Progressive myoclonic epilepsy type 1 (EPM1) is a progressive myoclonus epilepsy caused by pathogenic, autosomal recessive variants in the cystatin B (CSTB) gene mapped to chromosome 21q22.3. The disease is regarded as the “purest” progressive myoclonus epilepsy due to disabling stimulus-sensitive and action myoclonus and generalized tonic-clonic seizures whereas cognitive deterioration and cerebellar signs are mild and slowly progressive. Age at onset ranged between 6 and 13 years (mean, 10 years) and a relatively high frequency is observed on the shores of the Baltic and Mediterranean Seas. In this update, the authors combined progress in the understanding of the molecular pathophysiology of the disease with the latest updates on therapeutical strategies. Widening the knowledge over the molecular basis of this disease may also expand our chance of effective treatment, hence the field opened by neuroinflammation, which is increasingly becoming a suitable target for precision medicine-based approaches also in this disease.
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• EPM1 is an autosomal recessive progressive myoclonus epilepsy.
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• It manifests with action and stimulus-sensitive myoclonus, generalized tonic-clonic seizures, mild and slowly progressive cerebellar ataxia, and cognitive deficits. Myoclonic seizures are severe and debilitate teenagers throughout adolescence and early adulthood.
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• It is mainly caused by a homozygous expansion of a dodecamer repeat near the promoter of the cystatin B (CSTB) gene mapped to chromosome 21q22.3. Thus, the diagnosis can be confirmed by appropriate molecular genetic testing.
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• Valproate, levetiracetam, zonisamide, perampanel, benzodiazepines, and topiramate are first choice antiepileptic drugs for treatment. Conversely, carbamazepine and derivatives, phenytoin, gabapentin, pregabalin, and vigabatrin are contraindicated.
Historical note and terminology
Progressive myoclonic epilepsy type 1 (EPM1) is also known as Unverricht-Lundborg disease. Heinrich Unverricht was a German physician, born on September 18, 1853, in Breslau; he died on April 22, 1912, in Magdeburg.
He was Professor of Medicine in Dorpat, now Tartu, Estonia. In 1891 he described a family of Baltic German origin in which several siblings suffered from a progressive neurologic disease with prominent myoclonus and generalized seizures. Tremor and rigidity have not been described in his patients (87). He also published a volume named Die Myoclonie (100).
Lundborg, from 1898 to 1910, compiled information on 17 patients afflicted by what is now known as EPM1 disease. They all belonged to 1 extensive kindred, the "Lister" family in Listerlandet of southern Sweden. He and Blekinge traced the affected family back to the 1700s (68; 69; 70). Lundborg's thesis on “Die progressive Myoklonus-Epilepsie (Unverricht's Myoklonie)” was 1 of the earliest descriptions of recessive inheritance (69). He had published the names of those affected, and he had concluded that the family had degenerated because of “unwise marriages.” Subsequently, a marriage of relatives was carefully avoided in the group and no more cases occurred. According to Puschmann, Lundborg distinguished 3 stages of the disorder: Stage 1 began in childhood or early adolescence and consisted of nocturnal attacks of involuntary symmetric muscle twitches, which often were painful, caused anxiety, and reminded Lundborg of clonic, tonic-clonic, or tetanic seizures (87). Patients were awake and conscious during the attacks. Stage 2 appeared a few years later with diurnal tremor, myokymia, and myoclonic or dystonic muscle contractions. Typically, the contractions initially affected the upper extremities symmetrically and subsequently involved lower extremities, head, neck, and finally, all voluntary muscles. Tactile and auditory stimuli elicited and stress aggravated these involuntary muscle contractions. Symptom severity fluctuated markedly from day to day. Gradually, increased muscle tone was noted in the interval between attacks. Stage 3 appeared several years to some decades later with the disappearance of the nocturnal attacks while daytime muscle contractions became more and more pronounced. Regularly, marked generalized rigidity developed, leaving some patients utterly stiffened in certain poses, incapable of any voluntary movements. Lundborg noted that the clinical picture of some of his patients in the terminal phase reminded him of Parkinson disease.
Herman Bernhard Lundborg was a Swedish physician, born on April 7, 1868, in Vase, Varmlands lan, and he died in 1943. His radical racist ideas and his influence of Nazi ideology and acts overshadow his contribution to medicine. He was extremely negative to Jewish people and strongly involved in the ideology of racial hygiene. He was also responsible for the massive mapping, The Racial Character of the Swedish Nation, from 1926. He characterized 15% of patients in his work as morally or socially inferior (alcoholic, criminal, wanton, of bad character) and another 9.5% as psychiatrically inferior. He had served as a Professor for Racial Hygiene and he advocated the ideology of race biology. His influence contributed to the implementation of forced sterilization programs in Sweden and his view was that "The future belongs to the racially fine people" (71).
Over the next 80 years, there was a great deal of discussion and misunderstanding of the nature and classification of the progressive myoclonus epilepsies (07; 14; 30; 95; 67; 84; 06; 47; 87), of which EPM1 is the most common. Advances in molecular biology have identified EPM1 disease as a specific genetic disorder encountered in many populations and parts of the globe. It has been described under different names, including Baltic myoclonus or Mediterranean myoclonus, before their identification by genetic studies as the same disorder as EPM1. Similarly, Ramsay Hunt syndrome or dyssynergia cerebellaris myoclonica is no longer considered to be a separate disease (01; 35; 76).
An excellent source of information is an online review of EPM1 by Lehesjoki and Kalviainen (62) and other updates (48).