We describe two couples of sibs from a southern Italian family affected by epilepsy, myoclonus, mental retardation and slight ataxia. Onset was between 4 and 12 years and the course slowly progressive. The clinical picture suggested the diagnosis of Unverricht-Lundborg disease. Molecular study excluded linkage to EPM1. Other possible causes of progressive myoclonus epilepsy were also excluded.
"The autoptic results of pathologists on the brain of the deceased patients show neural degeneration in several areas of the central nervous system with cerebellar damage and serious alterations of the Purkinje cells . Although the cstb gene is responsible for the disease, recently, cases have been described that carry mutations associated with genes located on different chromosomes   . "
[Show abstract][Hide abstract] ABSTRACT: Progressive myoclonus epilepsy type 1 (EPM1) is a neurodegenerative disease correlating with mutations of the cystatin B gene. Cystatin B is described as a monomeric protein with antiprotease function. This work shows that, in vivo, cystatin B has a polymeric structure, highly resistant to SDS, urea, boiling and sensitive to reducing agents and alkaline pH. Hydrogen peroxide increases the polymeric structure of the protein. Mass spectrometry analysis shows that the only component of the polymers is cystatin B. EPM1 mutants of cystatin B transfected in cultured cells are also polymeric. The banding pattern generated by a cysteine-minus mutant is different from that of the wild-type protein as it contains only monomers, dimers and some very high MW bands while misses components of MW intermediate between 25 and 250 kDa. Overexpression of wild-type or EPM1 mutants of cystatin B in neuroblastoma cells generates cytoplasmic aggregates. The cysteine-minus mutant is less prone to the formation of inclusion bodies. We conclude that cystatin B in vivo has a polymeric structure sensitive to the redox environment and that overexpression of the protein generates aggregates. This work describes a protein with a physiological role characterized by highly stable polymers prone to aggregate formation in vivo.
[Show abstract][Hide abstract] ABSTRACT: Unverricht-Lundborg disease (ULD) is the purest and least severe type of progressive myoclonus epilepsy (PME), and is not associated with progressive cognitive deficit. Symptoms stabilize in adulthood, with a varying degree of permanent, often severe handicap that is mostly due to myoclonus. The disorder follows an autosomal recessive transmission pattern, with onset between 8 and 15 years years of age of generalized tonic-clonic or clonic-tonic-clonic seizures, action myoclonus (massive or segmental), photosensitivity, and often ataxia. Prevalence varies, it is highest in certain isolates (Finland, La Réunion Island) and in region with higher levels of inbreeding (Maghreb). ULD is due to a deficit in cystatin B (stefin B), but the mechanisms leading to the clinical symptoms are not well understood. The causative gene, PME1, was identified in 1991 and localized to chromosome 21q22.3. The mutations are mainly expansions of the CCCCGCCCCGCG dodecamer, but less common point mutations were also found. A variant has been recently reported in a Palestinian family, with localization on chromosome 12. The diagnosis of ULD is made on the basis of family history, age at onset, geographical and ethnic context, and on the typical features of myoclonus and epilepsy, in the absence of cognitive and sensory deficits. Neurophysiological evaluation yields interesting, but unspecific results. There are no biological or pathological markers for ULD. Molecular analysis confirms the diagnosis in most patients. Genetic testing for heterozygotes and even prenatal diagnosis are possible, although seldom performed, if the mutation has been identified. In spite of intensive research, ULD has yet to reveal all of its secrets. It remains a quasi “idiopathic“ type of PME, with limited progression. Clinicians and patients are still waiting for an etiologically oriented treatment, which should, ideally, be admnistered early in the course of the disease, if possible before the onset of invalidating symptoms.
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