To establish the extent of disease in an individual diagnosed with the disease, a clinical examination including evaluation of walking, coordination, handwriting, school performance, and emotional features is essential. In addition, examination of myoclonus should include evaluation of myoclonus at rest, with action, and in response to stimuli. EEG should be evaluated before a therapy is initiated, as it is most characteristic before use of anticonvulsive medication. Finally, the diagnosis can be further supported and confirmed with the detection of the mutation in cystatin B gene.
EPM1 is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
CSTB gene encoding cystatin B, a cysteine protease inhibitor, is the only gene known to be associated with ULD (Pennacchio et al., 1996, see also the review of Joensuu et al., 2007a). Virtually all affected individuals have an unstable expansion of a 12-nucleotide (dodecamer) repeat 5′-CCC-CGC-CCC-GCG-3′ (Lalioti et al., 1997) in at least one of the two altered CSTB alleles; the majority of individuals have two expanded repeats in abnormal allele range (Lafreniere et al., 1997; Lalioti et al., 1997; Virtaneva et al., 1997). The expanded dodecamer repeat mutation accounts for approximately 90% of ULD alleles found throughout the world. About 99% of affected Finnish cases are homozygotes for expanded alleles. Normal alleles comprise of 2-3 dodecamer repeats, whereas full penetrance alleles associated with the disease phenotype contain at least 30 dodecamer repeats. The largest allele observed to date using Southern blotting is about 125 dodecamer repeats (Virtaneva et al., 1997). Alleles of 12-17 dodecamer repeats have been observed, but individuals with alleles in this range have not undergone thorough clinical evaluation for signs and symptoms of EPM1; therefore, one cannot say that these alleles are normal (Lalioti et al., 1997). Alleles of 4-11 dodecamer repeats and 18-29 dodecamer repeats have not been reported.
Genetic testing of CSTB gene is used to confirm the ULD diagnosis as well as for carrier testing and prenatal diagnosis. Summary of genetic testing used in ULD is given in Table 1 (modified from Lehesjoki & Kälviäinen, 2007). Usually in clinical practice, testing for the common dodecamer repeat expansion mutation or testing for other CSTB gene mutations are applied. Mutation scanning or sequence analyses are the methods used mainly for research testing purposes. When heterozygosity for the dodecamer expansion is found in a clearly affected individual, it is appropriate to pursue molecular genetic testing of the other known CSTB mutations (Joensuu et al., 2007b) that are commercially available. If they remain negative, a complete sequence analysis should be then performed in every patient in whom only one allele is showing the dodecamer repeat expansion. DNA testing should not be confined to the testing of only the known mutations since this may lead to a false-negative diagnosis. Usually both children and adults who are symptomatic benefit from having a specific diagnosis established.
Table 1. Summary of molecular genetic testing used in ULD (modified from Lehesjoki & Kälviäinen, 2007)
|Molecular genetic testing used in Unverricht-Lundborg disease|
|Test method||Mutations detected||Mutation detection rate||Test availability|
|Targeted mutation analysis||Dodecamer repeat expansion in the promoter of CSTB||99% of disease alleles in Finnish individuals; ∼90% of disease alleles worldwide||Clinical testing|
| ||c.10G>C, c.67-1G>C, c.169-2A>G, c.202C>T, c.218_219delTC||Unknown|| |
|Mutation scanning or sequence analysis||Other mutations in CSTB||Unknown||Research only|
On the other hand, certain considerations should be taken into account when planning genetic testing of at-risk asymptomatic individuals. Usually affected individuals have their first symptoms before age 18 years; therefore, requests from parents for testing of asymptomatic at-risk individuals younger than age 18 years may arise (Lehesjoki & Kälviäinen, 2007). Consensus holds that asymptomatic individuals younger than age 18 years who are at risk for nontreatable disorders should not have testing. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications (Bloch & Hayden, 1990; Harper & Clarke, 1990). In addition, no preventive treatment is available (Lehesjoki & Kälviäinen, 2007).
Testing of at-risk asymptomatic adult family members is possible if they seek testing in order to make personal decisions regarding reproduction, financial matters, career planning, or simply because of the “need to know.” However, it is not useful in predicting whether symptoms will occur, or if they do, what the age of onset, severity, and type of symptoms, or rate of disease progression will be. An affected family member should be tested first to confirm the molecular diagnosis in the family. Testing of asymptomatic individuals usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of ULD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations (Lehesjoki & Kälviäinen, 2007).
Individuals with major mutations in CSTB are believed to develop similar disease manifestation regarding the main symptoms. So far no obvious correlation has been found between the length of the expanded dodecamer repeat and the age of onset or disease severity (Lafreniere et al., 1997; Lalioti et al., 1997; Virtaneva et al., 1997; Lalioti et al., 1998), but no detailed evaluation of phenotype-genotype correlation during the current era of clinical and molecular genetic methods has been performed. It is clear, however, that the disease severity may vary among affected individuals even within a family who have apparently similar repeat-size expansions. Regarding the other mutations, we have studied four adult patients who are compound heterozygotes for the dodecamer repeat expansion mutation and for the c.202C>T mutation. The age at onset of the clinical symptoms seems to be relatively early, at the age of 6–7 years and the myoclonus was severe in all cases at the age of 24–37 years. Two of the younger patients used a wheelchair occasionally, while the older patients were totally wheelchair-bound. The myoclonus was nearly continuous in the elderly patients. Cognitive impairment was also evident in all the patients and two of the patients could not have participated in the normal primary education. EPM1 patients who are compound heterozygotes with c.202C>T mutation associated with the common dodecamer repeat expansion mutation seem to have more severe form of PME with early onset of symptoms, more severe myoclonus, more cognitive impairment, and more severe brain atrophy. These preliminary findings may have important implications for revealing the pathogenesis of the EPM1, and therefore it is important to concentrate more in detail in the evaluation of the genotype-phenotype correlations in EPM1 subtypes.
Most of the EEG evaluations come from small series or have been performed during 1970s or 1980s. Initially, BA was reported to be slowed in the majority of EPM1 patients (Koskiniemi et al., 1974b; Lehesjoki & Koskiniemi, 1999). Recently a retrospective evaluation study of EEG obtained from 25 EPM1 patients since 1995 was published by Ferlazzo et al. (2007). In contrast to the previous reports, they have reported that BA was normal in most of the patients or mildly slow at the beginning of the disease and remained stable over time. It was concluded that the initial studies were mostly addressing patients with Baltic myoclonus that had more severe clinical course and possibly more disturbed EEG due to the extensive use of phenytoin therapy in these patients (Iivanainen & Himberg, 1982; Ferlazzo et al., 2007). Nevertheless, previously a disturbance of BA, in addition to generalized epileptiform discharges, was considered mandatory for the EEG diagnosis of EPM1. The absence of this slowing in EEG might have led to an erroneous diagnosis of juvenile myoclonus epilepsy (JME) in certain patients.
The EEG abnormalities (spike-wave discharges, photosensitivity, and polyspike discharges during REM sleep) are more pronounced during the initial stages of the disease, when there are usually also generalized tonic–clonic seizures (Koskiniemi et al., 1974b, Franceschetti et al., 1993). In addition, we have also observed focal epileptiform EEG changes, mostly in the occipital region, in approximately 25% of our EPM1 patients (unpublished data). Therefore, focal changes found beside generalized EEG abnormalities cannot exclude the EPM1 diagnosis.
It has been stated that EEG abnormalities tend to diminish with time correlating with the stabilization of the clinical condition within the years. Indeed, Ferlazzo et al., (2007) have also concluded that in a long-term, at average after 15 years of the disease, a gradual reduction of polyspike and wave discharges and photosensitivity could be observed in EPM1 patients. Moreover, EEG changes were in parallel with the reduction of epileptic seizures. In addition, physiological sleep patterns disappeared in about half of the EPM1 patients after an average of 16 years of the disease. That is different if compared with Lafora's disease, in which disappearance of physiological sleep pattern is an early and constantly progressing feature (Tassinari et al., 1974).
There are, however, patients, who seem to suffer from drug resistant and progressive myoclonias, which incapacitate them in adulthood. Myoclonic seizures can be easily misdiagnosed as tonic–clonic seizures in these patients and the treatment decisions can be inappropriate. Most of the myoclonic movements, especially the almost continuous, small amplitude jerks, are not time-locked to EEG discharges. This may lead to a wrong conclusion of pseudoepileptic or psychogenic phenomena. It is still unclear whether these symptoms not having an electroclinical correlation in routine EEG represent subcortical phenomena or restricted-field cortical discharges. Appearances of clinical jerks that are not time-locked to EEG discharges suggest that cortical myoclonus is not common. However, even the same patient may exhibit jerks that are associated either with cortical EEG spikes, slow waves, preceding EEGs slow baseline shifts, or jerks that are not associated with any EEG changes at all. There is thus evidence of multilevel origins for the jerks as well. Large-amplitude jerks may have EEG correlates; often very high-amplitude-generalized spike-wave bursts (Faught, 2003). It would be important to evaluate the EEG features of the current phenotypes at different stages of the disease.
Other diagnostic methods
At the time of diagnosis, the MRI is usually normal. However, at later stages, MRI of the brain has been studied in patients with genetically confirmed EPM1-ULD, and loss of neuronal volume in pons, medulla, and cerebellar hemispheres has been found. Cerebral atrophy was present in some patients (Mascalchi et al., 2002). Brainstem involvement could play a role in pathophysiology of EPM1-ULD. It would be important to evaluate imaging findings of the current phenotypes with different disease severity and different antiepileptic drug history.
At the onset of ULD (EPM1), if action myoclonus is absent or very mild, such patients can be easily misdiagnosed as affected by JME. JME has a favorable outcome, although, both conditions present with generalized spike and waves discharges, generalized photoparoxysmal response, well organized BA and myoclonic and tonic–clonic seizures. Individuals with JME have a normal neurological examination. The symptom that makes the difference is action myoclonus, which can become clearly evident even many years after the seizure onset. Especially during the course of a drug-resistant JME, a diagnosis of EPM1 should be considered with a careful history and neurological examination for signs of more severe myoclonic symptoms than originally thought and with discussion with patient for a possibility of gene testing for diagnostic certainty.
In case of exceptionally severe progression of especially cognitive symptoms or visual symptoms, other forms of PME, notably myoclonic epilepsy with ragged red fibers (MERRF), neuronal ceroid lipofuscinoses (NCL), Lafora's disease, and sialidoses, should be considered (see Table 2 and review of Shahwan et al., 2005). An inbred Arab family with an EPM1-like phenotype with somewhat earlier onset has been described (Berkovic et al., 2005). The phenotype in this family has been linked to chromosome 12, but the causative gene is unknown. In CSTB mutation-negative individuals with an EPM1-like phenotype of earlier onset, this disorder should be considered.
Table 2. Differential genetic and clinical characteristics of PME (modified from the review of Shahwan et al., 2005)
|Disease||Inheritance||Gene||Age at onset (years)||Prominent seizuresa||Cerebellar signs||Dementia/cognitive decline||Fundi||Dysmorphism||Evolution/prognosis|
|EPM1||AR||CSTB||6–16||Myoclonus ++++||Mild and late||Mild and late or absent||Normal||No||Severe in a minority of cases, usually mild/chronic|
|Lafora's disease||AR||EPM2A, NHLRC1||12–17||Myoclonus and occipital seizures||Early||Early and relentless||Normal||No||Very severe, death within 2–10 y|
|MERRF||Maternal||MTTK (mitochondrial)||Any age||Myoclonus ++||Variable||Variable||With or without optic atrophy or retinopathy||With or without||Variable from very mild to very severe|
|NCL||AR/ADb||TPP1, CLN3, CLN5, CLN6||Variable||Variable||Variable||Rapidly progressive||Macular degeneration and visual failure, except Kuf's disease||No||Severe|
|Sialidoses||AR||NEU1||Variable||Myoclonus +++||Gradual||Absent in type I; learning difficulty in type II||Cherry-red spot||type II ++||Variable, usually severe; late onset usually less severe|