In Huntington's disease, CAG repeat expansion of the Huntingtin gene produces mutant RNA and mutant protein containing elongated polyglutamine tract, which causes dysfunction and cell death of neurons. From our reseach of Huntington's disease and other polyglutamine diseases for nearly 20 years, we identified new disease-related genes including PQBP1, Ku70, HMGB, Maxer, and Omi. Through the analysis of these molecules, we unraveled new pathomechanisms deeply linked to nuclear functions such as transcription, splicing, DNA damage repair. These findings will become the basis to develop new molecule targeted therapeutics.
A 46-year-old woman was admitted to our hospital for examination of her amnesia. Psychiatric examinations revealed that her recent memory was moderately disturbed despite well-preserved general cognitive function. Brain MRI and I-IMP SPECT (eZIS) revealed mild brain atrophy and hypoperfusion localized to the hippocampus, superior parietal lobule, and posterior cingulate gyrus. She was diagnosed with amnestic MCI at that time. However, five years later, she developed personality changes, parkinsonism and dementia. Investigation of her family medical history revealed that the patient's two sisters are demented and under the medical care. DNA analysis revealed an intronic mutation IVS10 C>T in the MAPT gene. Although her two sisters also have the same mutation, her elder sister has typical FTD without parkinsonism. Approximately 10% of patients with amnestic MCI develop Alzheimer's disease each year. Thus, amnestic MCI has been usually considered to be an early stage of Alzheimer's disease. Interestingly our patient having a MAPT gene mutation started to develop amnestic MCI as an initial symptom. Therefore because of the diversity in early clinical features of FTDP-17, aggressive DNA analysis is necessary for accurate diagnosis.
Case Report: A 45-year-old man came to our hospital with a chief complaint of occipital pain followed by gait disturbance and developing hypohidrosis on the right side 6 days after the onset. Brain MRI revealed an acute infarction in the dorsolateral part of right medulla. Bladder catheter was inserted because of dysuria. 8 days after the onset, the bladder contraction and desire to urinate were normal, by cystometry. However, micturition was still impossible without a catheter. His dysuria was considered to be due to Detrusor-Sphincter Dyssynergia (DSD). 19 days after the onset, he was able to urinate without a catheter. We found only 5 reported cases of lateral medullary infarction with dysuria, all of which had abnormal bladder contraction. This is the first case report of lateral medullary infarction with dysuria in spite of normal bladder contraction.
A 59-year-old man with a long history of under-treated diabetes mellitus presented with severe inflammation that had spread from the sinus to the left orbital cavity. The bilateral internal carotid arteries were severely stenotic, causing multiple infarctions in the brain parenchyma. There was no β-D-glucan detected in the cerebrospinal fluid. Based on the presence of central nervous system (CNS) inflammation and vascular involvements that spread from the sinusitis, we tentatively diagnosed this patient as having invasive fungal CNS infection, i.e. zygomycosis or aspergillosis. Although the patient was treated with anti-fungal drugs such as liposomal amphotericin B and voriconazole, he died of respiratory failure. Pathological examination of the autopsied tissues demonstrated zygomycosis in the brain and heart. The prevalence of zygomycosis is generally very low (-5% of CNS infections) compared with that of other fungal infections. The lack of an appropriate diagnostic marker may lead to the under- or mis-diagnosis of zygomycosis. Moreover, it is hard to differentiate zygomycosis from aspergillosis because the two diseases share common clinical features such as the association of sinusitis and vascular involvement. The clinically diagnostic points that discriminate zygomycosis from aspergillosis are as followed; i) β-D-glucan is negative in zygomycosis but positive in aspergillosis; ii) diabetes is more frequent in patients with zygomycosis to those with aspergillosis; iii) the infectious lesion in aspergillosis shows an iso-low-intensity on T2 weighted MRI image but shows a high intensity lesion in zygomycosis. The mortality rate of CNS zygomycosis is so high that an early diagnosis of it is warranted and the start appropriate anti-fungal treatments or surgical drainage in the early stage of the disease.
A 59-year-old woman presented with a 7-year history of headache. She showed no neurological abnormality. T2 weighted magnetic resonance (MR) images showed a hyperintense signal in the white matter in the bilateral parieto-occipital lobe without abnormal enhancement. A small amount of prednisolone was administered for rheumatoid arthritis. After prednisolone was discontinued, the T2 weighted images showed an expansion of the hyperintense signal lesions seen in the white matter, and T2* weighted image showed multiple foci of petechial bleeding in the cortex and subcortex of the bilateral occipital lobe. A brain biopsy specimen from the right occipital lobe revealed deposition of amyloid in the subarachnoidal and cortical vessel walls and transmural infiltration of a few lymphocytes, eosinophils, and giant histiocytes. Subsequently the patient was diagnosed with central nervous system vasculitis associated with cerebral amyloid angiopathy (CAA). After 5 months, the T2 weighted images showed a remarkable regression of the hyperintense signal lesions in the white matter of the bilateral parieto-occipital lobe without the administration of any maintenance immunosuppressive agents. However, T2* weighted image showed an increase of multiple cortico-subcortical foci of petechial bleeding. Her headache did not improve during the illness. Thus, we should consider the diagnosis of CAA when patients present with reversible white matter lesions and multiple cerebral microbleeds simultaneously.
A 48-year-old woman presented with a 2-week history of headache. The headache was so severe in the standing position that she could hardly stand up. The results of general and neurological examination were unremarkable. MRI studies of the brain showed diffuse pachymeningeal gadolinium enhancement on the T1 weighted images. The cerebrospinal fluid (CSF) opening pressure on lumbar puncture was 70mm H2O. MR myelography and RI-cisternography disclosed leak of cerebrospinal fluid at the lumbar level. Then, we diagnosed her as headache associated with liquorrhea. Two weeks later, she noticed an inability to recognize familiar faces, including her own face in the mirror. The Cambridge Face Memory Test (CFMT) proved prospagnosia. Brain MRI revealed multiple subdural hematomas below the bilateral fusiform gyrus. SPECT demonstrated diffuse hypoperfusion in the brain including bilateral fusiform gyrus. Months later, she showed gradual improvement of prospagnosia. Follow-up brain MRI revealed disappearance of both subdural hematomas and diffuse pachymeningeal gadolinium enhancement. SPECT demonstrated marked improvement of cerebral blood flow in the whole brain including the right temporal-occipital lesion. This is the first report of acquired prospagnosia during the course of liquorrhea causing subdural hematomas. Subdural hematoma below a right fusiform gyrus may cause reversible prospagnosia.
We report the case of a 50-year-old man with subacute onset of bilateral visual field loss and visual acuity loss. His visual acuity was 0.07 OD/0.09 OS and Goldmann perimetry showed central scotomas. The optic fundi were normal bilaterally. Magnetic resonance imaging (MRI) showed hyperintensity in the right optic nerve on T2 weighted imaging and swelling of the optic chiasm with slight enhancement of the bilateral optic nerves and the optic chiasm on gadolinium-enhanced imaging. Since sensory disturbance in the left hand and leg was noted in addition to the visual problem, multiple sclerosis (MS) was suspected initially. The patient was treated with intravenous methylprednisolone (1,000mg/day), plasma exchange therapy, and immunosuppressant therapy. However, his visual disturbance did not improve. He had a history of deafness and family history of visual disturbance, because of which we performed an analysis of mitochondrial DNA. G11778A point mutation was found, and a diagnosis of Leber's hereditary optic neuropathy (LHON) was made. Although gadolinium contrast enhancement and swelling of the optic nerve are rare, this case shows that these findings are not in conflict with LHON. The present case also suggests that mitochondrial dysfunction may trigger the onset of MS-like extraocular symptoms in patients with LHON.
A 50-year-old woman with a history of palmoplantar pustulosis, femur osteomyelitis, and sterno-costo-clavicular hyperostosis presented with a chronic severe left temporal headache that had progressed during the previous year. Her CRP level was elevated. Cranial images showed Gadolinium-enhancement of the left temporal muscle, left parietal bone and dura mater. 99mTc-HMDP scintigram showed increased uptake in the left parietal bone, left sterno-costo-clavicular joint, right femoral head and intervertebral joints. Biopsy of the lesion demonstrated 1) proliferation of connective tissue in both perimysium and endomysium of the temporal muscle with mild inflammatory cell infiltration within the interstitium, 2) marked infiltration of granulocytes to the bone marrow of the parietal bone, 3) necrosis and moderate fibrosis in the interstitium with inflammatory cell infiltration in the parietal bone, and 4) moderate fibrosis and slight infiltration of inflammatory cells in the dura mater. The patient was diagnosed with a cranial lesion of synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. There was a moderate response to treatment with intravenous steroid pulse therapy and subsequent methotrexate. In a case of headache accompanied by inflammatory response, palmoplantar pustulosis and joint lesions such as hyperostosis, the possibility of a rare cranial manifestation of SAPHO syndrome should be considered.
A 40-year-old man presented with sudden onset of severe left buttock pain that radiated down the thigh to the leg. On examination, he showed moderate weakness and atrophy in the left quadriceps and tibialis anterior muscles, and absence of a left patellar tendon reflex. Needle electromyography revealed an active denervation pattern in the left quadriceps muscles, suggesting neuralgic amyotrophy. Contrast-enhanced MRI showed abnormal enhancement of the left cauda equina. Steroid pulse therapy relieved pain, and subsequent high-dose intravenous immunoglobulin prevented progression of muscle atrophy and weakness. Neuralgic amyotrophy is characterized by attacks of severe neuropathic pain and subsequent patchy paresis in the upper or lower extremities. Since overall recovery is less favourable than usually assumed, early diagnosis is very important. This case was remarkable in that contrast-enhanced MRI revealed abnormal enhancement and thickening of the cauda equina, which may help in achieving early diagnosis and treatment.