Objective: To investigate the genetic etiology of early-onset (AAO > 45 Years) parkinsonism.

Background: Parkinsonism is a neurological syndrome characterized by resting tremor, rigidity, bradykinesia and postural instability. Although Parkinson’s disease (PD) is the most frequent cause, a range of neurological conditions may present a similar set of symptoms, and early on in the disease, different forms of parkinsonism have greater overlap. Mutations in PRKN, PINK1, and DJ-1 causes a mild and slowly progressive early-onset disease, whereas mutations in ATP13A2, PLA2G6, FBXO7, DNAJC6 and SYNJ1 causes early/juvenile-onset atypical parkinsonism with additional clinical signs. Interestingly, proteins of aforementioned genes are important for mitochondrial maintenance and lysosomal degradation.

Methods: We studied 105 early-onset parkinsonism [Mean AAO = 39.3 ± 5.0 years] patients from Norway. Exon-dosage analyses, whole-exome sequencing and genome-wide genotyping were performed. Analysis of the data, under a recessive model, was done by: i) Describing variability in genes previously described in parkinsonism, ii) genetic components of nominated cellular pathways, and iii) mapping novel genes within shared runs of homozygosity (ROH).

Results: Patients had slowly progressive motor symptoms and were generally cognitively spared

Summary of clinical data for 105 early-onset (age at onset < 45 years) parkinsonism patients originating from Central Norway.

Characteristic	Total (n=105)
Gender ratio (M:F)	1.6:1
Age at study (y)
Mean ± SD	60.1 ± 11.2
Range	28-87
Age at onset (y)
Mean ± SD	39.1 ± 5.1
Range	22-45
UPDRS stage III at 10 years of disease
Mean ± SD	24.8 ± 12.1
Range	4-65
Hoehn & Yahr at 10 years of disease
Mean ± SD	2.6 ± 0.9
Range	1-5
MoCA at 15 years of disease
Mean ± SD	25.5 ± 4.1

L-Dopa-equivalent daily dosage (LEDD); The Montreal Cognitive Assessment (MoCA); The unified Parkinson’s disease rating scale (UPDRS). Seven patients were found carrying recessive variability in PINK1 or PRKN. Recessive variants in GBA were seen in three patients with additional cognitive impairment and variants in ITPR1 and SLC2A1 (GLUT1) was identified in three additional patients. Furthermore, recessive variability in TIMM44, EP300 and LRRK2, all important for mitochondrial maintenance and lysosomal degradation was found. Additional genes/variability in 250 nominated ROH is currently being evaluated.

Conclusions: There is a significant genetic component in the etiology of early-onset parkinsonism. Here we describe ∼12% of early-onset parkinsonism patients with mutations in genes previously implicated in disease. Additionally, we have found variability in genes involved in mitochondrial maintenance and lysosomal degradation. Unraveling of the genetic etiology and description of their clinical phenotype is of great benefit in distinguishing multiple disorders which present parkinsonism at early stages, as making an accurate and early diagnosis of such disorders is challenging.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-identification-of-early-onset-parkinsonism-among-norwegian-patients/