The history of progressive myoclonus epilepsies

Abstract

The history of the progressive myoclonus epilepsies (PMEs) spans more than a century. However, the recent history of PMEs begins with a consensus statement published in the wake of the Marseille PME workshop in 1989 (Marseille Consensus Group, 1990). 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.) which could lead to a precise diagnosis of a given PME type, with, in the best cases, a reliable correlation with clinical findings. In this article, we shall also examine the breakthroughs achieved in the wake of the 1989 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.

Keywords: Kufs; Lafora; Unverricht-Lundborg; progressive myoclonus epilepsy.

Figure 1

Herman Lundborg (1868–1943). Herman Lundborg wrote his dissertation in 1903 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 1922. He came under strong criticism and disrepute due to his adherence to Nazi ideology and his advocacy of eugenics and the sterilisation of “genetically unworthy” persons.

Figure 2

A pedigree showing recessive transmission in a family with Unverrich-Lundborg disease (From Lundborg & Runnstom [1921]).

Figure 3

Heinrich Unverricht (1853–1912). Bust erected in 1914 at Magdeburg University. During his short tenure at Dorpat (now Tartu, Estonia), which he left because of the Russification policies of the occupying forces, Heinrich Unverricht described a family with “Myoclonie”, i.e. with the condition now named after him, “Unverricht-Lundborg disease”. 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.

Figure 4

Gonzalo Rodriguez Lafora (1886–1971). After studying in Spain (with Santiago Ramón Cajal), France (with Pierre Marie and Joseph Jules Dejerine), Germany (with Alois Alzheimer and Emil Kraepelin) and the USA, Gonzalo Rodriguez Lafora returned to Spain (which he had left for Mexico during the Civil War in 1938; he returned to Madrid in 1947). 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. During his tenure as a neuropathologist at the Government Hospital for the Insane in Washington DC, he published his landmark paper on “myoclonic corpuscles”, in German.

Figure 5

James Ramsay Hunt (1874–1937). After studying in Philadelphia, Paris, Berlin and Vienna, James Ramsay Hunt practised and taught neurology in New York City (Cornell University and Columbia University). His name is associated with a small cutaneous zone innervated by the ganglion geniculi. His contribution to the field of PME from 1914 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 “Ramsay Hunt Syndrome”, when applied to a neurological condition with myoclonus, was used to refer to many disparate entities. The term is no longer in use, following the delimitation of discrete PME types.