Compound Heterozygous Parkin Mutations Research Articles

Disease Progression in Patients with Parkin-Related Parkinson's Disease in a Longitudinal Cohort.

There was a paucity of follow-up studies in the disease progression of early-onset PD patients with Parkin mutations (Parkin-EOPD). Here we conducted a longitudinal study to investigate the progression of motor and cognitive features of Parkin-EOPD patients. Genetic analysis was performed via target sequencing and multiplex ligation-dependent probe amplification. Thirty patients carrying homozygous or compound heterozygous Parkin mutations with at least 2 follow-up revisions were investigated as the Parkin-EOPD group. Fifty-two patients with at least 2 follow-up revisions, who did not have any known causative PD mutations, GBA or LRRK2 risk variants, a heterozygous Parkin mutation or 2 Parkin mutations without a segregation test, were defined as the genetically undefined EOPD (GU-EOPD) group. A linear mixed-effect model was implemented to evaluate longitudinal changes in motor symptoms and cognition. At baseline, the Parkin-EOPD group had a lower Unified Parkinson's Disease Rating Scale score (UPDRS-III) (off-medication) than the GU-EOPD group, without significant differences in cognition. A longitudinal study showed the estimated progression rate per year (standard error) of the UPDRS-III score (off-medication) was lower in the Parkin-EOPD group (0.203 [0.3162] points per year) than in the GU-EOPD group (1.056 [0.3001] points per year). The difference in the UPDRS-III score rate between the 2 groups was 0.853 (0.4183) (P = 0.042). The Parkin-EOPD group showed better maintenance of spatial processing ability compared with the GU-EOPD group (P = 0.027). Parkin-EOPD patients showed a slower deterioration of motor symptoms and a better spatial processing ability than GU-EOPD patients, which suggests that subtyping according to genetic features can help predict PD progression. © 2020 International Parkinson and Movement Disorder Society.

Non-motor Symptoms in Parkinson's Disease Patients with Parkin Mutations: More Depression and Less Executive Dysfunction.

The purpose of this study was to identify differences between genetically undefined (GU) early-onset Parkinson's disease (EOPD) patients and carriers of Parkin mutations on non-motor symptoms (NMSs). EOPD patients (N = 261) underwent targeted sequencing of Parkinson's disease (PD) related genes. Among them, 53 cases carried homozygous or compound heterozygous Parkin mutations (Parkin group) while 208 did not carry known causative PD mutations or risk factors of GBA or Parkin heterozygous mutations (GU group). NMSs were evaluated by face-to-face interviews, self-completed questionnaires and results on a neuropsychological battery. Linear regression and logistic regression models were applied to assess the predictors of NMSs. Parkin patients had younger ages of onset (AOO) (p < 0.001), longer disease durations (p < 0.001) and lower grades of Hoehn and Yarh (H&Y) (p = 0.007). Results on the neuropsychological battery showed a shorter time in Trail Making Test (TMT) (part B) in Parkin patients (p = 0.034) compared to GU patients. After adjusting for AOO, disease duration, H&Y, and levodopa equivalent daily dose (LEDD), there was a higher depression index on the Beck Depression Inventory (BDI) (p = 0.013) and better performance (p = 0.038) on executive function in the Parkin group compared to the GU group. No significant differences were found for autonomic functions, sleep-wake problems or other domains of cognitive function. Our study showed that the Parkin mutation status might be a good predictor of symptoms of depression without an impact on executive function. While these findings need to be confirmed in larger cohorts, they identify a need to screen for depression. Graphical Abstract Flow chart of genetic tests.

Metabolomics-based identification of metabolic alterations in PARK2.

Objective Parkin is the causative gene for autosomal recessive familial Parkinson's disease (PD), although it remains unclear how parkin dysfunction is involved with the general condition. Recently, serum and/or plasma metabolomics revealed alterations in metabolic pathways that might reflect pathomechanisms of idiopathic PD (iPD). Thus, we hypothesized that serum metabolomics of patients with homozygous or compound heterozygous parkin mutations (namely, PARK2) might reflect metabolic alterations due to parkin dysfunction.MethodsWe enrolled 15 PARK2 patients (52 ± 17.6 years) confirmed with homozygous (seven cases) and compound heterozygous (eight cases) parkin mutations, along with 19 healthy age‐matched controls (51 ± 11.5 years). We analyzed 830 metabolites from participants’ serum using well‐established metabolomics technologies, including ultra‐high performance liquid chromatography/tandem mass spectroscopy.ResultsBased on metabolic profiles, hierarchical matrix analysis can divide samples between control and PARK2 subjects. Profiles from PARK2 patients showed significantly higher levels of fatty acid (FA) metabolites and oxidized lipids, and significantly lower levels of antioxidant, caffeine, and benzoate‐related metabolites.InterpretationMetabolomics can identify specific metabolic alterations in PARK2 patients compared with controls. Alterations in FA metabolites suggest a relationship between parkin function and lipid metabolism. The elevation of oxidized lipids in combination with decreasing antioxidants may reflect general hyperoxidative stress. Decreasing benzoate‐related metabolites might be due to the alteration in gut microbiota. Consequently, caffeine and its metabolites may be decreased due to malabsorption. These findings are similar to metabolic alterations in iPD. Thus, serum/plasma metabolomics may reflect the association between parkin dysfunction and parkinsonism.

Olfaction in Parkin carriers in Chinese patients with Parkinson disease.

BackgroundOlfactory identification was reported to be better among PD (Parkinson disease) patients with Parkin mutations, but previous studies didn't eliminate the interference of other PD related genes on olfaction, and whether olfaction of Parkin mutations patients was better in Chinese population was still unknown.ObjectiveTo assess olfaction function among PD patients with Parkin mutations in Chinese population.Materials and MethodsA total of 226 PD patients with a positive family history or an early‐onset age (<50 years) were enrolled for genetic testing of PD related genes by target sequencing and multiple ligation‐dependent probe amplification. The clinical data including olfactory function test were investigated. Linear regression was performed to adjust for the covariates between all groups.ResultsThere were 68 patients found having a negative result in PD genetic testing and 43 patients carrying homozygous or compound heterozygous Parkin mutations. Among them, 49 PD panel negative patients and 33 PD‐Parkin patients had results of olfactory assessment. PD ‐Parkin patients performed significantly better on the Sniffin’ Sticks tests than panel negative patients (8.0 ± 1.7 vs. 5.7 ± 1.9, p < .001), but still worse compared to healthy controls (9.4 ± 1.5, p = .003). These differences persisted after adjusting for confounders.ConclusionsAmong Chinese population, PD ‐Parkin patients had relatively preserved olfaction compared to PD panel negative patients after eliminating the interference of other PD related genes, but were still worse than healthy controls.

PARKIN DISEASE–A CLINICOPATHOLOGICAL ENTITY?

IntroductionMutations in the gene encoding parkin (PARK2) are the commonest cause of autosomal recessive juvenile and young onset parkinsonism. The few available detailed neuropathological reports suggest that homozygous and compound...

High frequency of Parkin exon rearrangements in Mexican‐mestizo patients with early‐onset Parkinson's disease

Parkin mutations in patients with early-onset Parkinson's disease (EOPD) are estimated to occur in 49% of familial cases and 18% of sporadic cases. We analyzed the entire sequence-coding region and dosage mutations of parkin in 63 Mexican-mestizo EOPD patients and 120 controls. Parkin mutations were present in 34 patients (54.0%). Exon rearrangements, predominantly spanning exons 9 and 12 (31.7% and 19.0%, respectively) were present in 32 patients, with 17.5% carrying simple heterozygous and 25.4% carrying compound heterozygous parkin mutations. A higher frequency of parkin exon rearrangements than of sequence mutations was observed. Patients with parkin exons 9 and 12 rearrangements showed a later age at onset than did cases with other regions affected (40.3 ± 4.5 vs 30.1 ± 8.8; P = .005), suggesting a mutational hot spot in the etiology of Mexican-mestizo patients with EOPD. To our knowledge, this study represents the largest sampling of Mexican-mestizo patients with EOPD cases for which parkin sequence and dosage alterations were analyzed. .

Mitochondrial function and morphology are impaired in parkin‐mutant fibroblasts

There are marked mitochondrial abnormalities in parkin-knock-out Drosophila and other model systems. The aim of our study was to determine mitochondrial function and morphology in parkin-mutant patients. We also investigated whether pharmacological rescue of impaired mitochondrial function may be possible in parkin-mutant human tissue. We used three sets of techniques, namely, biochemical measurements of mitochondrial function, quantitative morphology, and live cell imaging of functional connectivity to assess the mitochondrial respiratory chain, the outer shape and connectivity of the mitochondria, and their functional inner connectivity in fibroblasts from patients with homozygous or compound heterozygous parkin mutations. Parkin-mutant cells had lower mitochondrial complex I activity and complex I-linked adenosine triphosphate production, which correlated with a greater degree of mitochondrial branching, suggesting that the functional and morphological effects of parkin are related. Knockdown of parkin in control fibroblasts confirmed that parkin deficiency is sufficient to explain these mitochondrial effects. In contrast, 50% knockdown of parkin, mimicking haploinsufficiency in human patient tissue, did not result in impaired mitochondrial function or morphology. Fluorescence recovery after photobleaching assays demonstrated a lower level of functional connectivity of the mitochondrial matrix, which further worsened after rotenone exposure. Treatment with experimental neuroprotective compounds resulted in a rescue of the mitochondrial membrane potential. Our study demonstrates marked abnormalities of mitochondrial function and morphology in parkin-mutant patients and provides proof-of-principle data for the potential usefulness of this new model system as a tool to screen for disease-modifying compounds in genetically homogenous parkinsonian disorders.

Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients

Homozygous or compound heterozygous parkin mutations cause juvenile parkinsonism. Heterozygous parkin mutations are also found in patients with typical Parkinson's disease (PD), but it is unclear whether a single "mutation" in a patient is related to disease or is coincidental, because the mutation frequency in control subjects is unknown. We present a comprehensive sequence analysis of parkin in control subjects. A total of 302 patients and 301 control subjects were sequenced, and findings were replicated in 1,260 additional patients and 1,657 control subjects. Thirty-four variants were detected, of which 21 were novel; 12 were polymorphisms and 22 were rare variants. Patients and control subjects did not differ in the frequency, type, or functional location of the variants. Even P437L, a common mutation thought to be pathogenic, was present in unaffected control subjects. parkin point mutations are not exclusive to PD. The mere presence of a single point mutation in a patient, in the absence of a second mutation, should not be taken as a cause of disease unless corroborated by family data and functional studies. This study does not support the notion that heterozygous parkin sequence variants (mutations or polymorphisms) are risk factors for PD. Whether heterozygous dosage anomalies are associated with PD remains to be determined.

Lewy bodies and parkinsonism in families with parkin mutations.

Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early-onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early-onset Parkinson's disease (<41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2-27 haplotype analysis was carried out independently of the trait; parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinson's disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of parkin protein may lead to early-onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinson's disease.

Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene

A kindred from South Tyrol (northern Italy) with familial, adult-onset parkinsonism of pseudo-dominant inheritance and mutations in the parkin gene was recently described. To gain insight into basal ganglia dysfunction in this form of hereditary parkinsonism, positron emission tomography (PET) with 18-fluorodopa (FDOPA) and 11C-raclopride (RAC) was performed in 5 affected family members and 5 asymptomatic relatives with proven compound heterozygous or heterozygous parkin mutations. Results were compared to findings in healthy control subjects and patients with typical sporadic, idiopathic Parkinson's disease. Similar to findings in the sporadic Parkinson's disease group, presynaptic striatal FDOPA storage was decreased in patients with compound heterozygous parkin mutations, with the most prominent reduction in the posterior part of the putamen. Along with the presynaptic lowered FDOPA uptake, we found a uniform reduction of the striatal 11C-raclopride binding index in all affected family members as compared to asymptomatic family members carrying a heterozygous parkin mutation, sporadic Parkinson's disease, and control subjects. Our PET data provide evidence that parkinsonism in this family is associated with presynaptic dopaminergic dysfunction similar to idiopathic Parkinson's disease pathophysiology, along with alterations at the postsynaptic D2 receptor level. In asymptomatic carriers of a single parkin mutation with an apparently normal allele, we found a mild but statistically significant decrease of mean FDOPA uptake compared to control subjects in all striatal regions. These data indicate a preclinical disease process in these subjects.

Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial Parkinsonism associated with mutations in the Parkin gene

A kindred from South Tyrol (northern Italy) with familial, adult-onset parkinsonism of pseudo-dominant inheritance and mutations in the parkin gene was recently described. To gain insight into basal ganglia dysfunction in this form of hereditary parkinsonism, positron emission tomography (PET) with 18-fluorodopa (FDOPA) and 11C-raclopride (RAC) was performed in 5 affected family members and 5 asymptomatic relatives with proven compound heterozygous or heterozygous parkin mutations. Results were compared to findings in healthy control subjects and patients with typical sporadic, idiopathic Parkinson‘s disease. Similar to findings in the sporadic Parkinson’s disease group, presynaptic striatal FDOPA storage was decreased in patients with compound heterozygous parkin mutations, with the most prominent reduction in the posterior part of the putamen. Along with the presynaptic lowered FDOPA uptake, we found a uniform reduction of the striatal 11C-raclopride binding index in all affected family members as compared to asymptomatic family members carrying a heterozygous parkin mutation, sporadic Parkinson's disease, and control subjects. Our PET data provide evidence that parkinsonism in this family is associated with presynaptic dopaminergic dysfunction similar to idiopathic Parkinson's disease pathophysiology, along with alterations at the postsynaptic D2 receptor level. In asymptomatic carriers of a single parkin mutation with an apparently normal allele, we found a mild but statistically significant decrease of mean FDOPA uptake compared to control subjects in all striatal regions. These data indicate a preclinical disease process in these subjects. Ann Neurol 2001;49:367–376