Norbert Brüggemann

Mutations in PINK1 and Parkin Impair Ubiquitination of Mitofusins in Human Fibroblasts

PINK1 and Parkin mutations cause recessive Parkinsons disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy. Here, we investigated the impact of mutations in endogenous PINK1 and Parkin on the ubiquitination of mitochondrial fusion and fission factors and the mitochondrial network structure. Treating control fibroblasts with mitochondrial membrane potential (Δψ) inhibitors or H2O2 resulted in ubiquitination of Mfn1/2 but not of OPA1 or Fis1. Ubiquitination of Mitofusins through the PINK1/Parkin pathway was observed within 1 h of treatment. Upon combined inhibition of Δψ and the ubiquitin proteasome system (UPS), no ubiquitination of Mitofusins was detected. Regarding morphological changes, we observed a trend towards increased mitochondrial branching in PD patient cells upon mitochondrial stress. For the first time in PD patient-derived cells, we demonstrate that mutations in PINK1 and Parkin impair ubiquitination of Mitofusins. In the presence of UPS inhibitors, ubiquitinated Mitofusin is deubiquitinated by the UPS but not degraded, suggesting that the UPS is involved in Mitofusin degradation.

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene

A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family.

Etiology of musician’s dystonia: Familial or environmental?

Objective: To test the hypothesis that there is familial aggregation of dystonia and other movement disorders in relatives of patients with musician’s dystonia (MD) and to identify possible environmental triggers. Methods: The families of 28 index patients with MD (14 with a reported positive family history of focal task-specific dystonia [FTSD] and 14 with no known family history [FH−]) underwent a standardized telephone screening interview using a modified version of the Beth Israel Dystonia Screen. Videotaped neurologic examinations were performed on all participants who screened positive and consensus diagnoses established. All patients were investigated for DYT1 dystonia and suitable families were tested for linkage to DYT7. All family members were administered questionnaires covering potential triggers of FTSD. Results: A diagnosis of dystonia was established in all 28 index patients and in 19/97 examined relatives (MD: n = 8, other FTSD: n = 9, other dystonias: n = 2), 5 of whom were members of FH− families. In 27 of the 47 affected individuals, additional forms of dystonia were seen; other movement disorders were observed in 23 patients. In total, 18 families were multiplex families with two to four affected members. Autosomal dominant inheritance was compatible in at least 12 families. The GAG deletion in DYT1 was absent in all patients. Linkage to DYT7 could be excluded in 1 of the 11 informative families. With respect to potential environmental triggers, there was no significant difference between patients with MD/FTSD compared to unaffected family members. Conclusion: Our results suggest a genetic contribution to musician’s dystonia with phenotypic variability including focal task-specific dystonia. BIDS = Beth Israel Dystonia Screen; FH+ = reported positive family history of focal task-specific dystonia; FH− = no known family history of focal task-specific dystonia; FTSD = focal task-specific dystonia; MD = musician’s dystonia; WC = writer’s cramp.

Recessively Inherited Parkinsonism: Effect of ATP13A2 Mutations on the Clinical and Neuroimaging Phenotype

OBJECTIVE To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers. DESIGN Prospective multimodal clinical and neuroimaging study. SETTING University of Lübeck, Lübeck, Germany. PARTICIPANTS Eight family members of a large Chilean pedigree with Kufor-Rakeb syndrome (KRS). INTERVENTIONS Clinical characterization, dopamine transporter (DAT) imaging, voxel-based morphometry (VBM), and transcranial sonography (TCS). MAIN OUTCOME MEASURES Frequency of parkinsonian signs, brain structure, and functional alterations. RESULTS The only available patient with compound heterozygous KRS showed a markedly reduced striatal DAT density bilaterally. Magnetic resonance imaging revealed severe global brain atrophy as well as iron deposition in the basal ganglia. The heterozygous mother had definite parkinsonism with reduced DAT density in both putamina. While all asymptomatic heterozygous siblings displayed subtle extrapyramidal signs, DAT imaging revealed striatal tracer uptake within physiological levels. Voxel-based morphometry revealed an increase in gray matter volume in the right putamen and a decrease in the cerebellum of the heterozygous carriers. In all mutation carriers, the substantia nigra had a normal appearance on TCS. CONCLUSIONS Single ATP13A2 heterozygous mutations may be associated with clinical signs of parkinsonism and contribute to structural and functional brain changes. Lack of hyperechogenicity in the substantia nigra may be a distinctive feature of this form of genetic parkinsonism. This, along with the finding of iron in the basal ganglia in our patient with KRS, implies a different underlying pathophysiology compared with other monogenic forms of parkinsonism and idiopathic PD and may place KRS among the syndromes of neurodegeneration with brain iron accumulation (NBIA).

Transcranial sonography findings in a large family with homozygous and heterozygous PINK1 mutations

Objective: To investigate substantia nigra (SN) echogenicity in members of a family with homozygous and heterozygous PTEN induced kinase (PINK1) mutations with or without signs of Parkinson’s disease (PD). Methods: Transcranial sonography (TCS) was used to investigate 20 members of a family with PINK1 mutations, including four homozygous and 11 heterozygous mutation carriers and five individuals with no mutation. For comparison, a healthy control group of 18 subjects without a positive family history of PD (control group) and a healthy control group of 15 subjects with a positive family history of sporadic PD (relative group) were investigated. For statistical analysis, the larger area of the two SNs echogenicity (aSNmax) of each individual was selected. Results: A significantly increased aSNmax was found for all subgroups compared with the control group. The group of homozygous carriers of a PINK1 mutation had a significantly increased aSNmax compared with all of the other subgroups, except the group of heterozygous mutation carriers. Conclusions: These findings in carriers of a PINK1 mutation are comparable with those in carriers of Parkin mutations and non-genetic PD. The increased aSNmax in family members without a mutation suggests an additional contributing factor independent of the PINK1 mutation that may also play a role in relatives of patients with sporadic PD.

Gaucher disease ascertained through a Parkinson's center: imaging and clinical characterization.

Among the genes implicated for parkinsonism is glucocerebrosidase (GBA), which causes Gaucher disease (GD). Despite a growing literature that GD may present as parkinsonism, neuroimaging, olfaction, and neuropsychological testing have not been extensively reported. We describe transcranial sonography (TCS), 18F‐fluorodopa (F‐dopa) and fluorodeoxyglucose (FDG) Positron emission tomography, olfaction testing, neuropsychological testing, and clinical features in homozygous and compound heterozygous GBA mutation carriers identified through screening of 250 Ashkenazi Jewish parkinsonian individuals treated at a tertiary care center. We identified two individuals with N370S/R496H compound heterozygous mutations and two with N370S homozygous mutations; one individual died before completing detailed evaluation. TCS (n = 3) demonstrated nigral hyperechogenicity that was greater than controls [median area maximal substantia nigra echogenicity (aSNmax) = 0.28 cm2 vs. 0.14 cm2, P = 0.005], but similar to idiopathic PD (aSNmax = 0.31 cm2). FDG PET (n = 2) demonstrated hypermetabolism of the lentiform nuclei, and F‐fluorodopa PET (n = 2), bilateral reduction in striatal F‐dopa uptake. Olfaction was markedly impaired in the two tested cases, including onset of smell disturbance in adolescence in one. Neuropsychological features (n = 3) were consistent with Parkinsons disease (PD) or diffuse Lewy body disease (DLB). The imaging, neuropsychological and olfactory markers suggest the GD phenotype includes PD with and without features of DLB, marked olfactory loss, nigral hyperechogenicity on TCS, and F‐dopa and FDG PET abnormalities.

Dominantly transmitted focal dystonia in families of patients with musician’s cramp

Musician’s dystonia is generally considered a sporadic disorder. We present three families with the index patient affected by musician’s dystonia, but other forms of upper limb focal task–specific dystonia (FTSD), mainly writer’s cramp, in seven relatives. Our results suggest a genetic contribution to FTSD with phenotypic variability, including musician’s dystonia.

Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia

Objectives: Deep brain stimulation of the internal pallidum (GPi-DBS) is an established therapeutic option in treatment-refractory dystonia, and the identification of factors predicting surgical outcome is needed to optimize patient selection. Methods: In this retrospective multicenter study, GPi-DBS outcome of 8 patients with DYT6, 9 with DYT1, and 38 with isolated dystonia without known monogenic cause (non-DYT) was assessed at early (1–16 months) and late (22–92 months) follow-up using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores. Results: At early follow-up, mean reduction of dystonia severity was greater in patients with DYT1 (BFMDRS score: −60%) and non-DYT dystonia (−52%) than in patients with DYT6 dystonia (−32%; p = 0.046). Accordingly, the rate of responders was considerably lower in the latter group (57% vs >90%; p = 0.017). At late follow-up, however, GPi-DBS resulted in comparable improvement in all 3 groups (DYT6, −42%; DYT1, −44; non-DYT, −61%). Additional DBS of the same or another brain target was performed in 3 of 8 patients with DYT6 dystonia with varying results. Regardless of the genotype, patients with a shorter duration from onset of dystonia to surgery had better control of dystonia postoperatively. Conclusions: Long-term GPi-DBS is effective in patients with DYT6, DYT1, and non-DYT dystonia. However, the effect of DBS appears to be less predictable in patients with DYT6, suggesting that pre-DBS genetic testing and counseling for known dystonia gene mutations may be indicated. GPi-DBS should probably be considered earlier in the disease course. Classification of evidence: This study provides Class IV evidence that long-term GPi-DBS improves dystonia in patients with DYT1, DYT6, and non-DYT dystonia.

ATP13A2 variants in early-onset Parkinson's disease patients and controls.

Four genes responsible for recessively inherited forms of Parkinsons disease (PD) have been identified, including the recently discovered ATP13A2 (PARK9) gene. Our objective was to investigate the role of this gene in a large cohort of PD patients and controls. We extensively screened all 29 exons of the ATP13A2 coding region in 112 patients with early‐onset PD (EOPD; <40 years) of mostly European ethnic origin and of 55 controls. We identified four carriers (3.6%) of novel single heterozygous ATP13A2 missense changes that were absent in controls. Interestingly, the carrier of one of these variants also harbored two mutations in the Parkin gene. None of the carriers had atypical features previously described in patients with two mutated ATP13A2 alleles (Kufor–Rakeb syndrome). Our data suggest that two mutated ATP13A2 alleles are not a common cause of PD. Although heterozygous variants are present in a considerable number of patients, they are—based on this relatively small sample—not significantly more frequent in patients compared to controls.

Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson's disease†

Olfaction is typically impaired in idiopathic Parkinsons disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both deficits are linked. We examined 100 patients with IPD, 27 manifesting mutation carriers (MC), 20 nonmanifesting mutation carriers (NMC), and 110 controls. Participants underwent a standardized neurological examination, the University of Pennsylvania Smell Identification Test (UPSIT), the Farnsworth‐Munsell (FM) color discrimination test, and mutation testing in known PD genes. The monogenic group consisted of 15 Parkin (6MC/9NMC), 17 PINK1 (10MC/7NMC), 8 LRRK2 (4MC/4NMC), 3 SNCA (MC), and 4 ATP13A2 (MC) carriers. Olfaction was most impaired in IPD (UPSIT percentiles 10.1 ± 13.5) compared with all other groups (MC 13.8 ± 11.9, NMC 19.6 ± 13.0, controls 33.8 ± 22.4). Within MC, carriers of two mutations in Parkin and PINK1 showed higher UPSIT percentiles than LRRK2 and SNCA carriers. Color discrimination was reduced in IPD (FM total error score 134.8 ± 92.7). In MC (122.4 ± 142.4), the reduction was most pronounced in LRRK2, NMC (80.0 ± 38.8) were comparable with controls (97.2 ± 61.1). UPSIT and FM scores were correlated in the control (r = −0.305; P = 0.002) and the IPD group (r = −0.303; P = 0.006) but not among mutation carriers. First, we confirmed olfaction and color discrimination to be impaired in IPD and suggest olfaction to be a premotor sign. Second, olfaction differed between carriers with one and two mutations in Parkin/PINK1‐associated PD. Third, olfaction and color discrimination impairment do not necessarily evolve in parallel.