UNVERRICHT-LUNDBORG DISEASE (ULD)

The first form of PME to be described was that of Unverricht-Lundborg syndrome1.  The major manifestation of the disease is either myoclonus or generalized seizures, both typically manifesting at an average age of 10 to 12 years, with a range of onset of 6 to 15 years2.
 

Unverricht initially described the condition in 1891, and in the early 1900s Lundborg described 17 patients from nine families with the same disease2. The term Baltic myoclonus arose because the descriptions, first by Unverricht, and then by Lundborg, were of families from Estonia and Eastern Sweden respectively, and many cases had also been reported from Finland (Figure 1), where the incidence is estimated to exceed 1 in 20 0003.  However, the disorder is not restricted to the Baltic region, and the term “Baltic myoclonus” has therefore fallen away.  It should be noted that Lundborg was a proponent of racial eugenics, and was appointed Professor for Racial Hygiene and Director of the State Institute for Racial Biology in Uppsala, Sweden, noting that eugenics was a pillar of Nazi ideology and led to the T-4 extermination program4

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Figure 1. Distribution of 127 cases of Unverricht-Lundborg disease about the Baltic sea (Figure from Eldridge, 1983).

A group of patients originating from the Western Mediterranean, including a large number of Northern African subjects with typical features of ULD, and with consanguinity present in 11 families, were proposed to have a novel illness, Mediterranean myoclonus, but this was subsequently shown to be genetically identical to ULD5.

Diagnosis

ULD has been clearly distinguished from PME of Lafora body type2.  The diagnosis is made on the following features:

  1. Stimulus-sensitive myoclonic jerks.
  2. Age at onset from 6-15 years.
  3. Generalized tonic-clonic seizures.
  4. Characteristic EEG.
  5. Progressive course, but typically absence of major cognitive impairment6
  6. Genetics: pathogenic mutation in both alleles of the EPM1 gene.

 

Inheritance

The disorder has an AR inheritance pattern.  The high prevalence in Finland, with a heterozygote frequency estimated at one in 70, as well as haplotype data, are compatible with a single ancestral founder mutation7.  Lundborg’s description was one of the first to detail recessive inheritance, and he published the names of the affected cases.  Subsequently, consanguineous marriages appear to have been avoided in Finland, one of the earliest and largest instances of group genetic counseling. 

 

Myoclonus

Myoclonus can be elicited by light, touch and other stimuli and is accentuated by voluntary movements2.  The myoclonus is described as developing from localised jerks to general shaking attacks of myoclonus,  sometimes leading to generalized seizures2.  Myoclonus was reported to be most severe in the morning and jerks were said to be so severe that they caused the patient to fall to the ground or from a chair.  With progression of the disease, myoclonus may become more severe, arrhythmic and asynchronous2.  The increased severity of myoclonus finally may make patients unable to move unaided and renders them bedridden and helpless towards the end of the second decade. 
Myoclonus may lead to cascade seizures, characterized by a build-up of increasingly intense and violent myoclonic jerks, culminating into a short GTCS. Patients may also experience GTCS or major seizures after a period of progressive increase in myoclonus and subsequently experience less myoclonus, with a decreased risk of major seizures for a period that can last days to weeks6.

 

Clinical Manifestations

In addition to myoclonus, gait ataxia with frequent falls may be an early symptom.  In patients with severe myoclonus, there may be signs of cerebellar disease, with ataxia and intention tremor2,6.  Generally, ataxia developed a few years after disease onset, although it might be mild and progress minimally.  As is usual in many severe forms of myoclonus, the distinction between intention tremor and ataxia was occasionally impossible due to myoclonus. 

Several years after the appearance of the first symptoms, features of the upper motor neuron syndrome were found in a third of patients2.

Intelligence ranges from significantly impaired to normal, and some patients remained intellectually normal 5 to 10 years after the onset of disease2.  However, cognitive function tended to deteriorate with time, with neuropsychological testing correlating well with the stage of disease8.  Some patients developed hallucinations.

 

The average age at death previously was in the middle of the third decade, about 15 years after the appearance of the first symptoms.  However, the progression is variable, and sometimes the illness stopped progressing after many years2.  Life expectancy of patients has improved, likely because of better anti-epileptic drugs, and survival into adulthood is usual, and a normal life expectancy is anticipated. Severity does not appear to be necessarily related to the duration of disease. The outcome in adults ranges from independent active life with minimal impairment to severe disability and being wheelchair-bound or even bedridden6.  Over several (up to 10) years following clinical onset, major seizures and photosensitivity disappear in most patients, while myoclonus stabilizes or progresses only minimally6.  Thus, ULD is characterized by clinical stability in later life.
 

ULD may have had its relatively benign course altered by phenytoin so that the progression resembled that of the much more malignant Lafora body disease9.  Thus, lifespan was reported to have shortened and dementia become more frequent in phenytoin treated patients2, with average duration of survival being 14 years from onset. This report was based on 27 affected members of 15 families in the United States. Phenytoin was of no apparent benefit in all who took it, and in a third, death was associated with its administration”, as compared with use of sodium valproate 9
 

Special Investigations

Until the advent of genetic testing, diagnosis was clinical, and ancillary tests served only to exclude other disorders1, since there are no biochemical abnormalities specific to the disease.  EEG shows generalized slowing with spike and wave discharges and may show photosensitivity, especially initially.  EEG is typically responsive to medication and abnormalities thus tend to resolve with time10. EEG background may be normal initially, resulting in confusion with juvenile myoclonic epilepsy (JME)10.
Identification of affected individuals through genetic testing is now available.

 

Pathology

In patients exposed to phenytoin, which is associated with Purkinje cells loss, a case was reported with marked change in the cerebellum with reduction in the number of Purkinje cells and degenerative changes in the remaining Purkinje cells9 .  The molecular layer had a cribriform appearance and there was a glial response noted in some areas of the inner granular layer.  Koskiniemi reported diffuse Purkinje cell loss, with relative preservation of the dentate nucleus; some neuronal degeneration was noted in the medial thalamic nuclei2.  Haltia reported detailed neuropathological findings in three patients: in addition to pronounced Purkinje cell loss, there was rarefaction and chromatolysis of neurons in cerebral cortex, subpial gliosis and rarefaction of myelin.  Severe neuronal loss was seen in the caudate nucleus, putamen and globus pallidus, as well as medial thalamus.  In the cerebellum, there was marked loss of basket fibers, fibrillary gliosis of the molecular layer, but only slight neuronal loss and degeneration of the dentate nuclei.  In the spinal cord, neurons of Clarke’s column showed chromatolysis11

 

Genetics

The locus for Unverricht-Lundborg disease is at chromosome 21q22.312.  The gene symbol is CSTB, and the gene name is cystatin B; with EPM1 being a synonym.  The gene product is Cystatin B, a cysteine protease inhibitor.  The genetics of the condition are remarkable in that the mutation within cystatin B is made up of a dodecamer repeat, “CCCGCCCCGCG’’ typically of 30-80 copies, which accounts for 90 % of known cases of Unverricht-Lundborg disease7,13,14

 

Epidemiology

The disorder is commonest in Finland, but is also prevalent in the Maghreb (Morocco, Algeria, and Tunisia).  Patients have been described from Japan, Europe, North America, and other countries. 

 

Management

The drugs of choice are the antimyoclonic agents valproic acid, clonazepam, and piracetam.  Antiepileptic agents relatively easily control the generalized seizures, but myoclonus often proves difficult to control. 
Unlike most forms of epilepsy, PME is best treated by polytherapy, including the three agents mentioned above. 

 

 

 

 

1.        Berkovic SF, Andermann F, Carpenter S, Wolfe LS. Progressive myoclonus epilepsies: specific causes and diagnosis. N Engl J Med [Internet] 1986;315(5):296–305. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3088452

2.        Koskiniemi M, Donner M, Majuri H, Haltia M, Norio R. Progressive myoclonus epilepsy. A clinical and histopathological study. Acta Neurol Scand [Internet] 1974 [cited 2013 Feb 16];50(3):307–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4835645

3.        Sipilä JOT, Hyppönen J, Kytö V, Kälviäinen R. Unverricht–Lundborg disease (EPM1) in Finland: A nationwide population-based study. Neurology 2020;10.1212/WNL.0000000000010911.

4.        Kondziella D, Hansen K, Zeidman LA. Scandinavian neuroscience during the Nazi era. Can J Neurol Sci 2013;40(4):493–503.

5.        Malafosse A, Lehesjoki AE, Genton P, et al. Identical genetic locus for Baltic and Mediterranean myoclonus. Lancet [Internet] 1992 [cited 2013 Apr 30];339(8801):1080–1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1349105

6.        Crespel A, Ferlazzo E, Franceschetti S, et al. Unverricht-Lundborg disease. Epileptic Disord [Internet] 2016;18(S2):28–37. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27582036

7.        Virtaneva K, Paulin L, Krahe R, de la Chapelle A, Lehesjoki AE. The minisatellite expansion mutation in EPM1: resolution of an initial discrepancy. Mutatations in brief no. 186. Online. Hum Mutat [Internet] 1998;12(3):218. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10660338

8.        Leino E, Partanen J, Helkala EL, Riekkinen PJ. Clinical stages of progressive myoclonus epilepsy in adult patients. Acta Neurol Scand [Internet] 1982;65(1):19–29. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6801911

9.        Eldridge R, Iivanainen M, Stern R, Koerber T, Wilder BJ. ‘Baltic’ myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin. Lancet [Internet] 1983 [cited 2013 Apr 30];2(8354):838–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6137660

10.      Gargouri-Berrechid A, Nasri A, Kacem I, et al. Long-term evolution of EEG in Unverricht-Lundborg disease. Neurophysiol Clin [Internet] 2016;46(2):119–24. Available from: http://dx.doi.org/10.1016/j.neucli.2016.03.003

11.      Haltia M, Kristensson K, Sourander P. Neuropathological studies in three Scandinavian cases of progressive myoclonus epilepsy. Acta Neurol Scand [Internet] 1969 [cited 2013 Apr 29];45(1):63–77. Available from: http://www.ncbi.nlm.nih.gov/pubmed/4979532

12.      Lehesjoki AE, Koskiniemi M, Sistonen P, et al. Localization of a gene for progressive myoclonus epilepsy to chromosome 21q22. Proc Natl Acad Sci U S A 1991;88(9):3696–9.

13.      Pennacchio LA, Lehesjoki AE, Stone NE, et al. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science (80- ) 1996;271(5256):1731–4.

14.      Lafrenière RG, Rochefort DL, Chrétien N, et al. Unstable insertion in the 5’ flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. Nat Genet [Internet] 1997;15(3):298–302. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9054946

 

References