Correlation of active contact location with weight gain after subthalamic nucleus deep brain stimulation: a case series.

BACKGROUND: Weight gain (WG) is a frequently reported side effect of subthalamic deep brain stimulation; however, the underlying mechanisms remain unclear. The active contact locations influence the clinical outcomes of subthalamic deep brain stimulation, but it is unclear whether WG is directly associated with the active contact locations. We aimed to determine whether WG is associated with the subthalamic deep brain stimulation active contact locations. METHODS: We enrolled 14 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation between 2013 and 2019. Bodyweight and body mass index were measured before and one year following the surgery. The Lead-DBS Matlab toolbox was used to determine the active contact locations based on magnetic resonance imaging and computed tomography. We also created sweet spot maps for WG using voxel-wise statistics, based on volume of tissue activation and the WG of each patient. Fluorodeoxyglucose-positron emission tomography data were also acquired before and one year following surgery, and statistical parametric mapping was used to evaluate changes in brain metabolism. We examined which brain regions' metabolism fluctuation significantly correlated with increased body mass index scores and positron emission tomography data. RESULTS: One year after surgery, the body mass index increase was 2.03 kg/m2. The sweet spots for WG were bilateral, mainly located dorsally outside of the subthalamic nucleus (STN). Furthermore, WG was correlated with increased metabolism in the left limbic and associative regions, including the middle temporal gyrus, inferior frontal gyrus, and orbital gyrus. CONCLUSIONS: Although the mechanisms underlying WG following subthalamic deep brain stimulation are possibly multifactorial, our findings suggest that dorsal stimulation outside of STN may lead to WG. The metabolic changes in limbic and associative cortical regions after STN-DBS may also be one of the mechanisms underlying WG. Further studies are warranted to confirm whether dorsal stimulation outside of STN changes the activities of these cortical regions.

Investigating the role of genetic counseling in neuromuscular disease considering life events.

Genetic diagnoses are becoming a routine in the medical practice of neuromuscular diseases. Many diagnoses, however, can have an influence on relatives and family members and thus must be handled carefully by genetic counseling (GC). Here, we aimed to assess the purpose of undergoing GC to verify the utility of collaborations between clinical and genetic divisions. We investigated consecutive GC cases of neuromuscular disease and examined the role of GC. Our study included 102 cases who underwent GC in our hospital from July 2005 to March 2018: 86.3% were women and 45.1% were in their 30's. Disease explanation was the most common reason for attending GC (29.4%), followed by prenatal diagnosis (25.5%), pre-symptomatic diagnosis (17.6%), and carrier diagnosis (14.7%). Clients typically visited the hospital for GC when some kind of life event occurred, such as marriage, had a desire to bear a child, or a change in the condition of the proband. Clinicians should be conscious of such life events from the perspective of both the client and their relatives, and guide the GC at an appropriate time. Overall, the degree of recognition of genetic risk by clients differed; thus, it is important for GC to determine the status of each unique situation and respond individually.

The Responsiveness of Triaxial Accelerometer Measurement of Gait Ataxia Is Higher than That of the Scale for the Assessment and Rating of Ataxia in the Early Stages of Spinocerebellar Degeneration.

We reported previously that the average medial-lateral gait amplitude while walking on a straight path determined using triaxial accelerometers fixed on the middle of the upper back may be a quantitative and concise indicator for the severity of cerebellar ataxia. Considering that gait ataxia is a typical initial symptom in a variety of spinocerebellar degeneration (SCD), we aimed to develop quantitative biomarkers for cerebellar ataxia as metric variables. We used triaxial accelerometers to analyze gait parameters in 14 patients with SCD at 3 points over 3 years (at baseline, 1.5 years and 3 years). Analysis of covariance (ANCOVA) models adjusted for the baseline scores were used to estimate sample sizes. The mean medial-lateral amplitude (ML) gained by a triaxial accelerometer fixed on upper back could detect the each 1.5-year change. In the 14 patients, the mean ML(m) was 0.032 ± 0.007(SD) at entry, 0.037 ± 0.008 after 1.5-year follow, and 0.042 ± 0.020 after 3-year follow. In contrast, SARA gait scores were 2.9, 2.9, and 3.0, respectively. The responsiveness of the quantitative evaluation of gait ataxia by triaxial accelerometers is higher than that of the SARA within a 1.5-year follow-up period. Gait analysis by triaxial accelerometers will be complementary to the evaluation of scales like SARA in the assessment of clinical severity of SCD patients in early stage.

YOD1 attenuates neurogenic proteotoxicity through its deubiquitinating activity.

Ubiquitination, a fundamental post-translational modification of intracellular proteins, is enzymatically reversed by deubiquitinase enzymes (deubiquitinases). >90 deubiquitinases have been identified. One of these enzymes, YOD1, possesses deubiquitinase activity and is similar to ovarian tumor domain-containing protein 1, which is associated with regulation of the endoplasmic reticulum (ER)-associated degradation pathway. Indeed, YOD1 is reported to be involved in the ER stress response induced by mislocalization of unfolded proteins in mammalian cells. However, it has remained unclear whether YOD1 is associated with pathophysiological conditions such as mitochondrial damage, impaired proteostasis, and neurodegeneration. We demonstrated that YOD1 possesses deubiquitinating activity and exhibits preference for K48- and K63-linked ubiquitin. Furthermore, YOD1 expression levels increased as a result of various stress conditions. We demonstrated that the neurogenic proteins that cause Huntington disease and Parkinson's disease induced upregulation of YOD1 level. We observed that YOD1 reduced disease cytotoxicity through efficient degradation of mutant proteins, whereas this activity was abolished by catalytically inactive YOD1. Additionally, YOD1 localized to Lewy bodies in Parkinson's disease patients. Collectively, these data suggest that the deubiquitinase YOD1 contributes to pathogenesis of neurodegenerative disease by decreasing ubiquitination of abnormal proteins and their subsequent degradation.

Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy.

Adult-onset inherited myopathies with similar pathological features, including hereditary inclusion body myopathy (hIBM) and limb-girdle muscular dystrophy (LGMD), are a genetically heterogeneous group of muscle diseases. It is unclear whether these inherited myopathies initiated by mutations in distinct classes of genes are etiologically related. Here, we exploit a genetic model system to establish a mechanistic link between diseases caused by mutations in two distinct genes, hnRNPA2B1 and DNAJB6. Hrb98DE and mrj are the Drosophila melanogaster homologs of human hnRNPA2B1 and DNAJB6, respectively. We introduced disease-homologous mutations to Hrb98DE, thus capturing mutation-dependent phenotypes in a genetically tractable model system. Ectopic expression of the disease-associated mutant form of hnRNPA2B1 or Hrb98DE in fly muscle resulted in progressive, age-dependent cytoplasmic inclusion pathology, as observed in humans with hnRNPA2B1-related myopathy. Cytoplasmic inclusions consisted of hnRNPA2B1 or Hrb98DE protein in association with the stress granule marker ROX8 and additional endogenous RNA-binding proteins (RBPs), suggesting that these pathological inclusions are related to stress granules. Notably, TDP-43 was also recruited to these cytoplasmic inclusions. Remarkably, overexpression of MRJ rescued this phenotype and suppressed the formation of cytoplasmic inclusions, whereas reduction of endogenous MRJ by a classical loss of function allele enhanced it. Moreover, wild-type, but not disease-associated, mutant forms of MRJ interacted with RBPs after heat shock and prevented their accumulation in aggregates. These results indicate both genetic and physical interactions between disease-linked RBPs and DNAJB6/mrj, suggesting etiologic overlap between the pathogenesis of hIBM and LGMD initiated by mutations in hnRNPA2B1 and DNAJB6.

SCA42 mutation analysis in a case series of Japanese patients with spinocerebellar ataxia.

Spinocerebellar ataxia (SCA) is a group of dominantly inherited heterogeneous disorders in which 43 subtypes have been identified to date. Recently, Japanese and French families with SCA type 42 (SCA42) were found to have a missense mutation (c.5144G>A; R1715H) in CACNA1G. We performed genetic analysis of 84 unrelated families to find the prevalence of SCA42 in Japan. Two families were found to have the previously reported missense mutation. Clinical presentations of the affected members of these families were similar to those of the previously reported French and Japanese families. Our study demonstrates that SCA42 exists in small numbers in Japan, and further supports the idea that SCA42 is a slowly progressive, pure cerebellar ataxia.

[Utility of Intraoperative Catheter Myelography during Intrathecal Baclofen Pump Implantation:Report of 2 Cases].

We report two patients in whom the intrathecal baclofen(ITB)catheter was located in the subdural space, although we had confirmed good outflow of spinal fluid from the spinal catheter. Patient 1 was a woman in her 30s with spastic quadriplegia due to subarachnoid hemorrhage. An ITB pump was implanted, and a good outflow of spinal fluid from the spinal catheter was observed during the surgery. Postoperatively, her spasticity did not improve. Catheter myelography revealed that the spinal catheter was located in the subdural space. Using intraoperative catheter myelography, we corrected the position of the catheter. Patient 2 was a man in his 20s diagnosed with adrenoleukodystrophy. An ITB therapy was performed to improve his spastic gait. Intraoperative catheter myelography showed that the spinal catheter was located in the subdural space, although there was good outflow of spinal fluid from the catheter. Our experience suggests that the outflow of spinal fluid alone should not be used to determine the location of the spinal catheter. Intraoperative catheter myelography is useful for the correct placement of the spinal catheter in the subarachnoid space.

Comparison of Different Symptom Assessment Scales for Multiple System Atrophy.

To identify the most sensitive scale for use in clinical trials on multiple system atrophy (MSA), a short and sensitive scale is needed for MSA clinical trials. Potential candidates are the Unified MSA Rating Scale (UMSARS), Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), MSA Health-Related Quality of Life scale (MSA-QoL), and Scales for Outcomes in Parkinson's Disease-Autonomic questionnaire (SCOPA-AUT). We enrolled patients with MSA from eight hospitals in Hokkaido, Japan. Board-certified neurologists assessed each patient at 6-month intervals and scored them on the UMSARS, SARA, BBS, MSA-QoL, and SCOPA-AUT. Score changes were evaluated using the standardized response mean (SRM). The correlation between disease duration and each score was examined. The first evaluation was conducted on 85 patients (60 patients with MSA cerebellar ataxia dominant subtype [MSA-C] and 25 patients with MSA Parkinsonism-dominant subtype [MSA-P]). Sixty-nine patients were examined after 6 months and 63 patients after 12 months. The UMSARS Part 4 had the largest SRM after 6 months and the SARA after 12 months. SRMs for MSA-P, the shorter duration group, and the early-onset group were larger than were those for MSA-C, the longer duration group, and the late-onset group. SRMs for items regarding skilled hand activities, walking, and standing were relatively large. Our study indicates that the UMSARS (parts 2 and 4), SARA, and BBS are sensitive scales for evaluating MSA progression over 12 months. Items with large SRMs effectively evaluated short-term changes.

G protein-coupled receptor 26 immunoreactivity in intranuclear inclusions associated with polyglutamine and intranuclear inclusion body diseases.

G protein-coupled receptor 26 (GPR26) is one of the G-protein-coupled receptors (GPCRs), which comprise the largest family of membrane proteins and mediate most of the physiological responses to hormones, neurotransmitters and environmental stimulants. Although GPCRs are considered to play an important role in the pathophysiology of neurodegenerative disorders, it is uncertain whether GPR26 is involved in the pathogenesis of polyglutamine and intranuclear inclusion body diseases. We immunohistochemically examined the brain tissues of patients with four polyglutamine diseases (Huntington's disease, dentatorubral-pallidoluysian atrophy, and spinocerebellar ataxia types 1 and 3) and intranuclear inclusion body disease, and normal control subjects. In controls, anti-GPR26 antibody immunolabeled the neuronal cytoplasm in a diffuse granular pattern. Neuronal nuclear inclusions in polyglutamine diseases were immunopositive for GPR26. In intranuclear inclusion body disease, GPR26-positive nuclear inclusions were found in both neurons and glial cells. Marinesco bodies in aged control subjects were also positive for GPR26. Double immunofluorescence analysis revealed co-localization of GPR26 with polyglutamine or ubiquitin in these nuclear inclusions. These findings suggest that GPR26 may have a common role in the formation or degradation of intranuclear inclusions in several neurodegenerative diseases.

Epidemiology of Multiple System Atrophy in Hokkaido, the Northernmost Island of Japan.

Multiple system atrophy (MSA) is an intractable neurodegenerative disorder that is characterized by various combinations of autonomic failure, cerebellar ataxia, and parkinsonism. We conducted an epidemiological study of MSA using the combined data of a national registry system and a postal survey in Hokkaido, Japan. A postal survey was conducted in 2013 based on national registry data from 2006 to 2011. This survey contained the current status of each patient with MSA that had been collected from attending physicians and recorded into a national registry. Survey items included date, outcomes, primary symptoms, and activities of daily living at the last medical examination. Confirmation data of the diagnosis by a board-certified neurologist was also collected. Based on the national registry data, 1,092 patients with MSA were selected as our target population. The response rate of the postal survey was 81% (885/1,092). After excluding inappropriate responses, 839 patients with MSA were analyzed. Forty-nine percent of the patients were male, and the mean onset age was 62.1 ± 10.4 years. A Kaplan-Meier survival curve revealed that patients with onset symptoms of cerebellar ataxia had a better prognosis than those with onset of parkinsonism or autonomic failure (p < 0.01). Additionally, we found that a higher onset age was associated with poor prognosis. We found that patients with cerebellar ataxia at onset had a better survival prognosis than those with parkinsonism or autonomic failure at onset and that patients with an older age at onset had a worse survival prognosis.

Localization of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in Lewy body disease and multiple system atrophy.

Nuclear receptor subfamily 4, group A, member 3 (NR4A3), also known as neuron-derived orphan receptor-1, is a nuclear receptor which plays key roles in cell cycle, neuronal differentiation, apoptosis and metabolism. These processes may be involved in the pathogenesis of certain neurodegenerative diseases. Previous studies have shown that there are high levels of NR4A3 mRNA in the CNS. Moreover, NR4A2, a transcription factor with homology to NR4A3, has been reported to contribute to the pathogenesis of Parkinson's disease. However, it is uncertain whether NR4A3 is also involved in diseases such as dementia with Lewy bodies, multiple system atrophy, and other neurodegenerative disorders such as tauopathies, TDP-43 proteinopathies and polyglutamine diseases. In the present study we used immunohistochemistry to examine the brain and spinal cord from patients with various neurodegenerative diseases and normal control subjects using two polyclonal anti-NR4A3 antibodies. In controls, the cytoplasm of neurons and glial cells was faintly immunostained with anti-NR4A3 antibodies. In tissues from patients with neurodegenerative diseases, immunoreactivity for NR4A3 was observed in cortical and brainstem-type Lewy bodies in Parkinson's disease and in dementia with Lewy bodies, as well as in neuronal and glial cytoplasmic inclusions in multiple system atrophy. A double-labeled immunofluorescence study showed co-localization of NR4A3 and phosphorylated α-synuclein in these inclusions. Neuronal and glial inclusions in other neurodegenerative disorders were NR4A3 negative. These findings suggest that accumulation of NR4A3 is specific to α-synucleinopathy.

Isopentenyl diphosphate isomerase, a cholesterol synthesizing enzyme, is localized in Lewy bodies.

Isopentenyl diphosphate isomerase (IDI) is a cytoplasmic enzyme involved in the biosynthesis of isoprenoids including cholesterols. IDI has two isoforms in humans: IDI1 and IDI2. Since lipids are known to be a component of Lewy bodies (LBs), we investigated the immunohistochemical localization of IDI1 and IDI2 in the brain of patients with LB disease and multiple system atrophy (MSA) and normal control subjects. In normal controls, the cytoplasm of neurons was weakly immunostained with anti-IDI1 and anti-IDI2 antibodies throughout the nervous system. In LB disease, brainstem-type LBs were strongly positive for IDI1 and IDI2, and cortical LBs were unstained or barely immunolabeled. Double immunofluorescence staining revealed co-localization of phosphorylated α-synuclein with IDI1 or IDI2. Glial cytoplasmic inclusions in MSA were unstained. Previous studies have shown that levels of cholesterol metabolites are increased in the cerebral cortex of patients with LB disease, and that these metabolites accelerate α-synuclein aggregation. The present findings suggest that IDI1 and IDI2 may be associated with the production of cholesterol metabolites in neurons, leading to α-synuclein aggregation during the process of LB formation.

Accumulation of the sigma-1 receptor is common to neuronal nuclear inclusions in various neurodegenerative diseases.

The sigma-1 receptor (SIGMAR1) is now known to be one of the endoplasmic reticulum (ER) chaperones, which participate in the degradation of misfolded proteins in cells via the ER-related degradation machinery linked to the ubiquitin-proteasome pathway. Mutations of the SIGMAR1 gene are implicated in the pathogenesis of familial frontotemporal lobar degeneration and motor neuron disease. Involvement of ER dysfunction in the formation of inclusion bodies in various neurodegenerative diseases has also become evident. We performed immunohistochemical staining to clarify the localization of SIGMAR1 in the brains of patients with neurodegenerative disorders, including trans-activation response DNA protein 43 (TDP-43) proteinopathy, tauopathy, α-synucleinopathy, polyglutamine disease and intranuclear inclusion body disease (INIBD). Double-immunocytofluorescence and Western blot analyses of cultured cells were also performed to investigate the role of SIGMAR1 using a specific exportin 1 inhibitor, leptomycin B and an ER stress inducer, thapsigargin. SIGMAR1 was consistently shown to be co-localized with neuronal nuclear inclusions in TDP-43 proteinopathy, five polyglutamine diseases and INIBD, as well as in intranuclear Marinesco bodies in aged normal controls. Cytoplasmic inclusions in neurons and glial cells were unreactive for SIGMAR1. In cultured cells, immunocytofluorescent study showed that leptomycin B and thapsigargin were shown to sequester SIGMAR1 within the nucleus, acting together with p62. This finding was also supported by immunoblot analysis. These results indicate that SIGMAR1 might shuttle between the nucleus and the cytoplasm. Neurodegenerative diseases characterized by neuronal nuclear inclusions might utilize the ER-related degradation machinery as a common pathway for the degradation of aberrant proteins.

ALS-associated protein FIG4 is localized in Pick and Lewy bodies, and also neuronal nuclear inclusions, in polyglutamine and intranuclear inclusion body diseases.

FIG4 is a phosphatase that regulates intracellular vesicle trafficking along the endosomal-lysosomal pathway. Mutations of FIG4 lead to the development of Charcot-Marie-Tooth disease type 4J and amyotrophic lateral sclerosis (ALS). Moreover, ALS-associated proteins (transactivation response DNA protein 43 (TDP-43), fused in sarcoma (FUS), optineurin, ubiquilin-2, charged mutivesicular body protein 2b (CHMP2B) and valosin-containing protein) are involved in inclusion body formation in several neurodegenerative diseases. Using immunohistochemistry, we examined the brains and spinal cords of patients with various neurodegenerative diseases, including sporadic TDP-43 proteinopathy (ALS and frontotemporal lobar degeneration). TDP-43 proteinopathy demonstrated no FIG4 immunoreactivity in neuronal inclusions. However, FIG4 immunoreactivity was present in Pick bodies in Pick's disease, Lewy bodies in Parkinson's disease and dementia with Lewy bodies, neuronal nuclear inclusions in polyglutamine and intranuclear inclusion body diseases, and Marinesco and Hirano bodies in aged control subjects. These findings suggest that FIG4 is not incorporated in TDP-43 inclusions and that it may have a common role in the formation or degradation of neuronal cytoplasmic and nuclear inclusions in several neurodegenerative diseases.

Suspected Postpartum Depression Revealed to be CSF1R-Related Leukoencephalopathy: A Case Report.

Introduction: This is a case of a 32-year-old woman who developed postpartum depression (PPD). She became anxious and depressive about caring for her child, and the Edinburgh Postnatal Depression Scale (EPDS) test showed a score of 9 at 2 weeks after delivery, and at 7 months postpartum, she presented with major melancholic depression followed by mild cognitive decline without any neurological symptoms except cluttering speech. Case Presentation: Cerebral magnetic resonance imaging showed confluent fluid-attenuated inversion recovery hyperintensities in the periventricular and frontal deep white matter, with multiple spotty calcifications in the frontal white matter by cerebral CT. Genetic testing revealed a mutation in the colony-stimulating factor 1 receptor (CSF1R). Conclusion: This case report is consistent with evidence that PPD may have organic causes in some cases, including CSF1R mutations. Atypical findings such as mild cognitive decline combined with PPD in psychiatric interview may justify brain imaging to avoid misdiagnosis, since CSF1R-related leukoencephalopathy is probably an under-recognized disease in medical psychiatry. Further investigations are needed to clarify a pathophysiological correlation between CSF1R signaling abnormality and PPD as well as major depression.

Dynamic molecular network analysis of iPSC-Purkinje cells differentiation delineates roles of ISG15 in SCA1 at the earliest stage.

Better understanding of the earliest molecular pathologies of all neurodegenerative diseases is expected to improve human therapeutics. We investigated the earliest molecular pathology of spinocerebellar ataxia type 1 (SCA1), a rare familial neurodegenerative disease that primarily induces death and dysfunction of cerebellum Purkinje cells. Extensive prior studies have identified involvement of transcription or RNA-splicing factors in the molecular pathology of SCA1. However, the regulatory network of SCA1 pathology, especially central regulators of the earliest developmental stages and inflammatory events, remains incompletely understood. Here, we elucidated the earliest developmental pathology of SCA1 using originally developed dynamic molecular network analyses of sequentially acquired RNA-seq data during differentiation of SCA1 patient-derived induced pluripotent stem cells (iPSCs) to Purkinje cells. Dynamic molecular network analysis implicated histone genes and cytokine-relevant immune response genes at the earliest stages of development, and revealed relevance of ISG15 to the following degradation and accumulation of mutant ataxin-1 in Purkinje cells of SCA1 model mice and human patients.

The Movement Disorder Society Criteria: Its Clinical Usefulness in Multiple System Atrophy.

Objective In 2022, Wenning et al. proposed the Movement Disorder Society Criteria (MDS criteria) for the Diagnosis of Multiple System Atrophy (MSA). These criteria were expected to provide useful alternatives to the second consensus statement. We examined trends in these diagnostic criteria. Methods We used patient data registered with the Hokkaido Rare Disease Consortium for Multiple System Atrophy, which has been recruiting patients with MSA through medical facilities in Hokkaido since November 2014. Patients were evaluated according to the MDS criteria based on neurological examinations and imaging findings at three separate times: the first evaluation, the time of enrollment (diagnosis), and the most recent evaluation (final evaluation). Results The MDS criteria were examined in 68 of 244 patients enrolled between November 2014 and July 2022. At the initial evaluation, the classifications were as follows: clinically established (n=27; 39.7%); clinically probable (n=13; 19.1%); possible prodromal (n=12; 17.6%); and negative [did not meet criteria (n=16; 23.5%)]. At the time of diagnosis, the classifications were as follows: clinically established (n=45; 66.2%); clinically probable (n=12; 17.6%); possible prodromal (n=4; 5.9%); and negative (n=7; 10.3%). At the final evaluation, the classifications were as follows: clinically established (n=52; 76.5%); clinically probable (n=9; 13.2%); possible prodromal (n=2; 2.9%); and negative (n=5; 7.4%). Conclusion We were able to clarify the changes in the criteria values and transition of patients due to the clarification of imaging and supportive findings in the MDS criteria.

TRIM67 protein negatively regulates Ras activity through degradation of 80K-H and induces neuritogenesis.

Tripartite motif (TRIM)-containing proteins, which are defined by the presence of a common domain structure composed of a RING finger, one or two B-box motifs and a coiled-coil motif, are involved in many biological processes including innate immunity, viral infection, carcinogenesis, and development. Here we show that TRIM67, which has a TRIM motif, an FN3 domain and a SPRY domain, is highly expressed in the cerebellum and that TRIM67 interacts with PRG-1 and 80K-H, which is involved in the Ras-mediated signaling pathway. Ectopic expression of TRIM67 results in degradation of endogenous 80K-H and attenuation of cell proliferation and enhances neuritogenesis in the neuroblastoma cell line N1E-115. Furthermore, morphological and biological changes caused by knockdown of 80K-H are similar to those observed by overexpression of TRIM67. These findings suggest that TRIM67 regulates Ras signaling via degradation of 80K-H, leading to neural differentiation including neuritogenesis.

Novel GNE compound heterozygous mutations in a GNE myopathy patient.

INTRODUCTION: Molecular studies have revealed that some patients with myopathies with rimmed vacuoles have pathogenic mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) and Z-band alternatively spliced PDZ motif-containing protein (ZASP) genes. METHODS: We investigated a patient with distal myopathy with rimmed vacuoles by muscle biopsy and sequenced 6 candidate genes. RESULTS: The patient carried GNE compound heterozygous missense mutations (p.V421A and p.N635K) and a ZASP variant (p.D673N). This patient also presented with distal weakness sparing the quadriceps muscles and had atypical results for Z-band-associated protein immunostaining. This finding indicates that the GNE mutations are pathogenic, and the diagnosis is compatible with GNE myopathy. CONCLUSIONS: By combining pathological studies and candidate gene screening, we identified a patient with GNE myopathy due to novel GNE compound heterozygous mutations.

3D neuromelanin-sensitive magnetic resonance imaging with semi-automated volume measurement of the substantia nigra pars compacta for diagnosis of Parkinson's disease.

INTRODUCTION: Neuromelanin-sensitive MRI has been reported to be used in the diagnosis of Parkinson's disease (PD), which results from loss of dopamine-producing cells in the substantia nigra pars compacta (SNc). In this study, we aimed to apply a 3D turbo field echo (TFE) sequence for neuromelanin-sensitive MRI and to evaluate the diagnostic performance of semi-automated method for measurement of SNc volume in patients with PD. METHODS: We examined 18 PD patients and 27 healthy volunteers (control subjects). A 3D TFE technique with off-resonance magnetization transfer pulse was used for neuromelanin-sensitive MRI on a 3T scanner. The SNc volume was semi-automatically measured using a region-growing technique at various thresholds (ranging from 1.66 to 2.48), with the signals measured relative to that for the superior cerebellar peduncle. Receiver operating characteristic (ROC) analysis was performed at all thresholds. Intra-rater reproducibility was evaluated by intraclass correlation coefficient (ICC). RESULTS: The average SNc volume in the PD group was significantly smaller than that in the control group at all the thresholds (P < 0.01, student t test). At higher thresholds (>2.0), the area under the curve of ROC (Az) increased (0.88). In addition, we observed balanced sensitivity and specificity (0.83 and 0.85, respectively). At lower thresholds, sensitivity tended to increase but specificity reduced in comparison with that at higher thresholds. ICC was larger than 0.9 when the threshold was over 1.86. CONCLUSIONS: Our method can distinguish the PD group from the control group with high sensitivity and specificity, especially for early stage of PD.