Parkinson Disease 6, Autosomal Recessive Early-Onset

A number sign (#) is used with this entry because PARK6 is caused by mutations in the PINK1 gene (608309).

Although patients with PARK6 were originally found to have homozygous mutations in the PINK1 gene, a subset of patients have been reported with heterozygous mutations in the PINK1 gene, suggesting that heterozygous mutations may also contribute to disease development.

A digenic form of Parkinson disease resulting from a mutation in the DJ1 gene (602533) and a mutation in the PINK1 gene has been reported.

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

Clinical Features

Hatano et al. (2004) reported 8 unrelated families with autosomal recessive PD from various regions in Asia that showed linkage to the PARK6 locus. Five families were consanguineous. Age at onset ranged from 18 to 56 years, although most had onset in the third or fourth decades. The main clinical features included rigidity, bradykinesia, asymmetric onset, postural instability, and favorable response to levodopa. Other variable features included resting tremor, frozen gait, sleep benefit, dystonia at onset (in 2 patients), hyperreflexia, and levodopa-induced dyskinesias. Progression was generally slow.

Bonifati et al. (2005) identified homozygous mutations in the PINK1 gene in 4 of 90 sporadic Italian patients with early-onset parkinsonism. Age at onset ranged from 28 to 35 years, and the disorder was characterized by tremor, bradykinesia, rigidity, postural instability, response to L-DOPA, and L-DOPA-induced dyskinesias. Two patients had asymmetric onset, 3 had dystonia at onset, and 2 reported benefit from sleep. Another 4 sporadic patients had heterozygous mutations in the PINK1 gene. Clinical features in this group were similar to those with homozygous mutations, except for a later age at onset (34 to 45 years). Bonifati et al. (2005) concluded that heterozygous PINK1 mutations may predispose some patients to disease development.

Albanese et al. (2005) described in detail the phenotype of a patient with PARK6 confirmed by genetic analysis. At age 39 years, he developed gait impairment due to akinesia of the right leg, followed by motor impairment of the upper right limb and favorable response to levodopa treatment. Fifteen years later, he had facial hypomimia, mild akinesia in the upper limbs, and mild periodic dystonia of the right foot. Sleep benefit, dystonia at onset, hyperreflexia, levodopa-induced dyskinesias, and cognitive impairment were absent. Other studies showed mild dysautonomia, striatal dopaminergic denervation, and normal skeletal muscle mitochondrial function. Albanese et al. (2005) concluded that the clinical phenotype in this patient was indistinguishable from idiopathic PD.

In a review of 21 patients with PINK1-related parkinsonism reported in the literature, Albanese et al. (2005) found that most patients (95 to 100%) had slow disease progression, good response to levodopa, bradykinesia, and rigidity. Also common were levodopa-induced dyskinesias (84%), resting tremor (80%), asymmetry at onset (74%), postural instability (63%), on/off phenomenon (60%), and gait impairment (55%). Other less common features included urinary urgency (44%), hyperreflexia (33%), sleep benefit (31%), psychiatric disturbances (25%), orthostatic hypotension (22%), dystonia at onset (16%), and dementia (5%). Thus, although most patients with PARK6 have features similar to those of idiopathic PD, a subset demonstrate features similar to those of PARK2 (600116).

Neuropathologic Findings

Samaranch et al. (2010) reported the neuropathologic findings of a Spanish patient from a large family with autosomal recessive PARK6. He first developed pain and rigidity in his left shoulder and arm at age 31 years. The disorder was progressive, and he showed gait impairment and postural instability that was responsive to dopamine treatment. He also had comorbid psychiatric disturbances, including cocaine addiction before the onset of parkinsonism, anxiety, increasingly strange behavior, and psychosis. He died at age 39 of nonnatural causes. There was neuronal loss in the substantia nigra with astrocytic gliosis and moderate microgliosis. A few remaining neurons showed Lewy bodies. There was no apparent cell loss or Lewy bodies in the locus ceruleus or amygdala. Lewy bodies were also found in some regions of the brainstem. The findings indicated that PINK1 mutations cause an alpha-synucleinopathy (SNCA; 163890). Of note, heterozygous mutation carriers in the family were not affected.

Mapping

In a large Italian family with autosomal recessive early-onset parkinsonism (see 600116), Valente et al. (2001) identified a novel locus, PARK6, in a 12.5-cM region of 1p36-p35. The large Sicilian family, which the authors designated the Marsala kindred, had 4 definitely affected members. The phenotype was characterized by early-onset (range 32 to 48 years) parkinsonism, with slow progression and sustained response to levodopa. A maximum lod score of 4.01 at recombination fraction 0.00 was obtained for marker D1S199.

Valente et al. (2002) confirmed linkage to the PARK6 locus in 8 additional families with autosomal recessive juvenile parkinsonism from 4 different European countries. The maximum cumulative pairwise lod score was 5.39 for marker D1S478. Multipoint linkage analysis gave the highest cumulative lod score of 6.29 for marker D1S478. Haplotype construction and determination of the smallest region of homozygosity in 1 consanguineous family reduced the candidate interval to a 9-cM region between markers D1S483 and D1S2674. No common haplotype could be detected, excluding a common founder effect. These families shared some clinical features with the phenotype reported for European cases positive for parkin (602544) mutations, with a wide range of ages at onset (up to 68 years) and slow progression. However, features typical of autosomal recessive juvenile parkinsonism, including dystonia at onset and sleep benefit, were not observed in PARK6-linked families, thus making the clinical presentation of late-onset cases indistinguishable from idiopathic Parkinson disease.

Hatano et al. (2004) found that 5 of 39 families with autosomal recessive early-onset PD showed significant linkage to the PARK6 locus (lod scores greater than 9.0 at marker D1S2732). Homozygosity was demonstrated by haplotype analysis in 5 families, which were all consanguineous, while compound heterozygosity was suggested in 3 additional families. Three families were Japanese, 2 Taiwanese, and 1 each were from Israel, Turkey, and the Philippines, indicating worldwide distribution of PARK6.

Molecular Genetics

Valente et al. (2004) identified 2 different homozygous mutations affecting the PINK1 kinase domain in 3 consanguineous PARK6 families. Cell culture studies suggested that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. Valente et al. (2004) concluded that their data provided a direct molecular link between mitochondria and the pathogenesis of Parkinson disease.

In 6 unrelated families (3 Japanese, 1 Israeli, 1 Filipino, and 1 Taiwanese) with PARK6, Hatano et al. (2004) identified 6 pathogenic mutations in the PINK1 gene (see, e.g., 608309.0003-608309.0005). The authors suggested that PINK1 may be the second most common causative gene next to parkin in early-onset autosomal recessive Parkinson disease. These families had also been reported by Hatano et al. (2004).

Valente et al. (2004) found that among 90 patients with sporadic early-onset parkinsonism, 1 patient had a homozygous mutation in the PINK1 gene and a second was compound heterozygous for mutations in PINK1. Five of 90 patients and 2 of 200 healthy controls had a heterozygous PINK1 mutation; 1 of the patients and 1 control shared the same mutation. The 5 patients with a heterozygous mutation had a typical parkinsonian phenotype with a mean age at onset of 44 years. Three patients had mild mood disturbances. Valente et al. (2004) suggested that heterozygous PINK1 mutations may produce subclinical dopaminergic dysfunction and represent a risk factor for the development of parkinson disease.

In 3 of 65 unrelated Italian patients with early-onset parkinsonism, Klein et al. (2005) identified 2 different mutations in the PINK1 gene (608309.0007 and 608309.0008). One patient was homozygous, and 2 patients were heterozygous.

Chishti et al. (2006) identified homozygosity for a mutation in the PINK1 gene (608309.0010) in affected members of a large consanguineous PARK6 family from Saudi Arabia, and Leutenegger et al., 2006 identified homozygosity for a PINK1 mutation (608309.0011) in affected members of a large consanguineous PARK6 family from northern Sudan. Heterozygous individuals in these families did not have signs of parkinsonism.

Hedrich et al. (2006) identified a homozygous mutation (Q456X; 608309.0012) in the PINK1 gene in 4 affected members of a large German family with early-onset parkinsonism. Six heterozygous offspring of the homozygous patients were found to have subtle signs of disease, and 5 heterozygous offspring were considered to be unaffected. The 6 affected heterozygous offspring were not aware of their signs, but clinical examination showed unilaterally reduced or absent arm swing and rigidity. Hedrich et al. (2006) concluded that heterozygous PINK1 mutations confer susceptibility to the development of PD. Of clinical note, parkinsonian signs were more marked on the dominant right-hand side in all mutation carriers, and 10 of 15 mutation carriers had psychiatric disturbances.

Abou-Sleiman et al. (2006) identified heterozygous mutations in the PINK1 gene (see, e.g., 608309.0013) in 9 (1.2%) of 768 patients with sporadic PD. Heterozygous mutations were identified in 0.39% of a larger control group without PD, suggesting that heterozygous PINK1 mutations are a risk factor for PD. The mean age of symptom onset in the patients was 54 years, and the disorder showed very slow progression.

Choi et al. (2008) identified mutations in the PINK1 gene (see, e.g., 608309.0008) in 4 of 72 unrelated Korean patients with onset of PD before age 50. Three patients were heterozygous, and 1 was compound heterozygous for the mutation(s).

Kumazawa et al. (2008) identified mutations in the PINK1 gene in 10 (2.5%) of 391 unrelated parkin-negative PD patients from 13 countries. Eight of the 10 patients with mutations were from Japan. The frequency of homozygous mutations was 4.26% (2 of 47) in families with autosomal recessive PD and 0.53% (1 of 190) in patients with sporadic PD. The frequency of heterozygous mutations was 1.89% (2 of 106) in families with potential autosomal dominant PD and 1.05% (2 of 190) in patients with sporadic PD. The mean age at onset in patients with single heterozygous mutations was 53.6 years, compared to 34.0 years in patients with homozygous mutations.

Ishihara-Paul et al. (2008) identified 4 different homozygous mutations in the PINK1 gene (see, e.g., Q456X; 608309.0012), including 3 novel mutations, in 14 (15%) of 92 Tunisian families with early-onset Parkinson disease. Six (2.5%) of 240 patients with no family history of PD. were also found to carry homozygous mutations. There was no evidence that heterozygous PINK1 mutations contributed to development of PD.

Modifier Genes

Piccoli et al. (2008) reported a family with early-onset PARK6 associated with a mutation (W437X; 608309.0002) in the PINK1 gene. The proband, who had very early onset at age 22 years, was homozygous for the W437X mutation, whereas both his parents were heterozygous. The father was unaffected at age 79, and the mother developed Parkinson disease at age 53. Biochemical studies of the proband's fibroblasts showed mitochondrial dysfunction, with decreased amounts of cytochrome c oxidase, impaired complex I activity, and increased hydrogen peroxide generation. Further analysis identified 2 mutations in mitochondrial genes: MTND5 (516005.0010) and MTND6 (516006.0008). Both the proband and his mother were homoplasmic for both mitochondrial mutations. Piccoli et al. (2008) concluded that the presence of the mitochondrial mutations in combination with the PINK1 mutation may have accelerated onset of the disease.

Parkinson Disease, Digenic, PINK1/DJ1

In 2 Chinese sibs with early-onset Parkinson disease, Tang et al. (2006) identified compound heterozygosity for a missense mutation (608309.0014) in the PINK1 gene and a missense mutation (602533.0007) in the DJ1 gene. The DJ1 and PINK1 mutations were not observed in 240 and 568 control chromosomes, respectively, and both were located in highly conserved residues. The findings were consistent with digenic inheritance of Parkinson disease. A 42-year-old unaffected family member also carried both mutations, suggesting incomplete penetrance. Coimmunoprecipitation studies showed that both wildtype and mutant PINK1 interacted with both wildtype and mutant DJ1. Expression of wildtype DJ1 increased steady-state levels of both mutant and wildtype PINK1, but mutant DJ1 decreased steady-state levels of both mutant and wildtype PINK1, suggesting that wildtype DJ1 can enhance PINK1 stability. Human neuroblastoma cells expressing either mutant PINK1 or DJ1 showed reduced viability following oxidative challenge with MPP compared to control cells, indicating that both proteins protect against cell stress. Coexpression of both wildtype proteins resulted in a synergistic increase in cell viability against MPP-induced stress. In addition, coexpression of both mutant proteins significantly increased susceptibility of cells to death, compared to either mutant alone. These findings indicated that DJ1 and PINK1 function collaboratively.