Recent advance of molecular biology reveals that quality control of intracellular environment takes an important role for maintaining the neuronal function. One is a quality control of protein and another is a quality control of nucleotide. Polyglutamine disease is a disease which caused by a failure of quality control of protein. Expanded polyglutamine repeats result in neurodegenerative disorders, but their cytotoxic structures remain to be elucidated. We have applied fluorescence resonance energy transfer analysis to clarify the cytotoxicity of soluble polyglutamine oligomers. By using this method we revealed that polyglutamine monomers assemble into oligomer in a parallel β-sheet or a head-to-tail cylindrical β-sheet manner. We distinguished oligomers from monomers and inclusion bodies in a single living cell. Survival assay of neuronally differentiated cells revealed that cells with soluble oligomers died faster than those with inclusion bodies or monomers. These results indicate that a formation of oligomers is an essential mechanism underlying neurodegeneration in polyglutamine-mediated disorders. About the quality control of nucleotide in neuron, DNA single-strand breaks were continually produced by endogenous reactive oxygen species or exogenous genotoxic agents. These damaged ends posses damaged 3'-ends including 3'-phosphate, 3'-phosphoglycolate, or 3'-α, β-unsaturated aldehyde ends, and should be restored to 3'-hydroxyl ends for subsequent repair processes. We have demonstrated by in vitro assay that aprataxin, the causative gene product for early-onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), specifically removes 3'-phosphoglycolate and 3'-phosphate ends at DNA 3'-ends, but not 3'-α, β-unsaturated aldehyde ends. The findings indicate that aprataxin removes blocking molecules from 3'-ends, and that the accumulation of unrepaired DNA single-strand breaks with damaged 3'-ends underlies the pathogenesis of EAOH/AOA1. The findings will provide new insight into the mechanism underlying degeneration and DNA repair in neurons. Taken together, these results indicate that the quality control of protein and nucleotide is crucial to understand the neurodegenerative disorder.
Various clinical trials of gene therapy for Parkinson's disease (PD) are finally underway. The vehicle used mainly for gene delivery to the human brain is recombinant adeno-associated viral (rAAV) vector, which is non-pathogenic and non-self-amplifying. At present, the gene therapy approach is not the best way for the treatment of PD patients, but we believe that the further progress is anticipated toward making this strategy a therapeutic option for PD in the future. This article will review currently ongoing clinical trials of PD gene therapy and then introduce our studies about the gene therapy for PD.
A 65-year-old woman was admitted to our hospital because of the acute onset of right hand weakness and reduction in spontaneous speech. The patient displayed right hemiparesis, subcortical aphasia and impaired executive function. An acute cerebral infarction involving the left basal ganglion (striatocapsular infarction) and an old infarction of the left superior frontal gyrus (Brodmann area 8) were detected on a brain MRI. While aphasia improved gradually, there was no improvement in the impaired executive function. A brain MRI performed after 6 months revealed a linear white matter lesion between the basal ganglion and superior frontal gyrus. We postulated that this lesion was caused by degeneration of nerve fibers between the two infarctions.
Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease characterized by slowly progressive spinal and bulbar muscular atrophy associated with signs of androgen insensitivity including gynecomastia. This disease becomes prominent clinically in the fourth and fifth decades of life. Mutations of the androgen receptor (AR) gene associated with an expansion of CAG repeats is the cause of this disease. Here we report a unique family case in two brothers with SBMA with very late onset of muscular weakness. Motor functional symptoms in the two brothers developed at the ages of 66 and 78 years. The number of CAG repeats in the AR gene in both patients was 42. According to previous reports, the number of CAG repeats is related to the age at onset of muscular weakness. Our patient's conditions were consistent with this concept as there was a short expansion of 42 CAG repeats linked to the clinical phenotype of very late onset of muscular weakness. However, the issue of whether the number of CAG repeats is related to the age at onset of androgen insensitivity is still controversial. In the younger brother, gynecomastia appeared in his 20's and preceded the development of muscular weakness by about 40 years, whereas the gynecomastia in the older brother was unremarkable throughout his life. Our brother cases, which had the same number of CAG repeats and should share many common genetic factors, exhibited the androgen insensitivity differed. We therefore consider that an expansion of CAG repeats in the AR gene is not necessarily related to the age at onset of androgen insensitivity. In conclusion, the etiologies of muscular weakness and androgen insensitivity in SBMA could be different.
We reported a 59-year-old woman who had complained of right temporalgia for 5 years. She was first diagnosed with a carious tooth, but treatment did not alleviate the pain. She then developed right facial pain and numbness at the right side of the tongue tip. In spite of repetitive examinations and medications, temporalgia worsened in August, 2007. Neurological examination on admission revealed a palpable soft-to-firm tumor with tenderness at the right temporal head region, right facial pain radiating to the right forehead induced by tapping on the middle of the forehead, and dysesthesia at the right tip of the tongue. C-reactive protein was negative and erythrocyte sedimentation rate was normal. Ultrasonographic examination showed beads-like tumors with low-echoic lesions without blood flow. MRI demonstrated multiple small ovoid lesions in the right subcutaneous tissue of the right temporal head. Although we initially suspected temporal arteritis, these findings were contrary. Tumor biopsy finally revealed solitary neurofibroma of the right auriculotemporal nerve. A sporadic localized intraneural neurofibroma at the extracranial region is an uncommon entity. Furthermore, nerve sheath tumors of the trigeminal nerve rarely manifest with intermittent painful burning or crawling sensations simulating trigeminal neuralgia. The present case manifested as a tumor with tenderness at the right auriculotemporal nerve and mimicked temporal arteritis. Therefore, it is important to understand that neurofibroma of the auriculotemporal nerve can mimic temporal arteritis and manifest with trigeminal neuralgia-like pain.
We report a 54-year-old man with right abducent nerve palsy, right facial nerve palsy, and left segmental sensory disturbance, which progressed for 2 weeks. He was found to have cavernous angioma in the lower pons. When he visited our hospital, he had right facial palsy, sensory disturbance of left half of the face and left upper limb, and diplopia. He had suffered right abducent nerve palsy 5 years previously and had recently developed hypertension. Neurological examination further revealed right abducent nerve palsy, right peripheral facial nerve palsy, sensory impairment of the left half of the face, and sensory impairment on the left side from C2 to Th3. Magnetic resonance imaging of the head revealed hemorrhage with a rim at the right dorsal part of the lower pons. No abnormalities were identified on cerebral angiography. He was diagnosed as having hemorrhage originating from a cavernous angioma. We assumed that the segmental sensory disturbance was caused by medial involvement of the lateral spinothalamic tract, which is somatotopically arranged; the fibers from the sacral segments being most lateral. The ventral trigeminothalamic tract, right abducent nerve, and right facial nerve were also disturbed. Segmental sensory disturbance usually accompanies a spinal cord lesion. But several cases with similar symptoms following a brainstem lesion have been reported. Most of them had stroke, showing acute onset of illness. Our case showed subacute onset of illness; cranial nerve palsy and segmental sensory disturbance progressed for 2 weeks.
We present the case of a 51-year-old man with a 5-year history of slowly progressive gait ataxia and dysarthria who showed a wide-based gait requiring assistance. The patient's score on the Revised Hasegawa Dementia Scale (HDS-R) was 22/30 and constructional apraxia was also evident. Cerebrospinal fluid analysis showed 3cells/μl, and the protein concentration was 58mg/dl. Brain MRI showed no evidence of cerebellar atrophy, and SPECT-eZIS showed no decrease in cerebellar blood flow. However, voxel based morphometry (VBM) and FineSRT revealed cortical cerebellar atrophy and reduced cerebellar blood flow. In addition, the patient tested positive for anti-gliadin (IgA) and anti-SS-A/Ro antibodies, and was thus diagnosed as having autoimmune cerebellar ataxia. The patient showed positive response to intravenous immunoglobulins (IVIg) and regained the ability to walk unassisted. The HDS-R score also improved to 27/30. If cortical cerebellar atrophy can be diagnosed in the early stages in patients with progressive cerebellar ataxia by imaging techniques such as MRI-VBM and FineSRT, and if such patients test positive for anti-gliadin, anti-GAD or anti-thyroid antibodies, it is possible that they have autoimmune cerebellar ataxia. The commencement of immunotherapy including IVIg should be considered in such cases.
We report a 23-year-old woman who slowly developed progressive tremulous myoclonus and rare convulsive seizures beginning at the age of 9 and 11 years, respectively. She also showed a mild degree of ataxia and cognitive dysfunction. Convulsive seizures were well suppressed by valproic acid since the age of 17 years, but tremulous myoclonus gradually progressed and became rather intractable in spite of treatment by clonazepam and piracetam. Her cognitive dysfunction was mild (total IQ score in Wechsler Adult Intelligence Scale Revised being 85 points). In addition, she had a fear of walking which disabled her in the daily life although she could actually walk without assistance. The brain MRI showed a mild cerebellar atrophy, and FDG-PET showed a mild hypometabolism in the cerebellar hemispheres. Somatosensory evoked potentials (SEPs) showed enlarged P25 and N33 amplitudes (giant SEPs). A Cystatin B gene analysis exhibited a homozygous expansion of the dodecamer repeat, and thus we made a diagnosis of Unverricht-Lundborg disease (ULD). We also did gene analysis and SEP study to her parents after written informed consents were obtained. They had heterozygous expansion of the dodecamer repeat. The mother also showed enlarged P25 and N33 amplitudes, whereas the father showed normal amplitudes. It is known that degree of clinical symptoms varies among patients with ULD diagnosed by gene analysis. Gene analysis was helpful for a diagnosis of ULD in this patient because the ataxia and cognitive dysfunction were much milder than those commonly seen in patients with ULD.
A 59-year-old Japanese woman developed numbness below the level of the lower chest (day 1). She showed mild paraparesis and mild sensory disturbance below the level of Th8. Anti-HTLV-1, antinuclear, and anti-SS-A antibodies were negative. The cerebrospinal fluid yielded 10lymphocytes/μl and IgG index 0.46. MRI demonstrated a centrally located hyperintense spinal cord lesion at the level of Th4-6, but there were no lesions in the brain. Weakness improved after two courses of intravenous infusion of methylprednisolone 1,000mg. On day 67, she developed paraplegia, urinary retention, a Th4 sensory level, and loss of position sense in the lower limbs. EDSS score was 8.0. MRI demonstrated a cord lesion extending from C6 through Th10 levels. Serum anti-aquaporin 4 (AQP4) antibody was positive. After immunoadsorption plasmapheresis, strength improved. Visual evoked potential was delayed in the right eye. This case represents a high-risk syndrome of neuromyelitis optica. As the patient had diabetes, ocular hypertension, and a high risk of osteoporosis, she was started on ciclosporin in addition to a tapering dose of glucocorticoid. The patient has remained relapse free for more than one year and serum anti-AQP4 antibody became negative. This case suggests possible beneficial effects of cyclosporin in preventing attacks of myelitis with anti-AQP4 seropositivity.