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Features of tumefactive demyelinating lesion (TDL) on magnetic resonance imaging (MRI)can facilitate the differential diagnosis of TDL and neoplastic lesions, but vary considerably among patients. The larger TDL grows, the more difficult it becomes to differentiate TDL from neoplastic lesions. The purpose of this study was to elucidate typical MRI features in 12 patients with large TDL (>30 mm in diameter). METHODSWe identified 12 patients with large TDL (six men, six women; age range 17-64 years, median age 27 years) and studied the clinical histories and the results of laboratory and various radiological studies in these patients. All cases of clinically definite multiple sclerosis were diagnosed in accordance with McDonald's revised criteria. RESULTS Common MRI features of large TDLs included variable degrees of mass effect (71%) and edema (100%), a T2 hypointense rim (79%), venular enhancement (57%), and peripheral restriction on diffusion-weighted images (50%). Ring enhancement (38%), open-ring enhancement (31%), or decreased N-acetylaspartate ratios on magnetic resonance spectroscopy (22%) were less frequently observed. Brain angiography demonstrated venous dilatations on and around the TDL. CONCLUSIONSThe diagnosis of large TDL is challenging. Our findings suggest that multiple venous dilatations on and around TDLs on angiography can facilitate diagnosis.

Triple A syndrome is an autosomal recessive neuroendocrinological disease caused by mutations in a gene that encodes 546 amino acid residues. The encoded protein is the nucleoporin ALADIN, a component of nuclear pore complex (NPC). We identified a mutant ALADIN I482S that fails to target NPC and investigated the consequences of mistargeting using cultured fibroblasts (I482Sf) from a patient with triple A syndrome. ALADIN I482S affected a karyopherin-␣͞␤-mediated import pathway and decreased nuclear accumulations of aprataxin (APTX), a repair protein for DNA singlestrand breaks (SSBs), and of DNA ligase I in I482Sf. This decrease was restored by wild-type ALADIN. ALADIN I482S had no effect on imports of M9͞kap-␤2, BIB͞kap-␤3, histone H1͞importin 7, the ubiquitin conjugating enzyme UbcM2͞importin 11, or the spliceosome protein U1A, indicating that ALADIN I482S selectively impaired transport of discrete import complexes through NPC. Cell survival assay showed hypersensitivity of I482Sf to L-buthionine-(S,R)-sulfoximine (BSO), a glutathione-depleting agent. BSO decreased nuclear APTX and ligase I levels in I482Sf and normal control fibroblasts, but increased SSBs only in I482Sf. These observations implied that I482Sf are hypersensitive to BSO and no longer sufficiently repair SSBs. Consistent with this notion, I482Sf transfected with both APTX and ligase I had increased resistance to BSO, whereas I482Sf transfected with LacZ vector remained hypersensitive to BSO. We propose that oxidative stress aggravates nuclear import failure, which is already compromised in patient cells. Consequent DNA damage, beyond the limited capacity of DNA repair proteins, i.e., APTX and ligase I, may participate in triggering cell death.aprataxin ͉ DNA ligase I ͉ nuclear pore complex

This study provides the first direct evidence for the functional involvement of APTX in SSBR and in vivo DNA damage in EAOH/AOA1, and suggests a benefit of antioxidant treatment.

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