[Abstract unavailable

Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.

Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.

No abstract

Torsion dystonia-1 (DYT1) dystonia, the most common inherited form of dystonia, is caused by a three base pair deletion that eliminates a single amino acid from the disease protein, torsinA. TorsinA is an "AAA" protein thought to reside in the endoplasmic reticulum (ER), yet both its cellular function and the basis for neuronal dysfunction in DYT1 remain unknown. A clue to disease pathogenesis is the fact that mutant, but not wild-type, torsinA forms membranous inclusions in cell culture. To explore the pathobiology of DYT1 dystonia, we generated PC12 neural cell lines that inducibly express wild-type or mutant torsinA. Although in this model torsinA displays some properties consistent with ER localization, mutant torsinA also accumulates in the nuclear envelope (NE), a structure contiguous with cytoplasmic ER. Consistent with this, membranous inclusions formed by mutant torsinA are shown to derive not from the ER, as thought previously, but from the NE. We demonstrate further that torsinA forms different disulfide-linked complexes that may be linked functionally to subcellular localization in the NE versus cytoplasmic ER. Despite mutant TA accumulation in NE structures, nucleocytoplasmic transport of a reporter protein was unaffected. These findings, togetherwithparallelstudiesfailingtodemonstrateperturbationofERfunction,implicatetheNEasaprimarysiteofdysfunctioninDYT1.DYT1 dystonia can be added to the growing list of inherited neurological disorders involving the NE.