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Array-based molecular strategies are employed to identify the gene responsible for the onset of action myoclonus-renal failure syndrome (AMRF). The myoclonus epilepsy and focal glomerulosclerosis is usually caused due to the deficiency of SCARB2/LIMP-2 protein in humans.

Byline: H.J. Schelhaas (1), P.F. Ippel (3), G. Hageman (1), R.J. Sinke (3), E.N. van der Laan (2), F.A. Beemer (3) Keywords: Key words Spinocerebellar ataxia; Myoclonus; Cognitive impairment; Wisconsin Card Sorting Test Abstract: The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders characterised by progressive cerebellar dysfunction in combination with a variety of other associative features. Since 1993 ADCAs have been increasingly characterised in terms of their genetic mutation and are referred to as spinocerebellar ataxias (SCAs). Some families with ADCA cannot be assigned to any of the known genotypes, which implies further genetic heterogeneity. We investigated the clinical symptoms of 12 patients of a four-generation family with ADCA and carried out mutation and genetic linkage studies. The family showed a relatively mild cerebellar ataxic syndrome with congitive impairment, poor performance on the Wisconsin Card Sorting Test, myoclonus, and a postural irregular tremor of slow frequency. Age at disease onset and severity of cerebellar signs and symptoms suggest anticipation. The genetic loci implicated in ADCA were excluded by mutation analyses (SCA 1,2,3,6,7,8,12) and genetic linkage (SCA 4,5,6,10,11). We conclude that this family represents a clinically and genetically distinct form of SCA. Author Affiliation: (1) Department of Neurology, Medical Spectrum Twente Enschede, The Netherlands, NL (2) Department of Medical Psychology, Medical Spectrum Twente Enschede, The Netherlands, NL (3) Department of Medical Genetics, University Medical Centre Utrecht, The Netherlands, NL Article note: Received: 31 March 2000 / Received in revised form: 14 July 2000 / Accepted: 12 August 2000

Assessment of linkage disequilibrium carried out by the decay of haplotype sharing (DHS) and applied to fine-scale chromosome mapping is discussed. Cystic fibrosis and progressive myoclonus epilepsy are used as examples. Linkage disequilibrium (LD) is of much interest for mapping of genes and study of population history, so this multilocus model for LD is proposed. It is most useful when the LD of interest is the result of introduction of a variant on an ancestral haplotype with recombinations in later generations giving preservation of a small region of the ancestral haplotype around the variant. The approach works extremely well for fine mapping and for estimation of LD based on simulations.

Benign adult familial myoclonic epilepsy (BAFME), an autosomal dominant idiopathic epileptic syndrome recently recognized in Japanese families, is discussed relative to its localization to chromosome 8q23.3-q24.1. The gene locus was assigned by linkage analysis in a large Japanese kindred.

Juvenile myoclonic epilepsy (JME) represents between 6 and 8 percent of all epilepsies. The syndrome consists of muscle jerks, often occurring in the morning upon wakening; there is no loss of consciousness. About 30 percent of patients with JME have family members with some form of epilepsy, not necessarily JME. Furthermore, JME is found in a family member of about 30 percent of epileptic patients. Research has suggested that a gene for JME might be located on chromosome 6, in close proximity to the genes of the major histocompatibility complex coding for HLA antigens that are important in immunology. A study has now been conducted using more sophisticated techniques of molecular biology to confirm this association. DNA fragments that are specific for the HLA-DQ region of the major histocompatibility complex were used to follow the putative inheritance of epilepsy among members of 21 families. This study confirmed that a gene important for the inheritance of epilepsy appears to be close to the HLA-DQ region on the short arm of chromosome 6 (6p). If only JME, absence seizures, or generalized tonic-clonic seizures are included in the analysis, the penetrance of the gene appears to be about 70 percent. This means that only about 70 percent of the people who inherit the gene actually develop one of these forms of epilepsy. However, some family members were found to have abnormalities on the electroencephalograph (EEG), without having actual symptoms of epilepsy. If these people are included in the analysis, then 90 percent of the people who inherit the gene have some sort of effect, even if they do not have actual symptoms of epilepsy. The random gene recombination events among the 21 families did not permit the researchers to determine if the gene in question is closer to the HLA-DQ genes than to other genes of the histocompatibility complex, such as HLA-A genes or HLA-B genes. Furthermore, the present study did not ascertain that the gene on chromosome 6 is the actual gene that causes the epilepsy. The gene studied may act only as a susceptibility gene, which renders the patient susceptible to some other gene or factors that cause the epileptic syndromes. (Consumer Summary produced by Reliance Medical Information, Inc.)

The progressive myoclonic epilepsy of the Unverricht-Lundborg type (EPM1) is caused by a mutation in a gene encoding cystatin B that suppresses cysteine protease activity. The gene contains 175 kilobases and is present on the human chromosome 21. Cystatin B is a protein that is present in many cells and tissues, such as the brain. Individuals with EPM1 have extremely low levels of cystatin B mRNA, as compared to asymptomatic and unaffected individuals. Affected individuals from different families show different mutations, while some families show no mutation.