[A case of adult-onset Sturge-Weber syndrome type III without intracranial calcification, presenting with transient homonymous hemianopia].

Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder. Almost all cases of SWS are diagnosed in children, but some are diagnosed in adults. We describe a case of isolated leptomeningeal angiomatosis without intracranial calcification. A 33-year-old woman was admitted because of sudden-onset right homonymous hemianopia with headache and nausea. These symptoms disappeared by the next morning. She had no history of seizure or mental retardation. No facial angioma was found on physical examination. Brain CT showed no intracranial calcification or atrophic cortex. The blood and cerebrospinal fluid analyses yielded normal results. The findings in the electroencephalogram were unremarkable. MRI with susceptibility weighting (SWI) revealed dilated transmedullary veins in the left occipital lobe. Contrast-enhanced T1-weighted imaging (CE-T1WI) illustrated abnormal leptomeningeal enhancement in the left occipitoparietal cortex and enhancement and enlargement of the choroid plexus in the left lateral ventricle. Post-gadolinium contrast-enhanced f FLAIR imaging demonstrated more extensive enhancement of the leptomeningeal lesions than did CE-T1WI. The symptoms and the findings on these images were suggestive of a diagnosis of SWS type III. Clinicians should keep in mind that some cases of SWS manifest with only minor symptoms, such as migraine. If SWS is suspected, SWI and contrast-enhanced MRI should be performed.

Structurally distinct α-synuclein fibrils induce robust parkinsonian pathology.

OBJECTIVE: Alpha-synuclein (α-syn) is a major component of Lewy bodies, which are the pathological hallmark in Parkinson's disease, and its genetic mutations cause familial forms of Parkinson's disease. Patients with α-syn G51D mutation exhibit severe clinical symptoms. However, in vitro studies showed low propensity for α-syn with the G51D mutation. We studied the mechanisms associated with severe neurotoxicity of α-syn G51D mutation using a murine model generated by G51D α-syn fibril injection into the brain. METHODS: Structural analysis of wild-type and G51D α-syn-fibrils were performed using Fourier transform infrared spectroscopy. The ability of α-syn fibrils forming aggregates was first assessed in in vitro mammalian cells. An in vivo mouse model with an intranigral injection of α-syn fibrils was then used to evaluate the propagation pattern of α-syn and related cellular changes. RESULTS: We found that G51D α-syn fibrils have higher ß-sheet contents than wild-type α-syn fibrils. The addition of G51D α-syn fibrils to mammalian cells overexpressing α-syn resulted in the formation of phosphorylated α-syn inclusions at a higher rate. Similarly, an injection of G51D α-syn fibrils into the substantia nigra of a mouse brain induced more widespread phosphorylated α-syn pathology. Notably, the mice injected with G51D α-syn fibrils exhibited progressive nigral neuronal loss accompanied with mitochondrial abnormalities and motor impairment. CONCLUSION: Our findings indicate that the structural difference of G51D α-syn fibrils plays an important role in the rapidly developed and more severe neurotoxicity of G51D mutation-linked Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society.

A small-angle X-ray scattering study of alpha-synuclein from human red blood cells.

α-synuclein (α-syn) is the main component of Lewy bodies, which are neuropathological hallmarks of patients with Parkinson's disease. As it has been controversial whether human α-syn from erythrocytes exists as a tetramer under physiological conditions, we tried solving this issue by the small-angle X-ray solution scattering method. Under two different conditions (high ionic strength with a Tris buffer and low ionic strength with an ammonium acetate buffer), no evidence was found for the presence of tetramer. When comparing erythrocyte and recombinant α-syn molecules, we found no significant difference of the molecular weight and the secondary structure although the buffer conditions strongly affect the radius of gyration of the protein. The results indicate that, even though a stable tetramer may not be formed, conformation of α-syn depends much on its environment, which may be the reason for its tendency to aggregate in cells.

Large expansion of CTG•CAG repeats is exacerbated by MutSß in human cells.

Trinucleotide repeat expansion disorders (TRED) are caused by genomic expansions of trinucleotide repeats, such as CTG and CAG. These expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have demonstrated the involvement of DNA repair proteins in repeat instability, although the key factors affecting large repeat expansion and contraction are unclear. Here we investigated these factors in a human cell model harboring 800 CTG•CAG repeats by individually knocking down various DNA repair proteins using short interfering RNA. Knockdown of MSH2 and MSH3, which form the MutSß heterodimer and function in mismatch repair, suppressed large repeat expansions, whereas knockdown of MSH6, which forms the MutSα heterodimer with MSH2, promoted large expansions exceeding 200 repeats by compensatory increases in MSH3 and the MutSß complex. Knockdown of topoisomerase 1 (TOP1) and TDP1, which are involved in single-strand break repair, enhanced large repeat contractions. Furthermore, knockdown of senataxin, an RNA/DNA helicase which affects DNA:RNA hybrid formation and transcription-coupled nucleotide excision repair, exacerbated repeat instability in both directions. These results indicate that DNA repair factors, such as MutSß play important roles in large repeat expansion and contraction, and can be an excellent therapeutic target for TRED.

[Brain abscess mediated through a pulmonary arteriovenous malformation in a patient with hereditary hemorrhagic telangiectasia].

The patient is a 66-year-old man with hereditary telangiectasia. He was diagnosed with pulmonary arteriovenous malformation (PAVM), which was revealed by contrast-enhanced chest computed tomography at the age of 65. He developed headache, right homonymous hemianopsia, and right hemiparesis and was admitted to our hospital. Contrast-enhanced magnetic resonance imaging revealed multiple lesions in the left hemisphere, which indicates brain abscesses. Thus, the diagnosis of brain abscess mediated through PAVM was established. Following management with drainage and coil embolization, all neurological symptoms resolved. Therefore, coil embolization should be considered for PAVM at an early stage to prevent brain abscess, even if it is asymptomatic.

[A case of possible neuro-Sweet disease with prolonged disturbance of consciousness and no dermal lesion during the course of dementia].

The patient was a 58-year-old man with 1-year history of cognitive decline, which was diagnosed as Alzheimer's disease in another hospital. He was admitted to our hospital for extreme fatigue, weight loss, and dysphagia, subsequent to the left peripheral facial paresis. Brain magnetic resonance (MR) imaging showed bilateral diffuse white matter lesions and hippocampal atrophy. After admission, he presented with sudden high fever, recurrent exacerbations of consciousness, and increased C-reactive protein level with marked neutrophilia, with the result that he underwent mechanical ventilation. Routine cerebrospinal fluid findings at the exacerbation were normal i.e. 4.7 cells/mm(3), 40 mg/dl of protein, but IL-6 concentration was mildly elevated to 22.2 pg/ml. After confirming the positivity of HLA (human leukocyte antigen) B54 and Cw1, we administered steroid to him and his physical activity and state of consciousness significantly improved. During the course of treatment, dermal lesion characterisitic of Sweet disease was absent. We diagnosed this case was possible neuroSweet disease proposed by Hisanaga in 2005.