PINK1 mutation in Taiwanese early-onset parkinsonism

Abstract

The PINK1 gene mutation is probably the second most common genetic cause of early-onset Parkinson's disease (EOPD). The frequency and the characteristics of the PINK1 mutation in the Taiwanese population are unknown. This study was designed to investigate the genotype, phenotype and dopaminergic function of PINK1 in a cohort of EOPD patients. The genetic settings were to detect the PINK1 gene mutations in 138 EOPD patients and in 191 controls. Using the (99m)Tc-TRODAT-1 (TRODAT) scan, we investigated the differences in the dopamine transporter (DAT) activities between the PINK1 patients, late-onset Parkinson's disease (LOPD) patients and healthy controls. Four EOPD patients with 3 genotypic mutations in the PINK1 gene were found: a compound heterozygous mutation (Q239X/R492X) in 2 sisters, a novel homozygous mutation (R492X) in a woman, and a novel heterozygous mutation (G193R) in a man. The three PINK1 patients had typical phenotype with juvenile onset, benign course, and frequently with dyskinesias. The TRODAT scan showed a rather even and symmetrical reduction of uptake in PINK1 patients, unlike the dominant decline in the putamen in the LOPD patients. The annual reduction rate of uptake in the striatum was much slower in PINK1 patients than that in the LOPD patients (1.7 % vs. 4.1%; p<0.005). In the patient with a heterozygous mutation in the PINK1 gene, the reduction ratio in the striatum, as well as the annual reduction rate, were closer to those in the LOPD group. We conclude that the incidence of carrying PINK1 mutations in the present cohort of Taiwanese EOPD patients was low, accounting for 2/39 (5.1 %) in familial cases, and 2/99 (2 %) in sporadic cases. The slower annual reduction of DAT activity might indicate the insidious degeneration of dopamine neurons and a benign prognosis.

The genetics and neuropathology of Parkinson’s disease

“…A homozygous stop mutation in two Italian families and a homozygous missense mutation in a consanguineous Spanish kindred. Mutations in PINK1 are usually private loss of function changes and have been found to be the second most common cause of early onset autosomal recessive PD [76, 89, 130]. As with PARK2 mutations, there has been speculation about the role of single PINK1 heterozygous mutations as a risk factor for PD.…”

“…Clinically, patients usually have a later age at onset in the 40s and 50s but otherwise are similar to the PD associated with PARK2 mutations, displaying slowly progressive levodopa-responsive disease. Atypical features are often observed and include prominent dystonia, sleep benefit and pyramidal signs [7, 14, 130]. …”

Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy

“…About 10% of cases are characterized by early onset, and these mostly occur in familial clusters (Mizuno et al 2001). Development of parkinsonian syndrome in such individuals has been attributed to mutations in several recently identified genes, including parkin, Leucine-rich repeat kinase 2 (LRRK2), á-synuclein, PINK-1, or DJ-1 (Polymeropoulos et al 1997; Sun et al 2006; Bonifati et al 2008; Weng et al 2007; Abou-Sleiman et al 2003; Jiang et al 2007). In contrast, development of idiopathic PD may represent the final outcome of a complex set of interactions among the innate vulnerabilities of the nigro-striatal DA system, potential genetic predisposition, and exposure to environmental toxins.…”

Recent Advances in Imaging of Dopaminergic Neurons for Evaluation of Neuropsychiatric Disorders

“…SNCA , Parkin , PINK1 , DJ-1 , LRRK2, and ATP13A2 have been identified to be the causative genes for familial and early onset Parkinson's disease (EOPD) [51]. A 99m Tc-TRODAT-1 scan revealed that patients with the PINK1 mutation displayed a rather even, symmetrical reduction of dopamine uptake, whereas patients with late-onset Parkinson's disease (LOPD) displayed a dominant decline in dopamine uptake in the putamen [56]. The contribution of genetic variants in ATP13A2 to Parkinson's disease of Taiwanese patients was investigated with 99m Tc-TRODAT-1 SPECT, showing that the striatal uptake of patients carrying the variants of G1014S and A746T were similar to that of idiopathic Parkinson's disease [51].…”