Amyotrophic Lateral Sclerosis-Parkinsonism/dementia Complex 1

A number sign (#) is used with this entry because of evidence that mutation in the TRPM7 gene (605692), encoding a member of the transient receptor potential cation channel family, influences susceptibility to the disorder.

See also PARK7 (606324) for discussion of a similar phenotype, which has been shown to be caused by a double homozygous mutation in the DJ1 gene (602533.0006) in 1 family.

Description

Amyotrophic lateral sclerosis-parkinsonism/dementia complex of Guam is a neurodegenerative 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.

Inheritance

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.

Pathogenesis

Garruto et al. (1983) and Blake et al. (1983) found no marker system associated with this disorder, and concluded that 'local environmental factors are most likely involved in pathogenesis.' The authors appear to view ALS and parkinsonism-dementia as separate disorders even though they occur in the same family, the same sibship, and the same individual.

Garruto et al. (1985) reported a striking decline in the incidence rates of ALS and PD among the Chamorros of Guam so that the rates became only slightly higher than those in the continental United States. They suggested that the change was consistent with the pathogenetic sequence of low calcium and magnesium intake in water and vegetables, secondary hyperparathyroidism, increased intestinal absorption of toxic metals, and the deposition of calcium and other metals in the central nervous system (CNS). ALS and PD have disappeared with the change in dietary habits and loss of exclusive dependence on locally grown food. Guiroy et al. (1987) found that the amyloid (104760) of neurofibrillary tangles of Guamanian parkinsonism-dementia has an identical amino acid sequence to that of Alzheimer disease (104300) and Down syndrome (190685).

Gajdusek (1986) presented evidence that the deposition of calcium aluminum silicon in neurons leads to paired helical filaments identical to those in patients with Down syndrome or Alzheimer disease. The high incidence of ALS-PDC in Guam and other locations disappears when isolation is disrupted and travel and economic changes lead to food and water sources from the outside.

Spencer et al. (1987) investigated the role of the neurotoxic plant Cycas circinalis, a traditional source of food and medicine that has been used less by the Chamorro people since the Americanization that occurred after World War II. Macaques fed a constituent of Cycas developed clinical and histopathologic changes similar to those of Guam ALS-parkinsonism-dementia. Duncan and Marini (2006) disputed the hypothesis that the disorder is caused by eating fruit bats containing toxic beta-methylamino-L-alanine (BMAA) from ingestion of cycad seeds, stating flawed data collection and analysis. The authors concluded that most of the evidence is artifactual.

Steele and McGeer (2008) reviewed and rejected the hypotheses that exposure to Cycas micronesica or consumption of fruit bats may lead to the disorder. They also concluded that there was no good evidence to support an environmental cause for the disorder and noted that the disease is still present on Guam despite a relative decline over the past several decades. They stated that neuropathologic findings suggest a similar mechanism to other neurodegenerative disorders with similar or overlapping clinical features.

Mapping

Because neurofibrillary tangles containing tau protein are present in Guam disease and because mutations in the tau gene (MAPT; 157140) cause autosomal dominant frontotemporal dementia, Poorkaj et al. (2001) examined MAPT as a candidate gene for the Guam type of ALS-parkinsonism-dementia. They observed linkage disequilibrium between Guam disease and a MAPT polymorphism. For this 2-allele system, ALS and PDC cases were significantly less likely than Guamanian controls to have the '1' allele. DNA sequence analysis of MAPT coding regions did not demonstrate a mutation responsible for the disorder; however, analysis of MAPT genotypes in an extended pedigree of subjects from Umatac, a village with an unusually high frequency of cases (250 per 100,000), showed obligate recombinants between MAPT and Guam disease. Linkage analysis of the Umatac pedigree indicated that MAPT is not the major gene for ALS-PDC. Poorkaj et al. (2001) concluded, however, that MAPT may be a modifying gene increasing risk for ALS-PDC in the presence of an unidentified gene.

Sundar et al. (2007) performed targeted genotype analysis of several SNPs on the H1 haplotype of the MAPT gene in 54 individuals with Guam ALS (ALS-G), 135 with Guam PDC (PDC-G), 153 with Guam dementia (GD), and 258 Chamorros controls. Variation at 3 different SNPs (sites 2, 6 and 9) influenced risk for ALS-G, PDC-G and GD. SNP2, in the IMP5 gene (608284) 5-prime region of MAPT, appeared to act through a dominant mechanism and was independent of the risk conferred by SNPs 6 and 9, which both acted through a recessive mechanism. Persons with the high-risk SNP6 and SNP9 AC/AC haplotype had a 3-fold, 4-fold, and 6-fold increased risk for GD, PDC-G, and ALS-G, respectively. Carriers of the SNP2 G allele had a 1.6-fold, 2-fold, and 1.5-fold increased risk for GD, PDC-G, and ALS-G, respectively. Sundar et al. (2007) concluded that these 2 independent cis-acting sites may influence risk for Guam neurodegenerative disorders by regulating MAPT expression, but stressed that the alleles themselves are not likely to cause the disorders.

Sieh et al. (2009) conducted both genomewide linkage and association analyses, using approximately 400 microsatellite markers, in a sample comprising nearly all living patients and previously-sampled deceased cases. A single, large, complex pedigree was ascertained from Umatac, and 11 smaller non-Umatac families and an unrelated case-control sample were ascertained from the rest of Guam. There was significant evidence of linkage with ALS-PDC for 2 loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. Marker D12S1617 on chromosome 12p gave the strongest evidence of linkage (Zmax = 4.03) in the Umatac pedigree with additional support provided by association analysis in the case-control sample. Marker D12S79 on chromosome 12q also provided significant evidence of linkage (Zmax = 3.14) in the Umatac pedigree with support from flanking markers by multipoint linkage analysis. The TRPM7 gene on chromosome 15 and regions on chromosome 14 and 20 were not supported by the results. Sieh et al. (2009) suggested that ALS-PDC may be influenced by as many as 3 loci.

Molecular Genetics

ALS-PDC of Guam

Hermosura et al. (2005) reported a heterozygous mutation in the TRPM7 gene (T1482I; 605692.0001; 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 proposita had parkinsonism and dementia and her brother had ALS. At the age of 63, the woman 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.

Ishiura et al. (2012) identified a pathogenic repeat expansion in the C9ORF72 gene (614260.0001) in 3 (20%) of 15 patients with ALS from the southernmost Kii peninsula of Japan in the Wakayama prefecture neighboring the Koza River. The patients did not have parkinsonism, and only 1 had moderate cognitive decline. Haplotype analysis indicated a founder effect, with a shared haplotype spanning 3.3-63 Mb; this haplotype overlapped a Finnish founder haplotype by 130 kb and was shared by another Japanese patient with ALS from another area of Japan. C9ORF72 expansions were not found in 6 ALS patients from a more northern Wakayama region or in 16 patients with ALS or 16 patients with PDC in the more northern Mie prefecture/Hohara district of the Kii peninsula. The findings suggested that part of the known ALS-PDC phenotype prevalent among Japanese from the Kii peninsula is caused by an expanded C9ORF72 repeat (FTDALS; 105550).

Population Genetics

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.