Amyotrophic lateral sclerosis-parkinsonsim/dementia complex of Guam is a neurodengenerative disorder with unusually high incidence among the Chamorro people of Guam. Both ALS and parkinsonism-dementia are chronic, progressive, and uniformly fatal disorders in this population. Both diseases are known ... Amyotrophic lateral sclerosis-parkinsonsim/dementia complex of Guam is a neurodengenerative disorder with unusually high incidence among the Chamorro people of Guam. Both ALS and parkinsonism-dementia are chronic, progressive, and uniformly fatal disorders in this population. Both diseases are known to occur in the same kindred, the same sibship, and even the same individual.
Plato et al. (1969) found about the same level of inbreeding in affected sibships as in unaffected sibships and interpreted this as an argument against recessive inheritance. Their finding that affected sibships were more closely related to each ... Plato et al. (1969) found about the same level of inbreeding in affected sibships as in unaffected sibships and interpreted this as an argument against recessive inheritance. Their finding that affected sibships were more closely related to each other than to the 'general population' suggested dominant transmission, although a communicable factor could not be excluded. Segregation analysis adjusted for age was consistent with the conclusion that the disorder on Guam is autosomal dominant with complete penetrance in males but only about 50% penetrance in females. On the whole, the evidence for a mendelian basis is minimal. In records from 1944 through 1985, Zhang et al. (1990) found documented clinical descriptions of this disorder in 363 Chamorros and 3 Filipino immigrants who had lived on Guam before onset of the disorder. After 1980, new cases occurred only among persons over 50 years of age, whereas a younger age of onset had been noted previously. The critical age of exposure to the unknown factor in the environment on Guam appeared to have been adolescence or early adulthood. Bailey-Wilson et al. (1993) concluded that purely environmental, mendelian dominant, and mendelian recessive hypotheses of causation could be rejected; however, a 2-allele additive major locus hypothesis could not be rejected. Stone (1993) reviewed the progressive disappearance of Guam disease. Majoor-Krakauer et al. (1994) investigated the hypothesis that there may be shared genetic susceptibility between classic amyotrophic lateral sclerosis with Parkinson disease and dementia in non-Guamanian individuals. They compared the family histories of 151 newly diagnosed ALS patients (7 of whom were familial) with 140 controls to examine the cumulative incidence of ALS, Parkinson disease, and dementia in parents, sibs, and grandparents. The risk for dementia was significantly higher in relatives of ALS patients than in those of controls and was similar for relatives of probands with sporadic or familial ALS. The risk of Parkinson disease was higher in relatives of patients with familial ALS than in patients with sporadic ALS, but these differences were not considered statistically significant. Their findings suggested that ALS, dementia, and Parkinson disease occur within families more often than expected by chance, suggesting that there may be a shared genetic susceptibility to these disorders.
Hermosura et al. (2005) reported a heterozygous mutation in the TRPM7 gene (T1482I; 605692.0001; dbSNP rs8042919) in 5 of 22 patients with ALS-Parkinsonism/dementia complex of Guam. The variant was not identified in ... - ALS-PDC of Guam Hermosura et al. (2005) reported a heterozygous mutation in the TRPM7 gene (T1482I; 605692.0001; dbSNP rs8042919) in 5 of 22 patients with ALS-Parkinsonism/dementia complex of Guam. The variant was not identified in 23 control Chamorro individuals. In vitro functional expression studies showed that mutant channels were functional but showed increased susceptibility to inhibition by intracellular magnesium concentrations compared to wildtype channels. Noting that the neurodegenerative disorders on Guam had been related to an environment deficient in calcium and magnesium, Hermosura et al. (2005) suggested that the T1482I variant in the TRPM7 gene may confer susceptibility to disease development. - ALS-PDC of the Kii Peninsula of Japan A high prevalence of ALS on the Kii peninsula of Japan had been described in the 1960s (Kimura et al., 1961). Neuropathologically, the cases resembled the ALS cases of Guam. Also similar to Guam, cases of ALS and PDC have been reported in the same Kii families. Kikugawa et al. (1997) performed mutation analyses of the SOD1 gene (147450) in 23 patients (3 familial and 20 sporadic) with ALS from the Kii Peninsula of Japan and its vicinity. In 2 of the 23 patients, they identified heterozygosity for a mutation in the SOD1 gene (I113T; 147450.0011). The I113T mutation had been identified in some familial as well as sporadic cases of ALS as a mutation with low penetrance. The mutation had been reported to be associated with the formation of neurofibrillary tangles and such was a characteristic feature of ALS in the Kii Peninsula. Kuzuhara et al. (2001) reported a family from the Kii peninsula in which the proband, a woman, had parkinsonism and dementia, and her brother had ALS. At the age of 63, the proband developed a progressive dopa-unresponsive parkinsonism characterized by akinesia, rigidity, and loss of balance, as well as dementia. Five years later, she was mute and had contractures, dystonia, and myoclonus. Her younger brother developed rapidly progressive bulbar ALS and died at age 49 years. Postmortem examination of both patients revealed a similar neuropathology: frontal and temporal lobe atrophy, many tau-immunoreactive neurofibrillary tangles throughout the brain, and loss of pigmented nuclei in the substantia nigra. The corticospinal tracts showed atrophy and pallor, and spinal anterior horn cells were depleted. Analysis of insoluble tau protein showed 3 major bands of 60, 64, and 68 kD. Analysis of the tau and SOD1 genes did not reveal any mutations. Kuzuhara et al. (2001) concluded that the ALS and PDC of this family may be phenotypic variants of a tauopathy caused by genetic abnormalities. Hara et al. (2010) did not find an association between the TRPM7 T1482I variant (605692.0001) and disease in affected members from a large extended family with ALS-PDC from the Kii peninsula. The frequency of the T1482I variant was similar to that observed in controls.
In a population-based survey of 1,984 Chamorro residents of Guam older than age 65, Galasko et al. (2007) found a 12.2% point prevalence of all forms of dementia. Subtypes included Guam dementia (8.8%), which is clinically equal to ... In a population-based survey of 1,984 Chamorro residents of Guam older than age 65, Galasko et al. (2007) found a 12.2% point prevalence of all forms of dementia. Subtypes included Guam dementia (8.8%), which is clinically equal to Alzheimer disease, parkinsonism-dementia complex (1.5%), pure vascular dementia (1.3%), and other (0.6%). The prevalence of dementia rose exponentially with age and was associated with low education, but not with the APOE (107741) E4 allele.