Rett syndrome (RTT) was first described in 1966. Its biological and genetic foundations were not clear until recently when Amir et al reported that mutations in the MECP2 gene were detected in around 50% of RTT patients. In this study, we have screened the MECP2 gene for mutations in our RTT material, including nine familial cases (19 Rett girls) and 59 sporadic cases. A total of 27 sporadic RTT patients were found to have mutations in the MECP2 gene, but no mutations were identified in our RTT families. In order to address the possibility of further X chromosomal or autosomal genetic factors in RTT, we evaluated six candidate genes for RTT selected on clinical, pathological, and genetic grounds: UBE1 (human ubiquitin activating enzyme E1, located in chromosome Xp11.23), UBE2I (ubiquitin conjugating enzyme E2I, homologous to yeast UBC9, chromosome 16p13.3), GdX (ubiquitin-like protein, chromosome Xq28), SOX3 (SRY related HMG box gene 3, chromosome Xq26-q27), GABRA3 ( -aminobutyric acid type A receptor 3 subunit, chromosome Xq28), and CDR2 (cerebellar degeneration related autoantigen 2, chromosome 16p12-p13.1). No mutations were detected in the coding regions of these six genes in 10 aVected subjects and, therefore, alterations in the amino acid sequences of the encoded proteins can be excluded as having a causative role in RTT. Furthermore, gene expression of MECP2, GdX, GABRA3, and L1CAM (L1 cell adhesion molecule) was also investigated by in situ hybridisation. No gross diVerences were observed in neurones of several brain regions between normal controls and Rett patients. (J Med Genet 2000;37:250-255)

Ifosfamide is an alkylating agent with well-demonstrated efficacy against a large number of malignant diseases. With cyclophosphamide it shares a toxicity profile characterized by myelosuppression and urotoxicity, but ifosfamide has additionally disclosed adverse neurological effects. Ifosfamide-related central nervous system toxicity is characterized by metabolic encephalopathy of varying severity. Symptoms have been reported in 5–30% of all patients treated with ifosfamide. The mechanism of ifosfamide-related central nervous system toxicity has not been fully elucidated, although the symptoms have most often been noted when the drug is given at high doses or administered orally. The neurotoxicity is generally self-limiting and reversible between 48 and 72 h after discontinuation of ifosfamide, although fatal sequelae have been reported. Therapeutic options are now available.

No abstract

We report the pathological findings of a woman with a sub-acute cerebellar syndrome who had undergone surgery 3 years before for endometrial carcinoma. Both serum and cerebrospinal fluid contained high titres of autoantibodies against the cytoplasm of Purkinje cells that recognized a band of 62 kDa on immunoblotting of neuronal extracted proteins (pattern anti-Yo). No tumour was found despite a full range of gynaecological investigations; the neoplastic marker CA125 was slightly elevated and oligoclonal bands were detected in the cerebrospinal fluid. The patient died from acute myocardial infarction 4 months after developing this syndrome. At autopsy, no macroscopic evidence of tumour was obtained and the brain showed no abnormalities. On microscopic examination of the central nervous system diffuse degeneration of Purkinje cells could be seen throughout the cerebellum. Immunohistochemical analysis showed a CD8 lymphocyte infiltration in the cerebellum and cerebral cortex and diffuse microglial activation throughout the brain. These cells expressed high levels of MHC-II antigens on their cell membranes. The serum autoantibodies reacted with the cytoplasm of the remaining Purkinje cells. The short interval between the onset of symptoms and death of the patient could explain the difference between our findings and those reported in the literature in which no inflammatory infiltrates were detected. The immunohistochemical findings as well as the inflammatory cerebrospinal fluid profile seen in our case seem to support the concept that in paraneoplastic cerebellar degeneration with anti-Yo antibodies, an immune mediated mechanism is responsible for the damage to the cerebellum.