Parkinson Disease 4, Autosomal Dominant

A number sign (#) is used with this entry because autosomal dominant Parkinson disease-4 (PARK4) is caused by heterozygous triplication of the alpha-synuclein gene (SNCA; 163890) on chromosome 4q22.

See also PD1 (168601) and Lewy body dementia (DLB; 127750), which are also caused by mutation in the SNCA gene and show overlapping phenotypes with PARK4.

For a phenotypic description and a discussion of genetic heterogeneity of Parkinson disease (PD), see 168600.

Clinical Features

Spellman (1962) described a family in which multiple members in 4 generations had autosomal dominant parkinsonism beginning in their thirties and progressing rapidly to death in 2 to 12 years. This extended family was of English and German origin and later referred to as the 'Iowa kindred' (Farrer et al., 2004). Waters and Miller (1994) and Muenter et al. (1998) later described this same family in greater detail. The proposita developed parkinsonism at age 45 years and died 6 years later. She had typical features of Parkinson disease except for an absence of rest tremor, although this was present in other affected family members. Neuropathologic examination confirmed the diagnosis of Lewy body parkinsonism. The disorder was characterized by early age at onset, early weight loss, and rapidly progressive dopa-responsive parkinsonism, followed by dementia and, in some, by hypotension. Intellectual dysfunction began with subjective memory loss and objective visuospatial dysfunction and was followed by decline of frontal lobe cognitive and memory functions. Neuropathologic examination of autopsied cases showed neuronal loss in substantial nigra and locus ceruleus and widespread Lewy bodies, many of them in the cerebral cortex; those in the hypothalamus and locus ceruleus were often of bizarre shapes. Other findings were vacuolation of the temporal cortex, unusual neuronal loss, and gliosis in the hippocampus (CA 2/3), and neuronal loss in the nucleus basalis. There were no neuritic plaques, neurofibrillary tangles, or amyloid deposits. Positron emission tomography in 3 patients showed decreased striatal uptake of fluorodopa. Neurochemical analysis of an autopsied brain showed a pronounced decrease in choline acetyltransferase activity in the frontal and temporal cortices and hippocampus and a severe depletion of striatal dopamine with a pattern not typical of classic Parkinson disease.

Gwinn-Hardy et al. (2000) reported neuropathologic findings of the proband from the Iowa kindred. There was striking cortical pathology, with there were regions of spongiosis and gliosis that were also rich in many thread-like dystrophic cell processes. These were accompanied by scattered glial cells with alpha-synuclein-immunoreactive inclusions somewhat similar to glial cytoplasmic inclusions of multiple system atrophy. There were also glial inclusions in the cerebral and cerebellar white matter and in certain white matter fiber tracts, especially in the basal ganglia and basal forebrain. There were also alpha-synuclein-immunoreactive round to pleomorphic inclusions within neurons, mostly in lower cortical layers, but not showing a clear laminar predilection. The latter inclusions were consistent with cortical Lewy bodies, and the number and distribution of cortical Lewy bodies were consistent with neocortical stage of dementia with Lewy bodies (127750). Immunoblots of brain homogenates using the alpha-synuclein polyclonal antibody against patients from the Iowa kindred and normal controls and brains of other synucleinopathies revealed a 26-kD band and several other high molecular weight species only in the affected cortex of the Iowa kindred patients. This 26-kD band was not present in the substantia nigra of the Iowa kindred patients or of patients with other synucleinopathies. Gwinn-Hardy et al. (2000) noted that a point mutation in the alpha-synuclein gene had not been identified in this family.

Farrer et al. (2004) identified a family of Swedish American descent with autosomal dominant early-onset parkinsonism and dementia due to a triplication of the SNCA gene. The proband, who had onset at age 31, had rapidly progressive parkinsonism with tremor, rigidity, and bradykinesia. At age 45, he developed visual and auditory hallucinations and paranoia. He also had postural hypotonia. He later developed intellectual impairment progressing to severe dementia with mutism, followed by death at age 52 years. Postmortem examination showed severe neuronal degeneration and loss in the substantia nigra, locus ceruleus, and hippocampal areas CA 2/3. Lewy bodies were present in the hypothalamus, basal nucleus of Meynert, and the cerebral cortex. SNCA mRNA expression was increased compared to controls.

Fuchs et al. (2007) determined that the Swedish American family reported by Farrer et al. (2004) was part of the Lister family complex originally described by Mjones (1949). The Swedish American branch of the family showed early-onset, rapidly progressive parkinsonism associated with dementia and dysautonomia. Fuchs et al. (2007) identified a Swedish branch of this extended kindred in which multiple family members had late-onset parkinsonism and early dysautonomia due to a duplication of the SNCA gene (163890.0005). Genotypes within and flanking the duplicated region were identical to genotypes in the Swedish American family reported by Farrer et al. (2004) and suggested a common founder. Hybridization signals indicated a tandem multiplication of the same genomic interval in the 2 families, 1 with duplication and 1 with triplication. Sequence analysis indicated that the multiplications were mediated by centromeric and telomeric long interspersed nuclear element (LINE L1) motifs.

Mapping

Farrer et al. (1999) suggested that a locus on 4p is responsible for autosomal dominant Lewy body parkinsonism, and that postural tremor, consistent with essential tremor (190300), may be an alternate phenotype of the same pathogenic mutation that causes Lewy body parkinsonism. They studied the large family described by Waters and Miller (1994) and Muenter et al. (1998) with levodopa-responsive Lewy body parkinsonism. After performing a genome screen, they identified a chromosome 4p haplotype that segregated with the disorder; however, this haplotype also occurred in individuals in the pedigree who did not have clinical Lewy body parkinsonism but rather suffered from postural tremor.

In a second genomewide search, Singleton et al. (2003) found a haplotype cosegregating with the disease over 26 cM, with a multipoint lod score of 3.50 at marker DS42460 on chromosome 4q.

Molecular Genetics

By quantitative PCR amplification of SNCA exons in an individual with parkinsonism from the large family reported by Waters and Miller (1994), Singleton et al. (2003) found evidence consistent with whole gene triplication (163890.0003). Analysis of other family members showed that the SNCA triplication segregated with parkinsonism, but not with postural tremor. The triplicated region contains an estimated 17 genes, including SNCA. Carriers of the triplication are predicted to have 4 fully functional copies of SNCA, with doubling of the effective load of the estimated 17 genes. The authors suggested that increased dosage of SNCA is the cause of PD in this family. They noted that the disease process may resemble the etiology of Alzheimer disease (AD; 104300) in Down syndrome (190685) with overexpression of the APP gene (104760) due to chromosome 21 trisomy.

Ibanez et al. (2009) identified SNCA gene triplication in 1 (1.5%) of 22 families with atypical PD, including rapid progression and severe cognitive impairment. Genotyping and dosage analysis indicated that SNCA multiplications occurred independently. The authors concluded that alterations in SNCA gene dosage due to rearrangements may be more common than point mutations.