The effect of rasagiline on swallowing function in Parkinson's disease.

Dysphagia, a potentially fatal symptom of Parkinson's disease, is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with Parkinson's disease and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation during swallowing. Rasagiline is a monoamine oxidase B (MAOB) inhibitor that facilitates continuous dopaminergic stimulation. We hypothesized that MAOB inhibition by rasagiline would be effective in improving swallowing function in patients with early- and mid-to late-stage Parkinson's disease. To this end, we performed an analytical observational study to determine the effects of rasagiline (1 mg/day) on swallowing function using videofluoroscopic swallowing study. This open-label, evaluator-blinded study enrolled 32 patients with Parkinson's disease, among whom 19 were drug-naïve and 13 were receiving add-on therapy. Our results showed that rasagiline significantly improved all swallowing measures during the oral and pharyngeal phases, including oral transit time and pharyngeal transit time, in all enrolled patients. Similar results were found in drug-naïve and mid-to late-stage patients, with no intergroup differences. In conclusion, drugs capable of continuous dopaminergic stimulation may effectively improve swallowing function in patients with Parkinson's disease, with similar effects in early- and mid-to late-stage Parkinson's disease. This study has been the first to show that rasagiline significantly improves swallowing function in mid-to late-stage patients receiving add-on therapy.

Memantine administration prevented chorea movement in Huntington's disease: a case report.

BACKGROUND: Huntington's disease is an autosomal dominant inherited disorder characterized by personality changes (such as irritability and restlessness) and psychotic symptoms (such as hallucinations and delusions). When the personality changes become noticeable, involuntary movements (chorea) also develop. The disease is caused by the CAG repeat expansion in the coding region of the HTT gene, and the diagnosis is based on the presence of this expansion. However, there is currently no effective treatment for the progression of Huntington's disease and its involuntary motor symptoms. Herein, we present a case in which memantine was effective in treating the chorea movements of Huntington's disease. CASE PRESENTATION: A 75-year-old Japanese woman presented to the hospital with involuntary movements of Huntington's disease that began when she was 73 years old. In a cerebral blood flow test (N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography), decreased blood flow was observed in the precuneus (anterior wedge) and posterior cingulate gyrus. Usually, such areas of decreased blood flow are observed in patients with Alzheimer's-type dementia. So, we administered memantine for Alzheimer's-type dementia, and this treatment suppressed the involuntary movements of Huntington's disease, and the symptoms progressed slowly for 7 years after the onset of senility. In contrast, her brother died of complications of pneumonia during the course of Huntington's disease. CONCLUSIONS: We recorded changes in parameters such as the results of the N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography and gait videos over 7 years. Treatment with memantine prevented the chorea movement and the progression of Huntington's disease. We believe this record will provide clinicians with valuable information in diagnosing and treating Huntington's disease.

CANVAS-related RFC1 mutations in patients with immune-mediated neuropathy.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy.

The effects of safinamide on dysphagia in Parkinson's disease.

Dysphagia is a potentially fatal symptom of Parkinson's disease (PD) and is characterized by frequent silent aspiration, a risk factor for aspiration pneumonia. The transdermal dopamine agonist rotigotine alleviates dysphagia in patients with PD and is more effective than oral levodopa, suggesting the importance of continuous dopaminergic stimulation (CDS) in swallowing. Safinamide is a monoamine oxidase B (MAOB) inhibitor that facilitates CDS. In this retrospective open-label evaluator-blinded research, swallowing functions in nine patients with PD were examined using a video fluoroscopic swallowing study (VFSS) before and after treatment with 50 mg of oral safinamide. The VFSS results showed that safinamide significantly improved some swallowing measures during oral and pharyngeal phases, including oral transit time and pharyngeal transit time, without worsening of any measures. Notably, improvements in lip closure, an oral phase component, seemed to be most attributable to improvements in oral phase scores. In conclusion, a medicine for CDS may effectively improve swallowing functions in patients with PD. This is the first study to show that the MAOB inhibitor safinamide partly but significantly improves swallowing function in patients with PD.

Identification of a novel mutation and genotype-phenotype relationship in MEGF10 myopathy.

Mutations in MEGF10 are associated with early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Recently, a mild variant phenotype of EMARDD has been reported in patients with multiple minicores in the myofibers. However, some reported patients had no clear cores. We present a patient who had progressive weakness since his 30 s and then developed severe respiratory failure at the age of 66 years and found that he had a novel mutation, p.G739R, in MEGF10. He had no clear core in the biopsied muscle. We summarize the clinical and genetic characteristics of the current and reported patients with MEGF10 and statistically evaluate the genotype-phenotype correlation. Results show that patients with missense mutations in at least one allele had significantly later onset than those with biallelic truncation mutations.

Hemiplegic migraine type 2 with new mutation of the ATP1A2 gene in Japanese cases.

We analyzed the clinical symptoms of hemiplegic migraine (HM) and their relevance in four Japanese patients considered to have ATP1A2 mutations as a cause. Sequencing of ATP1A2 was performed using the Sanger method in 43 blood samples from clinically suspected patients with familial HM. Subsequently, algorithm analysis, allele frequency determination, and three-dimensional structure analysis of the recognized variants were performed, and the recognized variants were evaluated. We found four heterozygous missense mutations in ATP1A2 (Case 1: p.R51C; Case 2: p.R65L; Case 3: p.A269P; Case 4: p.D999H), three of which had not been reported to date. These four mutations may also affect the structure of the protein products, as assessed using a three-dimensional structural analysis. In all four cases, the clinical symptoms included visual, sensory, motor, and verbal symptoms and the frequency and duration of headache attacks varied. Additionally, oral administration of a combination of lomerizine hydrochloride and topiramate had a partial effect in three cases. We report four missense mutations in ATP1A2. This report will be useful for the future analysis of mutations and clinical types in Asians, as well as Westerners, with migraine.

COQ2 V393A confers high risk susceptibility for multiple system atrophy in East Asian population.

Multiple system atrophy (MSA) is a rare, late-onset, and devastating neurodegenerative disease characterized by autonomic failure, alongside with various combination of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Since we first identified biallelic mutations in the COQ2 gene in two multiplex MSA families and further reported that heterozygous COQ2 V393A variant confers a susceptibility to sporadic MSA, the results of nearly a decade of investigating this association globally were quite remarkable. COQ2 V393A was virtually absent in the American and European populations but was shown to have varying associations with sporadic MSA in the East Asian populations. In our attempt to clarify the latter and provide a coherent regional conclusion, we conducted two independent case-control series which showed clear association of the V393A variant with sporadic MSA in the Japanese population. We then pooled the results with other studies from the East Asian population and conducted a meta-analysis which broadened and established the association regionally (pooled OR 2.12, 95% CI: 1.35-3.31, PI: 0.63-7.15, p = 0.0047). The subgroup analysis identified a strong association of V393A with MSA-C (pooled OR 2.57, 95% CI: 1.98-3.35; p = 2.56 × 10-12) but not with MSA-P (pooled OR 1.41, 95% CI: 0.88-2.26; p = 0.16). Our results highlighted the importance of investigating region-specific and pan-regional genetic variants that may potentially underlie the pathomechanisms of neurodegenerative diseases. COQ2 V393A variant remains a susceptibility variant rather than causative for MSA particularly, MSA-C subtype, in the East Asian population.

Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan.

BACKGROUND: We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan. METHODS: DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32. RESULTS: We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy. CONCLUSIONS: Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.

Neutral Lipid Storage Disease Associated with the PNPLA2 Gene: Case Report and Literature Review.

Mutations in the PNPLA2 gene cause neutral lipid storage disease with myopathy (NLSDM) or triglyceride deposit cardiomyovasculopathy. We report a detailed case study of a 53-year-old man with NLSDM. The PNPLA2 gene was analyzed according to the reported method. We summarized the clinical, laboratory, and genetic information of 56 patients, including our patient and 55 other reported patients with homozygous or compound heterozygous mutations in the PNPLA2 gene. We found a novel homozygous mutation (c.194delC) in the PNPLA2 gene that resulted in frameshift. The patient suffered from normal-tension glaucoma and pulmonary cysts, symptoms that are relatively common in the elderly but were not previously reported for this disease. Our summary confirmed that Jordan's anomaly, polymorphonuclear leukocytes with lipid accumulation, was the most consistent finding of this disease. Because this disease is potentially treatable, our results may help rapid and correct diagnosis.

Bardet-Biedl syndrome and related disorders in Japan.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by obesity, mental impairment, rod-cone dystrophy, polydactyly, male hypogonadism, and renal abnormalities. This disorder is caused by mutations in BBS1-21. Alström syndrome (AS), caused solely by mutations in ALMS1, is another genetic obesity syndrome clinically similar to BBS. We previously conducted the first nationwide survey of BBS in Japan and found four patients with genetically definite BBS. In this study, exome analyses were performed on new patients whose symptoms fulfilled the diagnostic criteria for BBS. We identified one reported heterozygous mutation in BBS1 (p.R429*) in one patient, two novel mutations (p.L493R and p.H719Y) in BBS20 in a second patient, and one novel mutation (p.Q920*) and one reported mutation (p.R2928*) in ALMS1 in a third patient, who was subsequently diagnosed with AS. The first patient with BBS was previously considered to have digenic heterozygous mutations in BBS1 and BBS4. RT-PCR and long-range genomic PCR analyses identified a new heterozygous mutation in BBS1, the deletion of exons 10 and 11. Thus, this patient was compound heterozygous for mutations in BBS1. Many studies have described digenic heterozygous mutations in BBS. However, undetected mutations might have existed in either one of the mutated genes.

Effects of the rotigotine transdermal patch versus oral levodopa on swallowing in patients with Parkinson's disease.

OBJECTIVES: Abnormal swallowing or dysphagia is a potentially fatal symptom in Parkinson's disease (PD) and is characterized by frequent silent aspiration, which is an unrecognized risk for aspiration pneumonia. While the effects of oral levodopa on swallowing functions remain controversial, several small-scale studies have reported that rotigotine transdermal patch seems effective. The different effects between levodopa and rotigotine may be attributed to continuous dopaminergic stimulation (CDS), however, the absence of direct comparative evidence precludes conclusion. METHODS: In the present retrospective open-label study of 50 patients with PD, swallowing functions were assessed via videofluoroscopic (VF) examination before and after treatment. Treatment included 2 mg/day rotigotine transdermal patch (N = 29) or 200 mg/day oral levodopa with carbidopa (N = 21) in drug-naïve and add-on groups of patients. RESULTS: Rotigotine more consistently improved all measures assessed via VF examination. Such effects were similar to those in the drug-naïve and add-on groups. Improvement and responder rates of certain measures were significantly higher in the rotigotine group than in the levodopa group. CONCLUSIONS: Our finding that rotigotine (levodopa equivalent dose = 60 mg) was more consistently effective than 200 mg/day oral levodopa suggests that CDS is more important in improving swallowing functions.

Pathological Findings in Male Patients With Anti-N-methyl-d-Aspartate Receptor Encephalitis.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common type of autoimmune encephalitis. The disease predominantly affects women (1:5-1:10), with only 3 reports of autopsy findings in women being published to date. The present study reports findings from the first autopsy performed on a man with anti-NMDAR encephalitis. The patient had some scattered lesions in the limbic system with neuronal loss, gliosis, and microglial activation. The temporal and frontal cortices showed additional patchy demyelination. T-lymphocyte infiltration was detectable in the fusiform gyrus lesion. These findings were partly similar to those reported in female patients. Although clinical differences based on the sex of the patient are reported for this disease, the observed pathological similarities potentially help to establish common therapeutic strategies for all patients. Severe testicular damage was additionally observed in the male patient in this study. Biopsy-proven severe testicular damage was also confirmed in another, previously fertile man who became azoospermic. Moreover, serum follicle-stimulating hormone levels, which often increased in response to disturbed spermatogenesis, were elevated, and testosterone/luteinizing hormone ratio reflecting Leydig cell function was low in all 5 male patients in this study. Overall, these findings suggest similar brain pathology in patients of both sexes and severe testicular damage in male patients.

PSP-Phenotype in SCA8: Case Report and Systemic Review.

Spinocerebellar ataxia type 8 (SCA8) is a rare autosomal dominant neurodegenerative disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Many patients had pure cerebellar ataxia, while some had parkinsonism, both without causal explanation. We analyzed the ATXN8OS gene in 150 Japanese patients with ataxia and 76 patients with Parkinson's disease or related disorders. We systematically reassessed 123 patients with SCA8, both our patients and those reported in other studies. Two patients with progressive supranuclear palsy (PSP) had mutations in the ATXN8OS gene. Systematic analyses revealed that patients with parkinsonism had significantly shorter CTA/CTG repeat expansions and older age at onset than those with predominant ataxia. We show the imaging results of patients with and without parkinsonism. We also found a significant inverse relationship between repeat sizes and age at onset in all patients, which has not been detected previously. Our results may be useful to genetic counseling, improve understanding of the pathomechanism, and extend the clinical phenotype of SCA8.

The novel de novo mutation of KIF1A gene as the cause for Spastic paraplegia 30 in a Japanese case.

Spastic paraplegia 30 is a recently established autosomal recessive disease characterized by a complex form of spastic paraplegia associated with neuropathy. Homozygous mutations of KIF1A reportedly lead to hereditary spastic paraplegia or hereditary sensory and autonomic neuropathy type 2 (HSAN2), whereas heterozygous mutations can cause nonsyndromic and syndromic intellectual disability (MRD9). Here we report the case of a 37-year-old female who presented with gait disturbance complicated with moyamoya disease. RESULTS: The patient exhibited hypotonia during infancy, after which intellectual disability, epileptic fits, spastic paraplegia, and cerebellar atrophy occurred. Genetic analysis revealed a novel de novo mutation (c.254C > A, p.A85D) in the motor domain of KIF1A.

Noncoding repeat expansions for ALS in Japan are associated with the ATXN8OS gene.

OBJECTIVE: To assess the contribution of noncoding repeat expansions in Japanese patients with amyotrophic lateral sclerosis (ALS). METHODS: Sporadic ALS in Western countries is frequently associated with noncoding repeat expansions in the C9ORF72 gene. Spinocerebellar ataxia type 8 (SCA8) is another noncoding repeat disease caused by expanded CTA/CTG repeats in the ATXN8OS gene. Although the involvement of upper and lower motor neurons in SCA8 has been reported, a positive association between SCA8 and ALS remains unestablished. Spinocerebellar ataxia type 36 is a recently identified disease caused by noncoding repeat expansions in the NOP56 gene and is characterized by motor neuron involvement. We collected blood samples from 102 Japanese patients with sporadic ALS and analyzed the ATXN8OS gene by the PCR-Sanger sequencing method and the C9ORF72 and NOP56 genes by repeat-primed PCR assay. RESULTS: Three patients with ALS (3%) had mutations in the ATXN8OS gene, whereas no patient had a mutation in the C9ORF72 or NOP56 gene. The mutation-positive patients were clinically characterized by neck weakness or bulbar-predominant symptoms. None of our patients had apparent cerebellar atrophy on MRI, but 2 had nonsymptomatic abnormalities in the white matter or putamen. CONCLUSIONS: Our finding reveals the importance of noncoding repeat expansions in Japanese patients with ALS and extends the clinical phenotype of SCA8. Three percent seems small but is still relatively large for Japan, considering that the most commonly mutated genes, including the SOD1 and SQSTM1 genes, only account for 2%-3% of sporadic patients each.

Diagnosis of Parkinson's disease and the level of oxidized DJ-1 protein.

Parkinson's disease (PD) is difficult to distinguish from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA); in addition, biomarker studies in PD mostly focused on those found in the cerebrospinal fluid, and there are few reports of simple biomarkers identified by blood analysis. Previously, the DJ-1 gene was identified as a causative gene of familial PD. Oxidized DJ-1 protein (oxDJ-1) levels were reported to increase in the blood of patients with unmedicated PD. Therefore, we determined the levels of oxDJ-1 in the erythrocytes of patients with PD, PSP, and MSA using ELISA. The oxDJ-1 levels were 165±117, 96±78, and 69±40ng/mg protein in the PD, PSP, and MSA groups, respectively. The mean level in disease control group was 66±31, revealing significant differences between the PD and PSP groups, the PD and MSA groups, and the PD and disease control groups. Our results indicated that oxDJ-1 levels in erythrocytes can be used as a marker for the differential diagnosis of PD.

Homozygous alpha-synuclein p.A53V in familial Parkinson's disease.

We have assessed the frequency of alpha-synuclein (SNCA) mutations in Japanese patients with familial or sporadic Parkinson's disease (PD) and surveyed their associated clinical manifestations. We screened SNCA exon 3 in 988 patients without SNCA multiplications (430 with autosomal dominant PD and 558 with sporadic PD). We detected 1 patient harboring a homozygous SNCA p.A53V substitution albeit with an autosomal dominant pattern of disease inheritance (frequency 2/860 = 0.2%). The proband manifested slow and progressive parkinsonism at 55 years. Later she complicated with cognitive decline and hallucinations. Several of her immediate family members also presented with parkinsonism, cognitive decline, and psychosis. Positron emission tomography imaging of 18F-6-fluoro-L-dopa (18F-DOPA) uptake, 11C(+)dihydrotetrabenzine (type 2 vesicular monoamine transporter), and 11C-d-threo-methylphenidate (a plasmalemmal dopamine transporter marker) binding in the striatum were significantly reduced. Hence, alpha-synuclein p.A53V homozygous mutation leads to a distinct phenotype of progressive parkinsonism and cognitive decline, commonly observed in patients with SNCA missense mutation or multiplications.

Time Course of Radiological Imaging and Variable Interindividual Symptoms in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Associated with p.Arg487His Mutation in the VCP Gene.

To our knowledge, this is the first study to report the time course of radiological imaging of 3 patients from 2 families with VCP-related amyotrophic lateral sclerosis (ALS) and dementia. Both families shared the same p.Arg487His mutation in the VCP gene encoding valosin-containing protein. The first patient started to have a typical form of ALS, followed by dementia 7 years later. The second patient, a brother of the first one, had frontotemporal dementia and parkinsonism. The third patient had simultaneous ALS and dementia. All patients seemed to have progressive brain atrophy as their clinical symptoms progressed. The common and characteristic finding was atrophy of the temporal lobes including the hippocampi. The relation between imaging findings and symptoms varied considerably among the 3 patients.

Unexpectedly mild phenotype in an ataxic family with a two-base deletion in the APTX gene.

INTRODUCTION: Early onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ataxia with oculomotor apraxia 1 (AOA1) is an autosomal recessive disorder caused by mutations in the APTX gene. In contrast to the recent progress on the molecular mechanism of aprataxin in DNA repair, the genotype and phenotype correlation has not been fully established. A previous study demonstrated that patients with truncation mutations had earlier onset of disease than those with missense mutations METHODS: Genomic DNA analysis was performed in a consanguineous family with relatively late-onset EAOH/AOA1. In addition, mRNA and protein analyses were performed. RESULTS: The proband of the family had a homozygous two-base deletion in the middle of exon 3. Reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of mRNA revealed an aberrantly spliced mRNA with a cryptic splice site located four bases upstream of the deletion site. The newly identified mRNA retained a frameshift mutation and encoded a truncated protein. Immunoblot analysis did not detect the truncated protein in the patient's fibroblasts, possibly because it was unstable. CONCLUSIONS: Although patients with truncation mutations had an earlier onset of disease, our findings suggest that patients with a truncation mutation resulting in an undetectable protein level can also have a later onset of disease.