: a re- 31. Bruni AC. Cloning of a gene bearing missense mutations
port on a couple from Sardinia, Italy. Ital J Neurol Sci in early onset familial Alzheimer’s disease. Funct Neurol
1998;19:97-100 1998;13:257-261
13. Bergomi M, Guidetti D, Vivoli R, Vinceti M. The occupa- 32. Morelli L, Prat MI, Levy E, Mangone CA, Castano EM. Pre-
tional risk factors for amyotrophic lateral sclerosis in an senilin 1 Met146Leu variant due to an A -> T transversion
Italian community. Ann Ig 1998;10:249-253 in an early-onset familial Alzheimer’s disease pedigree
14. Iwami O, Watanabe T, Moon CS, Nakatsuka H, Ikeda M. from Argentina. Clin Genet 1998;53:469-473
Motor neuron disease on the Kii Peninsula of Japan: ex- 33. Rainero I, Bergamini L, Bruni AC et al. A new Italian pedi-
cess manganese intake from food coupled with low mag- gree with early-onset Alzheimer’s disease. Journal of Geri-
nesium in drinking water as a risk factor. Sci Total Environ atric Psychiatry and Neurology 1994;7:28-32
1994;149:121-135 34. Sorbi S, Nacmias B, Forleo P, Piacentini S, Amaducci L.
15. Giagheddu M, Mascia V, Cannas A et al. Amyotrophic lat- Alzheimer’s disease and apolipoprotein E in Italy. Ann N Y
eral sclerosis in Sardinia, Italy: an epidemiologic study. Ac- Acad Sci 1996;777:260-265
ta Neurol Scand 1993;87:446-454 35. Chapman J, Ben-Israel J, Goldhammer Y, Korczyn AD.
16. Maurelli M, Marchioni E, Bosone D et al. Familial adult The risk of developing Creutzfeldt-Jakob disease in sub-
amyotrophic lateral sclerosis: report of cases. Ital J Neurol jects with the PRNP gene codon 200 point mutation. Neu-
Sci 1992;13:75-79 rology 1994;44:1683-1686
17. Rainero I, Pinessi L, Tsuda T et al. SOD1 missense muta- 36. Chatelain J, Delasnerie-Laupretre N, Lemaire MH, Cathala
tion in an Italian family with ALS. Neurology 1994;44:347- F, Launay JM, Laplanche JL. Cluster of Creutzfeldt-Jakob
349 disease in France associated with the codon 200 mutation
18. Gellera C, Castellotti B, Riggio MC et al. Superoxide dis- (E200K) in the prion protein gene. Eur J Neurol 1998;5:375-
mutase gene mutations in Italian patients with familial and 379
sporadic amyotrophic lateral sclerosis: identification of 37. D’Alessandro M, Petraroli R, Ladogana A, Pocchiari M.
three novel missense mutations. Neuromuscul Disord High incidence of Creutzfeldt-Jakob disease in rural Cal-
2001;11:404-410 abria, Italy. Lancet 1998;352:1989-1990
19. Tanner CM, Hubble JP, Chan P. Epidemiology and genet- 38. Lee HS, Sambuughin N, Cervenakova L et al. Ancestral
ics of Parkinson’s disease. In: Watts RL, Koller WC eds origins and worldwide distribution of the PRNP 200K muta-
Movement Disorders. Neurologic Principles and Practice. tion causing familial Creutzfeldt-Jakob disease. Am J Hum
New York; McGraw Hill 1997:137-152 Genet 1999;64:1063-1070
20. Chiò A, Magnani C, Schiffer D. Prevalence of Parkinson’s 39. Filla A, De Michele G, Santoro L et al. Spinocerebellar
disease in northwestern Italy: comparison of tracer methodol- ataxia type 2 in southern Italy: a clinical and molecular
ogy and clinical ascertainment of cases. Mov Disord study of 30 families. J Neurol 1999;246:467-471
1998;13:400-405 40. Giuffrida S, Saponara R, Trovato Salinaro A et al. Identifi-
21. Rosati G, Granieri E, Pinna L et al. The risk of Parkinson cation of SCA2 mutation in cases of spinocerebellar ataxia
disease in Mediterranean people. Neurology 1980;30:250- with no family history in mid-eastern Sicily. Ital J Neurol Sci
255 1999;20:217-221
22. Beghi E, Monticelli ML, Sessa A, Simone P, and the Italian 41. Adams C, Starkman S, Pulst SM. Clinical and molecular
Functional Neurology 2002; 17(4): 177-182 181A. Malaspina et al.
analysis of a pedigree of southern Italian ancestry with spin- ing extended X-ray absorption fine structure and cryo-elec-
ocerebellar ataxia type 2. Neurology 1997;49:1163-1166 tron microscopy. Brain 1999;122:667-673
42. Malaspina A, Zaman R, Mazzini L et al. Heterogeneous 47. Hirsch EC, Brandel JP, Galle P, Javoy-Agid F, Agid Y. Iron
distribution of amyotrophic lateral sclerosis patients with and aluminum increase in the substantia nigra of patients
SOD-1 gene mutations: preliminary data on an Italian sur- with Parkinson’s disease: an X-ray microanalysis. J Neu-
vey. J Neurol Sci 1999;162:201-204 rochem 1991;56:446-451
43. Cudkowicz ME, McKenna-Yasek D, Sapp PE et al. Epi- 48. Checkoway H, Nelson LM. Epidemiologic approaches to
demiology of mutations in superoxide dismutase in amy- the study of Parkinson’s disease etiology. Epidemiology
otrophic lateral sclerosis. Ann Neurol 1997;41:210-221 1999;10:327-336
44. Alimonti D, Malaspina A, Poloni TE, Ceroni M. Genotype- 49. Aiello I, Pastorino M, Sotgiu S et al. Epidemiology of myas-
phenotype correlation in familial amyotrophic lateral sclero- thenia gravis in northwestern Sardinia. Neuroepidemiology
sis with SOD1 mutation. Funct Neurol 2000;15:177-191 1997;16:199-206
45. Rizzuto N, Terzian H, Galiazzo-Rizzuto S. Toxic polyneu- 50. Musicco M, Sant S, Pettenati C. Mortality studies in the clari-
ropathies in Italy due to leather cement poisoning in shoe fication of gene-environment interactions. Funct Neurol
industries. A light- and electron-microscopic study. J Neu- 1998;13:253-256
rol Sci 1977;31:343-354 51. Roman GC. Gene-environment interactions in the Italy-Ar-
46. Griffiths PD, Dobson BR, Jones GR, Clarke DT. Iron in the gentina “Colombo 2000” project. Funct Neurol 1998;13:249-
basal ganglia in Parkinson’s disease. An in vitro study us- 252
182 Functional Neurology 2002; 17(4): 177-182You can also read
