Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 171695, 411602; DO: 0060367;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q22.1 | Parkinson disease 1 | 168601 | Autosomal dominant | 3 | SNCA | 163890 |
A number sign (#) is used with this entry because of evidence that Parkinson disease-1 (PARK1) is caused by heterozygous mutation in the alpha-synuclein gene (SNCA; 163890) on chromosome 4q22.
See also dementia with Lewy bodies (127750), an allelic disorder with overlapping clinical features.
Parkinson disease is the second most common neurogenic disorder after Alzheimer disease (AD; 104300), affecting approximately 1% of the population over age 50. Clinical manifestations include resting tremor, muscular rigidity, bradykinesia, and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia (Polymeropoulos et al., 1996).
For a general phenotypic description and a discussion of genetic heterogeneity of Parkinson disease, see 168600.
Golbe et al. (1990) reported 2 large kindreds originating from Contursi, a village in the Salerno province of Italy, in which 41 individuals in 4 generations had autosomal dominant Parkinson disease. Male-to-male transmission occurred, and penetrance was estimated at 96%; only 1 instance of definite nonpenetrance was recognized. The disorder was characterized by early onset (mean 46.5 years) and rapid progression (average 9.7 years from onset to death). Clinical appearance and response to levodopa were typical for Parkinson disease. Autopsy of 2 patients in 1 of the kindreds showed pathologic changes typical of PD with Lewy bodies. Affected persons who spent most of their lives in Italy survived longer than their affected U.S. relatives. Golbe et al. (1990) postulated a single gene as the main factor in these kindreds and concluded that the findings enhanced the likelihood of a significant genetic component in sporadic PD. In a follow-up study of these kindreds, Golbe et al. (1996) found 60 affected individuals in 5 generations. There was variation in clinical features regarding age of onset, tremor, and levodopa responsiveness, suggesting that a presumably single mutation can produce a heterogeneous PD phenotype, even among sibs. A suggestion of anticipation disappeared after adjustment for age-related ascertainment bias.
Spira et al. (2001) reported a family of Greek origin with 5 of 9 sibs affected with PD, 3 of whom were examined in detail and were found to carry a mutation in the SNCA gene (163890.0001). The 3 sibs presented in their forties with progressive bradykinesia and rigidity, which was initially dopa-responsive, and cognitive decline. Additional features included central hypoventilation, postural hypotension, bladder incontinence, and myoclonus.
Puschmann et al. (2009) reported 2 affected members of a Swedish family with the SNCA A53T mutation (163890.0001). Haplotype analysis indicated a different haplotype than the previously identified Greek founder haplotype, suggesting a de novo event in this Swedish family. The proband had insidious onset of decreased range of motion, stiffness, and hypokinesia between ages 39 and 41 years. About 6 months later, she developed word-finding difficulty and monotone speech. The disorder was progressive, and by age 47, she had developed dementia and severe motor disturbances, including myoclonus. Her father developed motor signs of the disorder at age 32, with speech difficulties at age 33. At age 38, he was moved to a nursing home, and at 40, he was aphonic with dementia and an inability to walk or feed himself independently. Both patients had an initial favorable response to levodopa treatment. Both patients had normal brain MRI and increased CSF protein levels, and SPECT scan of the daughter showed decreased blood flow in the language region. Puschmann et al. (2009) emphasized the early onset, rapid progression, and presence of dementia in this family with PD, and suggested that an underlying cortical encephalopathy contributed to the disease course.
Clinical Variability
Golbe et al. (1993) described a family with very slowly progressive atypical autosomal dominant Parkinson disease that showed, in most affected members, poor response to levodopa and subjective visual difficulty. Four cases in 3 generations had onset of symptoms at age 35, 25, 16, and 16, and 4 suspicious cases had occurred in 3 other generations. There seemed to be a trend toward progressively earlier age of onset. One autopsied case showed a distribution of cell loss and Lewy bodies typical of PD. Golbe et al. (1993) noted several previously described kindreds with clinically atypical autosomal dominant PD, including a report by Inose et al. (1988).
Lesage et al. (2013) reported a French family in which 4 individuals had a disorder comprising rapidly progressive Parkinson disease, pyramidal signs, and psychiatric features. Three affected individuals had onset at age 31 to 35 years, whereas the fourth had onset at age 60. The initial symptoms were parkinsonism with moderate response to levodopa and development of levodopa-induced dyskinesia. All also had pyramidal tract involvement, with hyperreflexia and extensor plantar responses; 1 had severe spasticity. Two patients had marked psychiatric manifestations, including hallucinations, delusions, anxiety, and depression, but not dementia. The disorder was rapidly progressive: all became bedridden within 5 to 7 years, and 3 patients died within 5 to 7 years of onset. Neuropathologic examination of 1 patient showed neuronal loss in the substantia nigra and striatum, as well as astrogliosis. There was also neuronal loss in the motor cortex, the anterior horn of the spinal cord, and the corticospinal tracts. Lewy bodies and dystrophic Lewy neurites were present mostly in the brainstem. There were fine, diffuse, neuronal cytoplasmic inclusions in all superficial cortical layers.
Pathologic Findings
In Parkinson disease, the specific pattern of neuronal degeneration is accompanied by eosinophilic intracytoplasmic inclusions known as Lewy bodies in surviving neurons in the substantia nigra, locus ceruleus, nucleus basalis, cranial nerve motor nuclei, central and peripheral divisions of the autonomic nervous system, hypothalamus, and cerebral cortex (Polymeropoulos et al., 1996).
Neuropathologic examination of 2 of the 5 sibs with PD reported by Spira et al. (2001) showed depigmentation of the substantia nigra, severe cell loss and gliosis in the brainstem, and multiple alpha-synuclein-immunopositive Lewy neurites. Cortical neuritic changes associated with tissue vacuolization were present, mostly in the medial temporal regions.
Seidel et al. (2010) reported neuropathologic findings of a patient with PD due to the SNCA A30P mutation (163890.0002). He had onset at age 54 years, had L-DOPA-related complications, and died in a mute, bedridden state at age 69. Progressive cognitive decline was also reported. Postmortem examination showed depigmentation and neuronal loss in the substantia nigra and neuronal loss in the locus ceruleus and dorsal motor vagal nucleus. There were widespread SNCA-positive Lewy bodies, Lewy neurites, and glial aggregates in the cerebral cortex and many other regions of the brain, including the hippocampus, hypothalamus, brainstem, and cerebellum. Biochemical analysis showed a significant load of insoluble SNCA. The findings were similar to, but more severe, than those observed in idiopathic PD.
The transmission pattern of PARK1 in the families reported by Golbe et al. (1990) and Lesage et al. (2013) was consistent with autosomal dominant inheritance.
Polymeropoulos et al. (1996) performed a genomewide linkage scan in the large Italian kindred previously reported by Golbe et al. (1990). Linkage to markers in the 4q21-q23 region was found with a maximum lod score of 6.00 at recombination fraction theta = 0.00 for marker D4S2380.
In a genomewide association study and 2 replication studies in a total of 2,011 cases and 18,381 controls from Japan, Satake et al. (2009) found strong association with the SNCA gene (163890) on 4q22.1 (p = 7.35 x 10(-17)), implicated in PARK1. In a genomewide association study in 1,713 individuals of European ancestry with PD and 3,978 controls, followed by replication in 3,361 cases and 4,573 controls, Simon-Sanchez et al. (2009) identified association with the SNCA gene (rs2736990, OR = 1.23, p = 2.24 x 10(-16)).
In the Italian kindred first reported by Golbe et al. (1990) and in 3 unrelated families of Greek origin with autosomal dominant inheritance of Parkinson disease, Polymeropoulos et al. (1997) identified a heterozygous mutation in the SNCA gene (A53T; 163890.0001), which encodes a presynaptic protein thought to be involved in neuronal plasticity.
Duvoisin and Golbe (1995) reviewed the genetics of parkinsonism with Lewy body pathology, which they considered to be 'true' Parkinson disease.
In 4 members of a French family with autosomal dominant PD, pyramidal signs, and psychiatric abnormalities, Lesage et al. (2013) identified a heterozygous missense mutation in the SNCA gene (G51D; 163890.0006). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies showed that the mutant protein oligomerized more slowly than wildtype, but that its fibrils conferred significant cellular toxicity.
In a Caucasian English woman with onset of pathologically confirmed PD at age 71 and death at age 83, Proukakis et al. (2013) identified a heterozygous missense mutation in the SNCA gene (H50Q; 163890.0007).
SNCA Gene Duplication
Nishioka et al. (2006) identified heterozygosity for duplication of the SNCA gene (163890.0005) in 2 of 113 Japanese probands with autosomal dominant PD. In the first family, 2 patients with the duplication had typical PD, whereas 4 duplication carriers over the age of 43 years were unaffected, yielding a penetrance of 33%. In the second family, 1 affected and 2 asymptomatic members had the duplication. The affected patient from the second family developed dementia 14 years after diagnosis of PD, consistent with Lewy body dementia.
Fuchs et al. (2007) reported a Swedish family with parkinsonism due to duplication of the SNCA gene. The proband presented with dysautonomia followed by rapidly progressive parkinsonism. Family history revealed multiple affected members with a similar disorder. Features of dementia, including hallucinations, occurred late in the disease. This family was determined to be a branch of a large family originally reported by Mjones (1949). A Swedish American branch of that family was found by Farrer et al. (2004) to have a triplication of the SNCA gene (163890.0003). Fuchs et al. (2007) found that genotypes within and flanking the duplicated region in the Swedish family were identical to genotypes in the Swedish American family reported by Farrer et al. (2004), suggesting a common founder. Hybridization signals indicated a tandem multiplication of the same genomic interval in the 2 families, a duplication and triplication, respectively. Sequence analysis indicated that the multiplications were mediated by centromeric and telomeric long interspersed nuclear element (LINE L1) motifs.
Brueggemann et al. (2008) and Troiano et al. (2008) independently identified duplications of the SNCA gene in 2 patients with sporadic early-onset PD, at ages 36 and 35 years, respectively. The mutation was confirmed to be de novo in the case of Brueggemann et al. (2008). Neither patient had cognitive impairment. The prevalence of the SNCA duplication in sporadic PD was reported to be 0.25 and 1%, respectively.
Lotharius and Brundin (2002) reviewed the literature on SNCA and suggested a possible role for this protein in vesicle recycling via its regulation of phospholipase D2 and its fatty acid-binding properties. They hypothesized that impaired neurotransmitter storage arising from SNCA mutations could lead to cytoplasmic accumulation of dopamine, resulting in breakdown of this labile neurotransmitter in the cytoplasm and promoting oxidative stress and metabolic dysfunction in the substantia nigra.
Kazantsev and Kolchinsky (2008) reviewed current concepts on the pathogenesis of PD and noted that the symptoms result from acute shortage of dopamine due to selective loss of dopaminergic neurons in the substantia nigra. The metabolism of dopamine yields toxic derivatives that are normally polymerized to form dark nontoxic neuromelanin, which is deposited in the cells. The lack of pigmentation in PD substantia nigra may reflect an inability to process these toxic metabolites. These findings support a role for reactive oxygen species (ROS) in PD. The presence of SNCA-containing Lewy bodies implicates protein misfolding as a pathogenic event that disrupts normal cellular function.
Kam et al. (2018) found that pathologic alpha-synuclein (163890) activates PARP1 (173870), and poly ADP-ribose (PAR) generation accelerates the formation of pathologic alpha-synuclein, resulting in cell death via parthanatos. PARP inhibitors or genetic deletion of PARP1 prevented pathologic alpha-synuclein toxicity. In a feed-forward loop, PAR converted pathologic alpha-synuclein to a more toxic strain. PAR levels were increased in the cerebrospinal fluid and brains of patients with Parkinson disease, suggesting that PARP activation plays a role in Parkinson disease pathogenesis.
Using unbiased phenotypic screens as an alternative to target-based approaches, Tardiff et al. (2013) discovered an N-aryl benzimidazole (NAB) that strongly and selectively protected diverse cell types from alpha-synuclein toxicity. Three chemical genetic screens in wildtype yeast cells established that NAB promoted endosomal transport events dependent on the E3 ubiquitin ligase Rsp5 (NEDD4; 602278). These same steps were perturbed by alpha-synuclein itself. Tardiff et al. (2013) concluded that NAB identifies a druggable node in the biology of alpha-synuclein that can correct multiple aspects of its underlying pathology, including dysfunctional endosomal and endoplasmic reticulum-to-Golgi-vesicle trafficking.
Chung et al. (2013) exploited mutation correction of iPS cells and conserved proteotoxic mechanisms from yeast to humans to discover and reverse phenotypic responses to alpha-synuclein (163890), a key protein involved in Parkinson disease. Chung et al. (2013) generated cortical neurons from iPS cells of patients harboring alpha-synuclein mutations (A53T; 163890.0001), who are at high risk of developing PD dementia. Genetic modifiers from unbiased screens in a yeast model of alpha-synuclein toxicity led to identification of early pathogenic phenotypes in patient neurons, including nitrosative stress, accumulation of endoplasmic reticulum-associated degradation substrates, and ER stress. A small molecule, NAB2, identified in a yeast screen, and NEDD4, the ubiquitin ligase that it affects, reversed pathologic phenotypes in these neurons.
To determine if SNCA lesions lead to neurodegeneration, Giasson et al. (2002) generated transgenic mice expressing the A53T mutation (163890.0001) in CNS neurons. Mice expressing the A53T mutant developed a severe and complex motor impairment leading to paralysis and death. The animals developed age-dependent intracytoplasmic neuronal SNCA inclusions paralleling disease onset, and the inclusions recapitulated features of human counterparts. Using immunoelectron microscopy, Giasson et al. (2002) revealed that the SNCA inclusions in the mutant mice contained fibrils similar to human pathologic inclusions. The authors concluded that A53T leads to the formation of toxic filamentous SNCA neuronal inclusions that cause neurodegeneration.
Kuo et al. (2010) developed transgenic mice expressing mutant alpha-synuclein, either A53T (163890.0001) or A30P (163890.0002), from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines showed abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also had abnormal motor behavior, but neither line demonstrated cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions, or neurodegeneration. These animals recapitulated the early gastrointestinal abnormalities seen in human Parkinson disease.
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