Epilepsy: Electroclinical Syndromes pp Cite as. Progressive myoclonic epilepsy or progressive myoclonus epilepsy PME is a rare condition. It is commonly hereditary, is characterized by generalized convulsive seizures and myoclonic jerks frequently provoked by volitional movements, and is frequently associated with cerebellar ataxia, mental deterioration, pyramidal signs, and rigidity. PME is regarded as a syndrome having various causes Table 9. Unable to display preview. Download preview PDF.
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The history of the progressive myoclonus epilepsies PMEs spans more than a century. This consensus helped define the various types of PME known at the time and set the agenda for a new era of genetic research which soon lead to the discovery of many PME genes. Prior to the Marseille meeting, and before the molecular era, there had been much confusion and controversy.
Because investigators had but limited and biased experience with these rare disorders due to the uneven, skewed distribution of PMEs around the world, opinions and nosologies were based on local expertise which did not match well with the experiences of other researchers and clinicians. The three major areas of focus included: 1 the nature and limits of the concept of PME in varying scopes, which was greatly debated; 2 the description of discrete clinical entities by clinicians; and 3 the description of markers pathological, biological, neurophysiological, etc.
In this article, we shall also examine the breakthroughs achieved in the wake of the Marseille meeting and recent history in the field, following the identification of several PME genes. As in other domains, the molecular and genetic approach has challenged some established concepts and has led to the description of new PME types. However, as may already be noted, this approach has also confirmed the existence of the major, established types of PME, which can now be considered as true diseases.
No clear disease entity was associated with these jerks Friedreich, Their contributions were widely read and commented upon, but failed to convince later authors that they had described a recognisable, specific condition. In order to reach a consensus, there were obviously too few cases in the patienthood of major neurologists at the time.
Herman Lundborg — Herman Lundborg wrote his dissertation in at the Karolinska Institutet, in Stockholm, about a family with the condition previously described by Unverricht, which he studied from a clinical point of view but also from a genetic perspective.
His interest in genetics led him to found the notorious State Institute of Racial Biology, in Uppsala, in Heinrich Unverricht — Bust erected in at Magdeburg University.
He was a prolific internist who also described other conditions polymyositis and pneumonia. His contribution is regarded as the founding description of progressive myoclonus epilepsy. Gonzalo Rodriguez Lafora — As a psychiatrist, he introduced the Freudian doctrine to both Spain and Argentina, but mainly dedicated his life to the care of intellectually disabled children.
Hunt figure 5 contributed to the complexity of the matter by describing patients with signs of Friedreich's ataxia associated with action myoclonus and in some cases epilepsy Hunt, RHS was finally discarded as a useful entity Andermann et al. James Ramsay Hunt — His name is associated with a small cutaneous zone innervated by the ganglion geniculi.
His contribution to the field of PME from onward was the source of great confusion; from his area of low prevalence, he selected several unrelated cases with myoclonus and other symptoms. The term is no longer in use, following the delimitation of discrete PME types.
There were, however, efforts to try and introduce order to the PMEs. Van Bogaert approached the issue from a mixed neuropathological and clinical point of view, and supported the concept of PME, but failed to establish clear boundaries between the various types Van Bogaert, Heralding the modern approach, the Montreal group also acknowledged the concept of PME and proposed a classification that was, subjectively, based on the relative frequency of these rare conditions Berkovic et al.
Before the genetic advances of the past twenty years had really had an impact, the Marseille group Genton et al. MERRF and sialidosis , those with a definite and reliable pathological marker e.
Table 1 summarises, for the major PMEs, the progression from clinical descriptions to molecular elucidation, which is currently nearly complete. However, it appears that the process was fairly uneven. Discovery and description of the main, classical PME types: the time flow, from clinical description to diagnostic marker to genetic localisation and elucidation, by chronological order of initial clinical descriptions.
For a detailed history of the various PME type, refer to the relevant chapter. In the classic sequence of events, a clinical description occurred first, followed by a more or less specific biological or neurophysiological marker which helped ascertain the diagnosis. This was the case for the various forms of NCLF.
While Batten had not initially distinguished these conditions from one another Batten, , in an ophthalmologist, Alfred Bielschowsky, characterised the ocular findings in the late infantile form of NCLF. The more specific pathological, ultrastructural changes associated with the infantile and juvenile types of NCLF were only described in the s Zeman et al.
Although it took some time to differentiate NCLF from other types of degenerative childhood diseases, which included mental decline and retinal impairment, they were fairly well distinguished, on clinical grounds, from other types of PMEs. However, another condition with optional ophthalmological symptoms, sialidosis, was only clearly identified in the s Rapin et al. In the case of Lafora's disease, the pathological marker, the presence of amyloid deposits in the brain, was described by Gonzalo Lafora in , together with a fairly precise clinical depiction of the condition named after him.
From this point onwards, LD was for most, but not all, a clearly identifiable entity. In subsequent years, several refinements were made to the clinical description, focusing on the characteristic EEG presentation and on the occurrence of occipital lobe seizures Roger et al. Diagnosis was much more difficult in the absence of precise markers, when the clinician was left to speculate on patient cases purely on the basis of clinical traits.
Some neurophysiological features were shared by several, clearly different conditions. Indeed, based on their own experience, various authors promoted a regional type of PME, which dominated local experiences.
An explanation had already been given for the difference in severity; in Northern Europe, phenytoin, the most prescribed anticonvulsant for epilepsies with convulsive seizures including myoclonic seizures , had clearly contributed to an artificial aggravation of the condition Elridge et al. In the s, convincing descriptions of new entities emerged, such as mitochondrial encephalopathy with ragged-red fibres MERRF Fukuhara et al. The time had come to compare the experience of researchers from Europe, America and Japan; an international workshop was organised in Marseille in June , which heralded the modern, genetic and molecular era in PME research.
Prior to , the year of the Marseille conference, it had only been possible to identify the gene for only one autosomal recessive PME NEU1; sialidosis , using classic biochemical methods Rapin et al.
The Marseille conference coincided with momentous developments in the history of genetics. The microsatellite maps that rapidly followed had just the right density for homozygosity and linkage mapping of autosomal recessive Mendelian diseases, and since the vast majority of PMEs are inherited in this fashion, their genes quickly began to be identified in the years that followed.
PME gene discoveries proceeded in the approximate order in which the diseases themselves had been described, which is likely to be a reflection of the relative frequencies of the various diseases.
The authors isolated lysosomal proteins and looked for a missing spot in two-dimensional gels in patients with late-infantile NCL, in order to identify CLN2, a lysosomal dipeptidyl peptidase Sleat et al.
The remaining childhood NCL genes followed in the first decade of the new millennium, again for the most part through homozygosity and linkage mapping Nita et al. Most recently, disease genes, including PME genes, emerged in larger numbers, through combined use of SNP mapping arrays and next-generation whole-exome and whole-genome sequencing. Here, identification of disease genes can be based on as few as one patient. The best example of this technical progress relates to Kufs disease adult-onset NCL.
While this disease has been known for 88 years, it was not until advanced mapping and sequencing techniques became routinely used that its genetic cause was uncovered.
This turned out not to be a single gene but, to date, at least four different genetic entities Nita et al. Some PMEs are very rare, caused by private mutations in single families. It is expected that many such PMEs will be identified, as has been the case for other diseases. Mutation for certain genes is limited to allow for viability, but may result in a specific pathology that cannot be replicated by other defects of the same protein.
As recessively inherited diseases, many PMEs occur fairly frequently in pets and farm animals, due to inbreeding. This includes LD, which is widespread in certain breeds of dog Lohi et al. In some cases, PME genes were first discovered in animals and then translated to humans, e. PME comparisons between humans and animals has also yielded fascinating insights into genome biology. For example, human ULD is a disease which is not due to the complete absence of the responsible gene EPM1 , but to drastic downregulation of the gene's expression caused by expansion of a dodecamer repeat sequence.
This repeat is present in the promoter of the human EPM1 gene but not in the promoter of the orthologous genes in animals. In humans, expansion of this dodecamer leads to significant downregulation but not to the complete absence of EPM1 mRNA. No patient is reported to have, or probably exists with, a total loss of EPM1. Because of the unique genomic particularity within the promoter sequence of the EPM1 gene, ULD is, therefore, a uniquely human disease and no natural animal model of the disease has been reported.
As a second example, the dog genome has a similar dodecamer repeat in the Epm2b gene, one of the genes mutated in LD. Recurrent expansion of this repeat in canine Epm2b makes LD particularly common in dogs, but this mechanism does not occur in human cases with LD Lohi et al.
PMEs comprise a group of rare, heterogeneous genetic mainly autosomal recessive disorders, characterised by cortical myoclonus, other types of epileptic seizures, and progressive neurocognitive impairment. PMEs usually present in late childhood or adolescence, which distinguishes them from epileptic encephalopathies that start with polymorphic seizures in early infancy.
However, adult-onset PMEs may be due to rare gene defects or to immune or late degenerative disorders. Recent advances in this area have clarified molecular genetic basis, biological basis, and natural history, and have also provided a rational approach to diagnosis.
However, PMEs still remain uncommon disorders which are difficult to diagnose in the absence of extensive experience with such conditions, and this severely limits the number of expert groups in the field. Thus, despite the advances in molecular medicine, aetiology remains undetermined in a substantial proportion of patients.
In particular, there are still huge areas in medically developing parts of the world, where the diagnosis of PME is probably overlooked. Therefore, the actual prevalence of these conditions is still debatable.
The history of PMEs shows that international collaboration and sharing experience is the right way to proceed. The Marseille conference occurred at a perfectly opportune moment, serving to clarify and classify the many PME syndromes known at that time.
This was the springboard from which scientists, armed with the genetic and genomic tools that were then being invented, were able to rapidly identify causative defects. It is probably safe to say that we have now identified most PME genes, but it is equally safe to expect that many others remain to be found.
Each one, however unique, will fill one of the gaps in the great PME puzzle. This will enable us to better understand this severe brain disease, and to move forward towards grasping some of the mysteries of the human brain. At the same time, the emerging picture and biological insights will allow us to find ways to provide our patients with meaningful treatment.
National Center for Biotechnology Information , U. Epileptic Disord. Author manuscript; available in PMC Jan Berge A. Author information Copyright and License information Disclaimer.
Copyright notice. The publisher's final edited version of this article is available at Epileptic Disord. See other articles in PMC that cite the published article. Abstract The history of the progressive myoclonus epilepsies PMEs spans more than a century.
The History of Progressive Myoclonus Epilepsies
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Progressive Myoclonic Epilepsy
The history of the progressive myoclonus epilepsies PMEs spans more than a century. This consensus helped define the various types of PME known at the time and set the agenda for a new era of genetic research which soon lead to the discovery of many PME genes. Prior to the Marseille meeting, and before the molecular era, there had been much confusion and controversy. Because investigators had but limited and biased experience with these rare disorders due to the uneven, skewed distribution of PMEs around the world, opinions and nosologies were based on local expertise which did not match well with the experiences of other researchers and clinicians. The three major areas of focus included: 1 the nature and limits of the concept of PME in varying scopes, which was greatly debated; 2 the description of discrete clinical entities by clinicians; and 3 the description of markers pathological, biological, neurophysiological, etc. In this article, we shall also examine the breakthroughs achieved in the wake of the Marseille meeting and recent history in the field, following the identification of several PME genes.