Myoclonic epilepsy of Unverricht and Lundborg is an autosomal recessive disorder characterized by onset of neurodegeneration between 6 and 13 years of age. Although it is considered a progressive myoclonic epilepsy, it differs from other forms in that ... Myoclonic epilepsy of Unverricht and Lundborg is an autosomal recessive disorder characterized by onset of neurodegeneration between 6 and 13 years of age. Although it is considered a progressive myoclonic epilepsy, it differs from other forms in that is appears to be progressive only in adolescence, with dramatic worsening of myoclonus and ataxia in the first 6 years after onset. The disease stabilizes in early adulthood, and myoclonus and ataxia may even improve, and there is minimal to no cognitive decline (summary by Ramachandran et al., 2009). - Genetic Heterogeneity of Progressive Myoclonic Epilepsy Progressive myoclonic epilepsy refers to a clinically and genetically heterogeneous group of neurodegenerative disorders, usually with debilitating symptoms, although severity varies. See also EPM1B (612437), caused by mutation in the PRICKLE1 gene (608500); Lafora disease (EPM2A/B; 254780), caused by mutation in either the EPM2A (607566) or the NHLRC1 (608072) gene; EPM3 (611726), caused by mutation in the KCTD7 gene (611725); EPM4 (254900), caused by mutation in the SCARB2 gene (602257); EPM5 (613832), caused by mutation in the PRICKLE2 gene (608501); and EPM6 (614018), caused by mutation in the GOSR2 gene (604027). Other disorders characterized by progressive myoclonic epilepsy include the neuronal ceroid lipofuscinoses (see, e.g., CLN1; 256730); sialidosis (256550); MERFF (545000); and DRPLA (125370), among others (reviews by Ramachandran et al., 2009 and Mendonca de Siqueira, 2010).
Unverricht (1891, 1895) and Lundborg (1903) first reported a type of progressive myoclonic epilepsy common in Finland. Onset of the disorder occurred around age 10 years, and was characterized by progressive myoclonus resulting in incapacitation, but only mild ... Unverricht (1891, 1895) and Lundborg (1903) first reported a type of progressive myoclonic epilepsy common in Finland. Onset of the disorder occurred around age 10 years, and was characterized by progressive myoclonus resulting in incapacitation, but only mild mental deterioration. Histological studies of the brain showed 'degenerative' changes without inclusion bodies. Severity and survival were variable (Norio and Koskiniemi, 1979). Eldridge et al. (1981, 1983) referred to this disorder as the 'Baltic type' of myoclonic epilepsy because the descriptions first by Unverricht and then by Lundborg were in families from Estonia and Eastern Sweden and subsequent patients were found in Finland. Eldridge et al. (1983) found 15 families in the United States. The 27 affected members had the following features starting at about age 10 years: stimulus- and photo-sensitive and occasionally violent myoclonus, usually worse upon waking; generalized tonic-clonic seizures, sometimes associated with absence attacks; and light-sensitive, generally synchronous, spike-and-wave discharges on EEG that preceded clinical manifestations. Necropsy showed marked loss of Purkinje cells of the cerebellum, but no inclusion bodies. Phenytoin was associated with progressive motor and intellectual deterioration, marked ataxia, and even death. Treatment with valproic acid was associated with marked improvement. Contrary to myoclonic epilepsy with Lafora bodies, intelligence in this form was only slightly affected and psychotic symptoms were not found. In addition, Lafora body disease is invariably fatal. Kyllerman et al. (1991) described 4 sibs who demonstrated a subclinical stage of this disorder at the age of 9 to 11 years, with visual blackouts and polyspike electroencephalographic (EEG) activity on photic stimulation; an early myoclonic stage at the age of 12 to 15 years, with increasing segmental, stimulus-sensitive myoclonus, occasional nocturnal buildup myoclonic 'cascade' seizures, slowing of EEG alpha-activity, episodic 4-6 Hz bilateral sharp waves and polyspikes with myoclonus on photic stimulation; and a disabling myoclonic stage at the age of 16 to 18 years, with periodic generalized myoclonus, nocturnal myoclonic 'cascade' seizures, ataxia, dysarthria, mental changes, intermittent wheelchair dependency, and continuous EEG slow waves with polyspikes and intense myoclonus on photic stimulation. One of the sibs died at the age of 18 years with no apparent cause of death. As pointed out by the Marseille Consensus Group (1990), patients with Ramsay Hunt syndrome (159700) cannot be distinguished clinically from patients with Unverricht-Lundborg disease. Linkage studies may help determine whether that disorder is caused by mutation at the same locus. Cochius et al. (1994) reported for the first time a pathologic abnormality outside the central nervous system in patients with Unverricht-Lundborg disease. They found membrane-bound vacuoles with clear contents in eccrine clear cells and dark cells in 5 of 7 patients, as well as in 1 clinically unaffected sib. Sweat gland vacuoles were not seen in the biopsies of 8 patients with Lafora disease. Photosensitivity, i.e., precipitation of myoclonic jerks by intermittent photic stimulation, is a characteristic feature of progressive myoclonic epilepsies. Mazarib et al. (2001) described an affected Arab family in which photosensitivity was absent. Mascalchi et al. (2002) performed MRI and proton MRS on 10 patients with genetically confirmed EPM1 and found significant loss of bulk of the basis pontis, medulla, and cerebellar hemispheres as well as mild cerebral atrophy, compared to 20 healthy controls. The findings differed in some critical features from those in olivopontocerebellar atrophy. Mascalchi et al. (2002) concluded that their findings support the hypothesis that the disease results from a decreased inhibitory control of the cerebral cortex by the brainstem and cerebellum via the thalamocortical loop. Canafoglia et al. (2004) found different electrophysiologic profiles representing sensorimotor cortex hyperexcitability in 8 patients with Lafora disease (age range, 14 to 27 years) and 10 patients with Unverricht-Lundborg disease (age range, 25 to 62 years). In general, the ULD patients had a quasistationary disease course, rare seizures, and little or no mental impairment, whereas the Lafora disease patients had recurrent seizures and worsening mental status. Patients with ULD had prominent action myoclonus clearly triggered by voluntary movements. Lafora disease patients experienced spontaneous myoclonic jerks associated with clear EEG paroxysms with only minor action myoclonus. Although both groups had enlarged or giant somatosensory evoked potentials, the pattern in the Lafora group was consistent with a distortion of cortical circuitry. Patients with ULD had enhanced long-loop reflexes with extremely brief cortical relay times. The findings were consistent with an aberrant subcortical or cortical loop, possibly short-cutting the somatosensory cortex, that may be involved in generating the prominent action myoclonus that characterizes ULD. Patients with Lafora disease had varied cortical relay times and delayed and prolonged facilitation as evidenced by sustained hyperexcitability of the sensorimotor cortex in response to afferent stimuli. The findings were consistent with an impairment of inhibitory mechanisms in Lafora disease.
Pennacchio et al. (1996) used a combination of genetic and physical mapping information to search systematically for the causative gene for EPM1. Several cDNAs identified with a bacterial artificial chromosome (BAC) clone encoded a previously described protein, cystatin ... Pennacchio et al. (1996) used a combination of genetic and physical mapping information to search systematically for the causative gene for EPM1. Several cDNAs identified with a bacterial artificial chromosome (BAC) clone encoded a previously described protein, cystatin B (601145), a cysteine protease inhibitor. Because of the wide expression of the cystatin B gene in normal individuals and the finding of reduced expression in lymphoblastoid cells from affected individuals, Pennacchio et al. (1996) sequenced the cystatin B gene (also known as stefin B) from affected individuals and identified 2 different mutations in the gene. Cystatin C (CST3; 604312) is the site of heterozygous mutations causing hereditary cerebral amyloid angiopathy. This dominantly inherited disorder is characterized by the deposition of cystatin C-rich amyloid fibrils in affected brain arteries. EPM1 is inherited as a recessive and appears to be the result of decreased amounts of cystatin B, suggesting different mechanisms for the 2 diseases. The genes responsible for Lafora disease (254780) (EPM2A; 607566) and juvenile myoclonic epilepsy (254770) mapped to 6q and 6p, respectively. The identification of cystatin B defects in EPM1 suggested that other members of the cystatin superfamily or their substrates may be defective in these related epilepsies. See 601145 for point mutations identified in the stefin B gene in patients with EPM1. Lafreniere et al. (1997) and Virtaneva et al. (1997) reported a novel type of disease-causing mutation, an unstable minisatellite repeat expansion in the putative promoter region of the gene (601145.0003). The mutation accounted for most EPM1 patients worldwide. Virtaneva et al. (1997) noted that haplotype data from their study were compatible with a single ancestral founder mutation. The length of the repeat array differed between chromosomes and families, but changes in repeat number seemed to be comparatively rare events. Lalioti et al. (1997) identified 6 nucleotide changes in the CSTB gene in non-Finnish EPM1 families from northern Africa and Europe. One of these, a homozygous G-to-C transversion at nucleotide 426 in exon 1, resulted in a gly4-to-arg substitution (G4R; 601145.0004) and was the first missense mutation described in association with EPM1. Molecular modeling predicted that this substitution would severely affect the contact of cystatin B with papain. The 6 mutations were found in 7 of the 29 unrelated EPM1 patients analyzed, in homozygosity in 1, and in heterozygosity in the others. They also found a tandem repeat of a dodecamer (CCCCGCCCCGCG) in the 5-prime untranslated region as a polymorphism (601145.0003). They identified 2 allelic variants with 2 or 3 tandem copies. The frequency of the 3-copy allele was 66% in the normal Caucasian population. In an elaboration on their previous work, Lalioti et al. (1997) stated that the common mutation mechanism in EPM1 is the expansion of the dodecamer repeat (601145.0003), and considered this mutation to be the most likely source of the disorder. An examination of 58 EPM1 alleles revealed that 50 of these contained the dodecamer repeat expansion. In addition to the expanded repeat mutation and the 2 or 3 repeats found in alleles considered to be normal, Lalioti et al. (1997) identified alleles with 12 to 17 repeats, which they termed 'premutational,' that were transmitted unstably to offspring. These 'premutational' alleles were not connected with a clinical phenotype of EPM1. Lalioti et al. (1997) stated that no correlation between number of repeat expansions and age of onset or severity had been found. Antonarakis (1997) confirmed that the only EPM1-related point mutation in the cystatin B gene found in homozygous state was the G4R amino acid substitution. All other point mutations identified in EPM1 patients were found as compound heterozygotes with the 12-bp repeat expansion allele. The repeat expansion allele was also homozygous in some patients. Antonarakis (1997) found no patients with null point mutations (e.g., nonsense, frameshift, or splice site) in homozygous state; all EPM1 patients had residual gene activity. He proposed that homozygosity for null alleles was either nonviable or presented a different phenotype.
Koskiniemi et al. (1980) estimated that over 100 cases in 70 sibships had been identified in Finland. Fewer cases had been found in all the rest of the world. The incidence in Finland is about 1 in 20,000. ... Koskiniemi et al. (1980) estimated that over 100 cases in 70 sibships had been identified in Finland. Fewer cases had been found in all the rest of the world. The incidence in Finland is about 1 in 20,000. Moulard et al. (2002) stated that Unverricht-Lundborg disease is also common North Africa but less common in western Europe. They performed a haplotype study of Unverricht-Lundborg disease chromosomes with a dodecamer repeat expansion in the CSTB gene (601145.0003), the most frequent cause of the disorder. They found that 29 (61.7%) of 47 patients from North Africa shared the same haplotype, thus establishing a founder effect in this population. The haplotypes from 48 Caucasian patients from western Europe were heterogeneous.