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Keywords:

  • Benign adult familial myoclonus epilepsy;
  • Clinical anticipation

Summary

  1. Top of page
  2. Summary
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

The clinical anticipation in Japanese benign adult familial myoclonus epilepsy (BAFME), defined as earlier onset age of either cortical tremor or generalized seizures or new appearance of those symptoms in the next generation, remains unknown. The onset age and the degree of both cortical tremor and generalized seizures were investigated in nine patients of four BAFME families (mean age: 46.6 ± 18.7 years). Clinical anticipation in the onset age of cortical tremor or generalized seizures was observed in three families, and generalized seizures newly appeared in the next generation in those two families and in another family. Clinical anticipation was observed in four families, which suggests the clinical progression over generation in Japanese BAFME families.

Benign adult familial myoclonus epilepsy (BAFME) is an autosomal dominant condition. The principal symptoms are a cortical tremor (Ikeda et al., 1990), a tremulous myoclonus similar to essential tremor, and infrequent generalized seizures (Ikeda et al., 1990; Yasuda, 1991; Terada et al., 1997). Electrophysiologically, BAFME exhibits the features of cortical reflex myoclonus (Ikeda et al., 1990; Terada et al., 1997). BAFME has been reported from Japan and Europe and the condition has been given various names including cortical tremor (Ikeda et al., 1990), BAFME (Yasuda, 1991), familial cortical myoclonic tremor (Terada et al., 1997), familial cortical tremor with epilepsy (Okuma et al., 1997), familial cortical myoclonic tremor with epilepsy (van Rootselaar et al., 2005) and familial adult myoclonic epilepsy (Plaster et al., 1999) in the last two decades.

The onset age of cortical tremor ranges between 11 and 50 years in Europe (Striano et al., 2009) and 10 and 70 years in Japan (Hitomi et al., 2011), and that of generalized seizure ranges between 12 and 67 years in Europe (Striano et al., 2009) and 17 and 73 years in Japan (Hitomi et al., 2011).

The term “benign” was designated for its non-progressive course and rare occurrence of generalized seizures, and thus BAFME was distinguished from the various forms of progressive myoclonus epilepsy (PME). However, we recently reported increased cortical hyperexcitability and exaggerated myoclonus with aging in BAFME, which suggests that the pathophysiology of BAFME shows a slight but progressive tendency (Hitomi et al., 2011). Similarly, the clinical features have also been reported to progress in some European cases (Coppola et al., 2011). We have previously reported a Japanese BAFME family (Ikeda et al., 2005) apparently showing clinical anticipation in relation to the age of onset of cortical tremor and seizures. We have now accumulated three additional BAFME families showing clinical anticipation. In this report, we describe and summarize the clinical anticipation in these four Japanese BAFME families.

Subjects and Methods

  1. Top of page
  2. Summary
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

In nine patients in four Japanese BAFME families (four men and five women, mean age: 46.6 ± 18.7 years), details of the age of onset of cortical tremor and generalized seizures, the frequency of generalized seizures and the degree of cortical tremor are given in Table 1. All showed cortical tremor and six patients also showed infrequent generalized seizures. Generalized seizures occurred after the onset of the cortical tremor in five out of six patients and both symptoms appeared simultaneously in the remaining one patient (IV-01) in Family 2 (Table 1). In nine patients in four BAFME families detailed information was not available and so these were not included in the analysis (one patient [I-01] in Family 1, three patients [I-01, III-01 and III-03] in Family 2, two patients [II-02 and III-01] in Family 3 and three patients [II-04, III-06 and IV-02] in Family 4) (Fig. 1). One family (Family 2) was previously reported (Ikeda et al., 2005) and some of the patients were reported elsewhere (Hitomi et al., 2011). Diagnostic criteria for BAFME were adopted from the previous study (Hitomi et al., 2011).

Table 1.   Onset age and the degree of cortical tremor and generalized seizures in four families with BAFME
 Cortical tremorGeneralized seizures
AgeOnset ageSeverityaOnset ageFrequency
  1. aSeverity indicates: 0, absence of myoclonus; 1, mild myoclonus without disturbance of daily activity; 2, moderate myoclonus with some disturbance of daily activity; 3, severe myoclonus with clear disturbance of daily activity; 4, marked myoclonus causing incapacity (Ikeda et al., 1996).

Family 1     
 II-037250262Once
 III-024020128<1/year
Family 2     
 II-0274404None
 III-0538332351/year
 IV-0121201201/year
Family 3     
 II-0558501None
 III-053424133<1/year
Family 4     
 III-055110s2None
 IV-0130191241–4/year
image

Figure 1.  The pedigree of the four BAFME families was shown in (AD). Family 2 (B) corresponds to the family in Ikeda et al. (2005). Black symbols indicate that the patient was directly interviewed and examined about cortical tremor and infrequent generalized seizures. Gray ones indicate that the patient was not directly interviewed about clinical information. Arrows indicate the proband in each pedigree. The pair of numbers or letters at each symbol indicates onset age of cortical tremor (left) and seizures (right). UC stands for uncertain age and – for no symptoms.

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Clinical anticipation was defined as earlier onset age of either cortical tremor or generalized seizures or new appearance of those symptoms in the next generation. These studies were done as a part of their clinical evaluation in Kyoto University Hospital.

Results

  1. Top of page
  2. Summary
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Clinical anticipation in cortical tremor

Despite the extensive interview, one patient (III-06 in Family 4) could not remember the exact onset age of cortical tremor (Fig. 1), but it seemed that her cortical tremor started within the second decade of life. Thus we excluded this patient from the analysis for the onset age of cortical tremor. The onset age was 32.0 ± 13.3 (19–50) years, and the duration of the morbidity was 13.8 ± 10.8 (1–34) years in the remaining eight patients. There was a clear anticipation in the onset age of the cortical tremor in three families (by 30 years in Family 1, 10 years in Family 2 and 26 years in Family 3, respectively) except one family (Family 4) (Table 1 and Fig. 1). There was no clear relationship between clinical anticipation of cortical tremor and the gender. On the other hand, regarding the severity of cortical tremor at the time of examination as shown in Table 1, it was severer in the prior generation in three families (Family 1, 2 and 4) (Table 1).

Clinical anticipation in generalized seizures

The onset age was 33.7 ± 14.9 (20–62) years, and the duration of the morbidity was 5.5 ± 4.8 (1–12) years in six patients. Generalized seizures newly appeared in the next generation in three out of four families (Family 2, 3 and 4) (Table 1 and Fig. 1) and the remaining one family (Family 1) showed anticipation in the onset age by 34 years. The frequency of the generalized seizures was invariably very low, being almost identical between generations in two families (Family 1 and 2) (Table 1). There was no clear relationship between clinical anticipation of generalized seizures and the gender.

Discussion

  1. Top of page
  2. Summary
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Comparison of onset age between cortical tremor and generalized seizures

We found an earlier onset age of cortical tremor in three out of four BAFME families in the next generation. The condition appeared to be more severe in the prior generation in three out of four families (Family 1, 2 and 4) (Table 1). However, severity was scored in each patient at different ages, and this could account for the apparently different severity (Hitomi et al., 2011). The clinical anticipation of the cortical tremor could reflect a decreased threshold in each generation, or just simply that the patients in later generations notice the symptoms earlier and in a more mild form. However, we also found that the clinical anticipation in generalized seizures in all four families. Generalized seizures newly appeared in the next generation in three out of four BAFME families.

Cortical tremor, i.e., a variant of cortical reflex myoclonus, reflects epileptic hyperexcitability of the primary sensori-motor cortices occurred while generalized seizures reflects rather diffuse epileptic hyperexcitability. Therefore, “diffuse cortical hyperexcitability” may develop in the next generation. Furthermore, since cortical tremor usually appeared prior to the onset of generalized seizures in most of the BAFME patients investigated by us (Ikeda et al., 1990; Terada et al., 1997; Hitomi et al., 2011), “diffuse cortical hyperexcitability” also may develop during the clinical course within each BAFME patient. On the other hand, the difference of frequency of generalized seizures between generations was not well estimated in this study because of the rare seizure frequency as well as small number of patients.

Comparison with PME

Dentatorubral-pallidoluysian atrophy (DRPLA), one of PMEs without manifesting cortical reflex myoclonus, has clinical anticipation. The molecular basis of the clinical anticipation is well known, namely, the inverse proportional relationship between the number of CAG repetition (genetic anticipation) and the onset age of the symptoms (clinical anticipation) in Japanese patients (Ikeuchi et al., 1995). On the other hand, Unverricht-Lundborg disease (ULD), one of the common PMEs manifesting cortical reflex myoclonus, has no obvious correlation between the number of dodecamer repeat and the onset age of symptoms and their severity (Kälviäinen et al., 2008). With respect to the genetic studies of BAFME, Japanese families are linked to chromosome 8q (Plaster et al., 1999), whereas European families are linked to chromosome 2p (Striano et al., 2004) and 5p (Depienne et al., 2010). The causative gene for BAFME remains unknown. Based on the results of the current study, BAFME might have similar molecular pathology to that of DRPLA. However, anticipation in BAFME occurred only in the onset age or appearance of symptoms, but not the severity of symptoms, and there was no clear relationship between gender and clinical anticipation, suggesting that a triplet repeat may not be the genetic mechanism.

Limitations

There were several limitations in this study. First, the number of studied families and patients was relatively small and some data were missing in these families. Therefore, we could not show a statistically significant difference in the onset age of symptoms among generations. Second, our findings were based on the extensive interview and neurological examination and could not be supported by the laboratory data. It is possible that later generations may recognize the symptoms earlier, giving the impression of anticipation when in fact this was due simply to earlier diagnosis. In order to minimize this risk, we included only the patients whom were directly interviewed by the authors and examined in order to secure the precision of the information. In addition, our findings were quite consistent at least within the studied families.

Acknowledgment

  1. Top of page
  2. Summary
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

This study was supported by the Research Grant for the Treatment of Intractable Epilepsy (22-1) from the Japan Ministry of Health, Labor and Welfare.

Disclosure

  1. Top of page
  2. Summary
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

The authors report no conflict of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Subjects and Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References