Reduced histone H3K4 trimethylation in oral mucosa of patients with DYT-KMT2B.

BACKGROUND: DYT-KMT2B, also known as DYT28, is a childhood-onset hereditary dystonia caused by KMT2B mutation. The pathogenesis of DYT-KMT2B involves haploinsufficiency of KMT2B, an enzyme that catalyzes specific histone methylation (H3K4me3). Dysmorphic features in patients with DYT-KMT2B suggest that KMT2B dysfunction may extend beyond the neuronal system. Therefore, valuable diagnostic insights may be obtained from readily available tissue samples. OBJECTIVES: To explore the altered H3K4me3 levels in non-neural tissue of DYT-KMT2B patients. METHODS: A database analysis was performed to determine in which parts of the body and in which cells KMT2B is highly expressed. Twelve clinically and genetically diagnosed patients with DYT-KMT2B and 12 control subjects participated in this study. Oral mucosa-derived purified histone proteins were analyzed using Western blotting with anti-H3K4me3 and anti-H4 antibodies. RESULTS: Higher expression of KMT2B was observed in oral keratinocytes and gingival fibroblasts, constituting the oral mucosa. In oral mucosa analyses, DYT-KMT2B cases exhibited markedly reduced H3K4me3 levels compared with the controls. Using a cutoff window of 0.90-0.98, the H3K4me3/H4 expression ratio was able to distinguish patient groups. CONCLUSIONS: Oral mucosa H3K4me3 analysis is currently not sufficient as a diagnostic tool for DYT-KMT2B, but has the advantage for screening test since it is a non-invasive means.

Pallidal deep brain stimulation for patients with myoclonus-dystonia without SGCE mutations.

BACKGROUND: Pallidal deep brain stimulation (GPi-DBS) is effective for treating myoclonus and dystonia caused by SGCE mutations (DYT-SGCE, DYT11). However, it is unknown whether GPi-DBS is effective for the treatment of myoclonus-dystonia which is not associated with the SGCE gene mutations. In this study, we investigated the efficacy of GPi-DBS in treating myoclonus-dystonia in SGCE mutation-negative cases. METHODS: Three patients with myoclonus-dystonia without SGCE mutations who underwent GPi-DBS were evaluated preoperatively and 6 months postoperatively using the Unified Myoclonus Rating Scale (UMRS) and Fahn-Marsden Dystonia Rating Scale (FMDRS) for myoclonus and dystonia, respectively. In two of the three patients, myoclonus was more evident during action. Myoclonus was predominant at rest in the other patient, and he was unaware of his dystonia symptoms. The results were compared with those of the four DYT-SGCE cases. RESULTS: The mean UMRS score in patients with myoclonus-dystonia without SGCE mutations improved from 61.7 to 33.7 pre- and postoperatively, respectively, and the mean FMDRS score improved from 7.2 to 4.5. However, the degree of improvement in myoclonus-dystonia in patients without SGCE mutations was inferior to that in patients with DYT-SGCE (the UMRS score improved by 45% and 69%, respectively). CONCLUSIONS: GPi-DBS is effective for treating myoclonus-dystonia in patients with and without SGCE mutations. GPi-DBS should be considered as a treatment option for myoclonus-dystonia without SGCE mutations.

Focal task-specific hand dystonia related to esports in a rhythm gamer: A case report.

Herein, we report a novel case of focal task-specific dystonia of the upper extremity that occurred in a 27-year-old man who presented with flexion of the left third, fourth, and fifth fingers exclusively during rhythm gameplay. Dystonia during electronic sports should be recognized as a new type of occupational dystonia.

Degeneration of nigrostriatal dopaminergic neurons in the early to intermediate stage of dementia with Lewy bodies and Parkinson's disease.

OBJECTIVE: To investigate differences in nigrostriatal dopaminergic neuron degeneration between dementia with Lewy bodies (DLB) and Parkinson's disease (PD) in the early to intermediate stage of these diseases. METHODS: An integrative neuroimaging analysis was developed using 3-Tesla neuromelanin-sensitive MRI and 123I-FP-CIT dopamine transporter SPECT, and the relationship and laterality of three variables, including neuromelanin-related contrast in the substantia nigra (NRCSN) and locus coeruleus (NRCLC) and the specific binding ratio (SBR) in the striatum, were examined in detail. Patients with DLB and PD and control subjects (n = 29, 52, and 18, respectively) were enrolled. RESULTS: A significantly greater decrease in the SBR in the bilateral hemispheres was observed in DLB than in PD. After adjusting for the interhemispheric asymmetry in neuromelanin-related MRI contrast by using the Z-score, linear regression between the NRCSN and SBR was performed for the most-affected/least-affected sides of the hemispheres as defined by the interhemispheric differences in each variable (SBR, NRCSN, standardized [SBR + NRCSN]). In DLB, the highest, albeit statistically non-significant, correlation was observed in the SBR-based, most-affected side. In PD, the highest correlation was observed in the (SBR + NRCSN)-based, most-affected side, which approximated the value of the clinically-defined, most-affected side. A non-significant correlation was observed only in the (SBR + NRCSN)-based or clinically-defined, least-affected side. CONCLUSION: Loss of the soma and presynaptic terminals may occur independently in DLB with a large decrease in the presynaptic terminals. The close relationship observed between the degeneration of the soma and presynaptic terminals suggested that axon degeneration may dominate in PD.

Dopa-responsive dystonia in spinocerebellar ataxia 6: A case report.

Spinocerebellar ataxia 6 (SCA6) often presents with pure cerebellar ataxia. It is rarely accompanied by extrapyramidal symptoms, such as dystonia and parkinsonism. Here, we describe a case of SCA6 with dopa-responsive dystonia for the first time. A 75-year-old woman was admitted to the hospital with slowly progressive cerebellar ataxia and dystonia in the left upper limb for the past six years. Genetic testing confirmed the diagnosis of SCA6. Her dystonia improved with oral levodopa, and she was able to raise her left hand. Oral levodopa administration may provide early-phase therapeutic benefits for SCA6-associated dystonia.

Dystonic Tremor in Adult-onset DYT-KMT2B.

KMT2B-related dystonia (DYT28, DYT-KMT2B) is an inherited dystonia that generally begins in the lower limbs during childhood and evolves into generalized dystonia. We herein report a case of adult-onset DYT28 with dystonic tremor. A 27-year-old woman initially displayed right upper limb and cervical tremors over the course of 1 year. A neurological examination also revealed cervical and lower limb dystonia. Although the disease generally develops during childhood, we diagnosed the woman with DYT28, as genetic testing revealed a mutation in KMT2B. Adult-onset patients with DYT28 might also show uncommon symptoms as well as DYT-TOR1A (DYT1).

Is Generalized and Segmental Dystonia Accompanied by Impairments in the Dopaminergic System?

Background: The pathogenesis of dystonia is remarkably diverse. Some types of dystonia, such as DYT5 (DYT-GCH1) and tardive dystonia, are related to dysfunction of the dopaminergic system. Furthermore, on pathological examination, cell loss in the substantia nigra (SN) of patients with dystonia has been reported, suggesting that impaired dopamine production may be involved in DYT5 and in other types of dystonia. Objectives: To investigate functional dopaminergic impairments, we compared patients with dystonia and those with Parkinson's disease (PD) with normal controls using neuromelanin-sensitive magnetic resonance imaging (NM-MRI) and dopamine transporter single photon emission computed tomography (DAT SPECT). Methods: A total of 18, 18, and 27 patients with generalized or segmental dystonia, patients with PD, and healthy controls, respectively, were examined using NM-MRI. The mean area corresponding to NM in the SN (NM-SN) was blindly quantified. DAT SPECT was performed on 17 and eight patients with dystonia and PD, respectively. The imaging data of DAT SPECT were harmonized with the Japanese database using striatum phantom calibration. These imaging data were compared between patients with dystonia or PD and controls from the Japanese database in 256 healthy volunteers using the calibrated specific binding ratio (cSBR). The symptoms of dystonia were evaluated using the Fahn-Marsden Dystonia Rating Scale (FMDRS), and the correlation between the results of imaging data and FMDRS was examined. Results: The mean areas corresponding to NM in the SN (NM-SN) were 31 ± 4.2, 28 ± 3.8, and 43 ± 3.8 pixels in patients with dystonia, PD, and in healthy controls, respectively. The mean cSBRs were 5 ± 0.2, 2.8 ± 0.2, 9.2 (predictive) in patients with dystonia, PD, and in healthy controls, respectively. The NM-SN area (r = -0.49, p < 0.05) and the cSBR (r = -0.54, p < 0.05) were inversely correlated with the FMDRS. There was no significant difference between the dystonia and PD groups regarding NM-SN (p = 0.28). In contrast, the cSBR was lower in patients with PD than in those with dystonia (p < 0.5 × 10-6). Conclusions: Impairments of the dopaminergic system may be involved in developing generalized and segmental dystonia. SN abnormalities in patients with dystonia were supposed to be different from degeneration in PD.

Maternal prolactin during late pregnancy is important in generating nurturing behavior in the offspring.

Although maternal nurturing behavior is extremely important for the preservation of a species, our knowledge of the biological underpinnings of these behaviors is insufficient. Here we show that the degree of a mother's nurturing behavior is regulated by factors present during her own fetal development. We found that Cin85-deficient (Cin85-/-) mother mice had reduced pituitary hormone prolactin (PRL) secretion as a result of excessive dopamine signaling in the brain. Their offspring matured normally and produced their own pups; however, nurturing behaviors such as pup retrieval and nursing were strongly inhibited. Surprisingly, when WT embryos were transplanted into the fallopian tubes of Cin85-/- mice, they also exhibited inhibited nurturing behavior as adults. Conversely, when Cin85-/- embryos were transplanted into the fallopian tubes of WT mice, the resultant pups exhibited normal nurturing behaviors as adults. When PRL was administered to Cin85-/- mice during late pregnancy, a higher proportion of the resultant pups exhibited nurturing behaviors as adults. This correlates with our findings that neural circuitry associated with nurturing behaviors was less active in pups born to Cin85-/- mothers, but PRL administration to mothers restored neural activity to normal levels. These results suggest that the prenatal period is extremely important in determining the expression of nurturing behaviors in the subsequent generation, and that maternal PRL is one of the critical factors for expression. In conclusion, perinatally secreted maternal PRL affects the expression of nurturing behaviors not only in a mother, but also in her pups when they have reached adulthood.

CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice.

Despite extensive investigations of Cbl-interacting protein of 85 kDa (CIN85) in receptor trafficking and cytoskeletal dynamics, little is known about its functions in vivo. Here, we report the study of a mouse deficient of the two CIN85 isoforms expressed in the central nervous system, exposing a function of CIN85 in dopamine receptor endocytosis. Mice lacking CIN85 exon 2 (CIN85(Deltaex2)) show hyperactivity phenotypes, characterized by increased physical activity and exploratory behaviour. Interestingly, CIN85(Deltaex2) animals display abnormally high levels of dopamine and D2 dopamine receptors (D2DRs) in the striatum, an important centre for the coordination of animal behaviour. Importantly, CIN85 localizes to the post-synaptic compartment of striatal neurons in which it co-clusters with D2DRs. Moreover, it interacts with endocytic regulators such as dynamin and endophilins in the striatum. Absence of striatal CIN85 causes insufficient complex formation of endophilins with D2DRs in the striatum and ultimately decreased D2DR endocytosis in striatal neurons in response to dopamine stimulation. These findings indicate an important function of CIN85 in the regulation of dopamine receptor functions and provide a molecular explanation for the hyperactive behaviour of CIN85(Deltaex2) mice.