We describe here a previously unknown, dominantly inherited, late-onset basal ganglia disease, variably presenting with extrapyramidal features similar to those of Huntington's disease (HD) or parkinsonism. We mapped the disorder, by linkage analysis, to 19q13.3, which contains the gene for ferritin light polypeptide (FTL). We found an adenine insertion at position 460-461 that is predicted to alter carboxy-terminal residues of the gene product. Brain histochemistry disclosed abnormal aggregates of ferritin and iron. Low serum ferritin levels also characterized patients. Ferritin, the main iron storage protein, is composed of 24 subunits of two types (heavy, H and light, L) which form a soluble, hollow sphere. Brain iron deposition increases normally with age, especially in the basal ganglia, and is a suspected causative factor in several neurodegenerative diseases in which it correlates with visible pathology, possibly by its involvement in toxic free-radical reactions. We found the same mutation in five apparently unrelated subjects with similar extrapyramidal symptoms. An abnormality in ferritin strongly indicates a primary function for iron in the pathogenesis of this new disease, for which we propose the name 'neuroferritinopathy'.

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Hyperekplexia is a rare condition characterised by the presence of neonatal hypertonia and an exaggerated startle response. Mutations have been described in GLRA1, the gene encoding the al subunit of the glycine receptor, in dominant families with hyperekplexia and in a single sporadic case, thought to represent an autosomal recessive form of the disease.In this study the coding region of the GLRA1 was analysed in eight probands with hyperekplexia by restriction digest and sequencing. Two familial cases were found to possess the previously described G1192A (R271Q) mutation in exon 6. In an additional family in which hyperekplexia cosegregates with spastic paraparesis, a novel A to G transversion at nucleotide 1206 in exon 6 was detected that changes a lysine at amino acid 276 to a glutamate (K276E). In four sporadic cases no mutations were found. In addition, one familial case did not have a mutation in the coding region of the gene.

Magnetometry analysis of brain tissue sub-samples from two neuroferritinopathy patients provides a preliminary indication that the amount of magnetic iron compounds associated with this rare disease is significantly larger than in age/sex-matched controls. The primary iron compounds contributing to the remnant magnetization of the tissue above 50 K and at body temperature are both blocked and superparamagnetic (SPM) biogenic magnetite (Fe3O4) and/or maghemite (gamma-Fe2O3). The concentration of SPM magnetite is significant and appears to be proportional to the concentration of ferritin, which varies with progression of the disease. The mutated ferritin protein appears to be responsible for the presence of iron oxide nano-particules, which in turn could be responsible for extensive damage in the brain.

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from its regulation of CDK 2 in the nucleus. 9 Therefore, the role of p27 in the pathogenesis of myeloma requires further study.Lastly, the infrequent p57 methylation in patients with MM is similar to another study, which showed p57 methylation in only four (15.4%) of 26 myeloma patients. 10 Moreover, gene silencing associated with methylation was demonstrated in WL2 cell line, in which demethylation led to re-expression of p57 transcript.In conclusion, in contrast to frequent methylation of p15 and p16, both CKI members of the INK4 family, we showed the absence of p21 and p27 methylation and infrequent p57 methylation in 55 patients with MM. This is also consistent with the absence of p21 and p27 methylation, and the infrequent methylation of p57 in myeloma cell lines. Our data suggested that epigenetic dysregulation of the INK4 family, instead of the CIP/KIP family of CKI, is the predominant mechanism to abrogate negative regulation of the G 1 S cell cycle control in MM. This is consistent with recent data showing an essential role of CDK4 but not CDK2 in cell proliferation. Promoter hypermethylation of the cyclin-dependent kinase inhibitor (CDKI) gene p21WAF1/CIP1/SDI1 is rare in various lymphomas and carcinomas.