Ring 14 Chromosome with Complex Partial Seizures: A Case Report Yukiyoshi Shirasaka, MD, Masatoshi Ito, MD, Takehiko Okuno, MD, Tatsuya Fujii, MD, Kohji Nozaki, MD and Haruki Mikawa, MD
A two-year-old girl was found to have a ring 14 chromosome: [46, Xx, r( 14) (Pi 3 q32.3)]. Her development, including verbal ability, was retarded, her CT scan displayed a low density area anterior to the left temporal lobe, and she suffered from complex partial seizures. Focal central nervous system abnormalities may be present in patients with ring 14 chromosome, and their seizures are not exclusively of the parimary generalized type. This is the first case with ring 14 chromosome and complex partial seizures. Key words: Ring 14 chromosome, epilepsy, complex partial seizure, focal CNS disturbance. Shirasaka Y, Ito M, Okuno T, Fujii T, Nozaki K, Mikawa H Ring 14 chromosome with complex partial seizures: a case report. Brain Dev 1992; 14: 25 7-60
The mechanism by which genetic factors contribute to epileptogenesis is at present poorly understood. Epilepsy is generally considered to be polygene tic ally determined [1]. Current research now seeks to locate the genes which cause epilepsy [2], and some patients with a known chromosomal abnormality have severe epileptic seizures [3]. In order to determine the pathogenesis underlying the epilepsy and its relationship to each chromosome, it is considered important to describe in detail the type of seizure displayed by the patient. In this paper, we describe a patient having ring 14 chromosome and complex partial seizures. CASE REPORT Our patient was a girl who had been born at term without difficulty to nonconsanguineous parents. There was no history of neurological disease in her family, including
From the Department of Pediatrics, Faculty of Medicine, Kyoto University, Kyoto (YS, TO, TF, KN, HM); Department of Pediatrics, Shimane Medical University, Izumo (MI). Received for publication: January 24,1991. Accepted for pUblication: Apri127, 1992. Correspondence address: Dr. Masatoshi Ito, Department of Pediatrics, Shimane Medical University, 89-1 Enya-cho, Izumo 693, Japan.
her 7-month-old brother. Very soon after her birth, her mother noticed that she was very sensitive to noise. Head control was achieved at 3 months, and she walked at 13 months of age. Her first words were spoken at 12 months of age, but her verbal development was very slow thereafter. At six months of age her mother noticed episodes in that she did not respond to the sounds and showed abnormal eye movements, slow opening and closing of the mouth, and tongue protrusion. These lasted for approximately 20 minutes, and then she would fall asleep. She was admitted to a local hospital for observation. Two days later, convulsions with hypertonicity of the extremities occurred, and recurred a few to several dozen times a day for 3 to 8 days in a row, almost once a month. During these episodes, her eyes opened suddenly, she seemed to be staring, her upper extremities were flexed, and her lower extremities were extended. These seizures lasted a few seconds and neither laterality nor antecedent phenomena occurred. At two years and seven months of age, she was admitted to our department for further evaluation and treatment. Upon admission, no abnormalities of the cardiopulmonary system or viscera were noted. Weight, height and head circumference were all within the normal range. Her face did not look peculiar, and no external anomalies were noted. Psychomotor development was borderline retarded with a developmental quotient of 78 to 85 ac-
Fig 1 A: CT scan on admission. Plagiocephaly, slight frontal cor· tical atrophy, and low density area anterior to left temporal lobe are shown (arrow). B: MRI on admission. (Upper) T, weighted image (TR 2,500 msec, TE 80 msec) shows plagio· cephaly, slight cortical atrophy and a high intensity area anterior to left temporal lobe (arrow). (Lower) Proton density image (TR 2,500 msec, TE 30 msec) shows low intensity area medial and inferior to left temporal lobe (arrow).
cen
P13 (
~ q323 ~ r (14
)
14
Fig 2 Ring 14 chromosome of this patient. The karyotype is 46, XX, r(14) (PJ3,q32.3).
cording to the Kyoto Scale of Psychological Development (a modification of Gessell's developmental scale). This retardation was especially noted with respect to language development. There were no abnormalities of consciousness, cranial, motor or sensory nerves nor was there any cerebellar or motor dysfunction. CT scan (Fig 1A) re-
258 Brain & Development, Vol 14, No 4,1992
vealed plagiocephaly, slight frontal cortical atrophy, and a low density area anterior to the left temporal lobe. A metrizamide CT scan showed that this low density area communicated with the subarachnoid space and seemed to be an area of atrophy in the temporal lobe or a cyst. MRI (Fig 1B) showed the same findings as the CT scan. 123I·IMP-SPECT showed a low uptake of IMP only in the area of low density as seen in the CT scan. Auditory, visual, and sensory evoked potentials were all within the normal range. Chromosomal analysis revealed, 46, XX, r(14) (P13 q32.3) in the patient (Fig 2), but normal karyotypes in her parents. All other laboratory examination results were normal, including serum immunoglobulins. Interictal EEGs showed multiple sporadic focal discharges: single spikes, spikes and waves, and polyspikes and waves in the bilateral anterior and middle temporal, and right occipital regions. Her medications (phenytoin, phenobarbital, valproate) were continued, and two weeks after admission an attack occurred early in the morning during sleep. Both arms were convulsed at 2-3Hz and were raised above the head, and, at the same time, the lower extremities convulsed in extension. The muscle tone increased in all extremities equally, but they could easily be moved, i.e., they were
A 0.- P, PJ -e.
e
l -
T,
T, - F, F, - F.. F. - F. F.,- F,
F, - T.
T.
-c.
C. - p.
P. -0, 0, -0. ECG
c
o
1'HC"""" l00),Y
Fig 3 A: EEG before the attack with hypertonicity. Diffuse high voltage slow wave and focal spikes are seen in the right anterior and middle temporal regions. B: At the beginning of the attack. 2 Hz slow waves are dominant in the right middle temporal region and gradually change to 2.5 Hz spike-polyspike and waves. C: During the attack. Diffuse 2.5 Hz spike-polyspike and wave complexes are seen. D: At the end ofthe attack. Spike-polyspike and wave complexes gradually decrease in frequency to 1.5 Hz and cease abrnptly and spontaneously.
not rigid. Both eyes were wide open and staring. This attack continued for 3-4 seconds, then all extremities became flaccid. Consciousness remained disturbed between the attacks, which recurred every 30-60 seconds for 45 minutes, after which she fell asleep again. The same episodes occurred 1-2 times per week, usually in groups, and the duration of attacks varied from several seconds to several minutes. EEG recordings showed that before the seizures with hypertonicity there were diffuse high voltage slow waves and sporadic spikes in the right anterior and middle temporal regions (Fig 3A). At the beginning of the seizures, 2 Hz slow waves were dominant in the right temporal region, and these gradually changed to 2.5 Hz spike-polyspike and waves (Fig 3B). During seizures, 2.5 Hz spike-polyspike and wave complexes were
spread diffusely and continued throughout the seizure, with relative sparing of the frontal region (Fig 3C). These complexes decreased gradually in frequency and ceased abruptly and spontaneously 30 seconds after the beginning of the attack (Fig 3D). From the above noted clinical manifestations and EEG findings we diagnosed complex partial seizures (CPS), and the medication was changed to carbamazepine and c1onazepam. The frequency of the seizures decreased to approximately once a month.
DISCUSSION Patients with abnormal chromosome 14 often have epileptic seizures [3]. These chromosomal abnormalities
Shirasaka etal: Ring 14 chromosome with CPS 259
involve partial trisomy [4], deletion with pericentric inversion [5], reciprocal translocation [6], and ring chromosome [7, 8]. The incidence of epileptic seizures in patients with ring 14 chromosome is reported to be 100% [3]. Seizures in patients with chromosomal abnormalities tend to be considered as primary generalized ones, and the seizures described in the literature are mainly of the primary generalized type including the ones in patients with ring 14 chromosome [7,9]. However, Lippe and Sparkes noted that seizures might also be associated with focal cerebral atrophy in ring 14 chromosome patients [8] ; in addition, some patients actually exhibited partial onset seizures [8, 10] and unbalanced developmental subnormality [7,9] indicating the presence of a focal disturbance in the CNS. Thus, in ring 14 chromosome patients, focal CNS disturbances can be present. In our patient, complex partial seizures were diagnosed on the basis of EEG findings and clinical manifestations, and the CPS were considered to be a symptom of the focal lesions in the CNS. There remains the possibility that her seizures were caused not only by genetic factors, but by some disturbances during pregnancy, however, it is likely that the genetic defect does enhance the appearance of CPS. Reviewing the reports of 25 patients with ring 14 chromosome, our case report is the first one involving a patient with ring 14 chromosome and CPS and shows that focal CNS lesions can also occur in ring 14 chromosome patients.
REFERENCES 1. Doose H, Baier W. Genetic aspects of chidhood epilepsy. Clev Clin J Med 1989;56(suppl1):S105-1O. 2. Delgado-Escueta AV, Greenberg D. The search for epilepsies ideal for clinical and molecular genetic studies. Ann Neural 1984 ;16(suppl):Sl-l1. 3. Ieshima A, Takeshita K. Chromosome abnormalities and epileptic seizures. Jpn J Human Genet (Tokyo) 1988 ;33:49-60. 4. Smith A, Dulk GD, Elliott G. A severely retarded 18-yearold boy with tertiary partial trisomy 14. J Med Genet 1980; 17:230-2. 5. Nielsen J, Homma A, Rasmussen K, Ried E, Sorensen K, Saldana-Garcia P. Deletion 14q and pericentric inversion 14. J Med Genet 1978; 15: 236-8. 6. Hattori H, Hayashi K, Okuno T, et al. De novo reciprocal translocation t(6;14) (q27;q13,3) in a child with infantile spasms. Epilepsia 1985;26:310-3. 7. Howard PJ, Clark D, Dearlove 1. Retinal/macular pigmentation in conjunction with ring 14 chromsome. Hum Genet 1988;80:140-2. 8. Lippe BM, Sparkes RS. Ring 14 chromosome: association with seizures. Am J Med Genet 1981 ;9:301-5. 9. Abe T, Misawa S, Nishioka K, Okuno T, Nakagome Y. Formation of a ring chromosome 14 subsequent to the de novo 13/14 reciprocal translocation: a new cytogenetic evidence obtained by the nucleolus-organizer staining. Ann Genet 1978;21: 109-12. 10. Amarose AP, Dorus E, Huttenlocher PR, Csaszar S. A ring 14 chromsome with deleted short arm. Hum Genet 1980; 54:145-7.
Cortical Reflex Myoclonus Associated with Mitochondrial Myopathy~ Encephalopathy~ Lactic Acidosis and Stroke-like Episodes (MELAS): A Case Report Shinji Saitoh, MD, Shinobu Kohsaka, MD, Susumu Mizukami, MD, and Naofumi Kajii, MD
A 9-year-old female MELAS patient with myoclonus is reported, with emphasis on the results of electrophysiological studies of the myoclonus. At age 5 years she experienced a stroke-like episode, and a diagnosis of MELAS was made at age 6 years on the basis of muscle biopsy findings. At age 9 years spontaneous and segmental myoclonus, predominantly affecting the upper extremities, developed because of complications. Electrophysiological examination, including of somatosensory-evoked potentials (SEPs) and averaged EMG for long loop reflexes, revealed the so-called "giant SEP" and enhanced long loop reflexes reflecting cortical hyperexcitability. Jerk-locked averaging yielded no myoclonus related
260 Brain & Development, Vol 14, No 4,1992
A two-year-old girl was found to have a ring 14 chromosome: [46, Xx, r( 14) (Pi 3 q32.3)]. Her development, including verbal ability, was retarded, her CT scan displayed a low density area anterior to the left temporal lobe, and she suffered from complex partial seizures. Focal central nervous system abnormalities may be present in patients with ring 14 chromosome, and their seizures are not exclusively of the parimary generalized type. This is the first case with ring 14 chromosome and complex partial seizures. Key words: Ring 14 chromosome, epilepsy, complex partial seizure, focal CNS disturbance. Shirasaka Y, Ito M, Okuno T, Fujii T, Nozaki K, Mikawa H Ring 14 chromosome with complex partial seizures: a case report. Brain Dev 1992; 14: 25 7-60
The mechanism by which genetic factors contribute to epileptogenesis is at present poorly understood. Epilepsy is generally considered to be polygene tic ally determined [1]. Current research now seeks to locate the genes which cause epilepsy [2], and some patients with a known chromosomal abnormality have severe epileptic seizures [3]. In order to determine the pathogenesis underlying the epilepsy and its relationship to each chromosome, it is considered important to describe in detail the type of seizure displayed by the patient. In this paper, we describe a patient having ring 14 chromosome and complex partial seizures. CASE REPORT Our patient was a girl who had been born at term without difficulty to nonconsanguineous parents. There was no history of neurological disease in her family, including
From the Department of Pediatrics, Faculty of Medicine, Kyoto University, Kyoto (YS, TO, TF, KN, HM); Department of Pediatrics, Shimane Medical University, Izumo (MI). Received for publication: January 24,1991. Accepted for pUblication: Apri127, 1992. Correspondence address: Dr. Masatoshi Ito, Department of Pediatrics, Shimane Medical University, 89-1 Enya-cho, Izumo 693, Japan.
her 7-month-old brother. Very soon after her birth, her mother noticed that she was very sensitive to noise. Head control was achieved at 3 months, and she walked at 13 months of age. Her first words were spoken at 12 months of age, but her verbal development was very slow thereafter. At six months of age her mother noticed episodes in that she did not respond to the sounds and showed abnormal eye movements, slow opening and closing of the mouth, and tongue protrusion. These lasted for approximately 20 minutes, and then she would fall asleep. She was admitted to a local hospital for observation. Two days later, convulsions with hypertonicity of the extremities occurred, and recurred a few to several dozen times a day for 3 to 8 days in a row, almost once a month. During these episodes, her eyes opened suddenly, she seemed to be staring, her upper extremities were flexed, and her lower extremities were extended. These seizures lasted a few seconds and neither laterality nor antecedent phenomena occurred. At two years and seven months of age, she was admitted to our department for further evaluation and treatment. Upon admission, no abnormalities of the cardiopulmonary system or viscera were noted. Weight, height and head circumference were all within the normal range. Her face did not look peculiar, and no external anomalies were noted. Psychomotor development was borderline retarded with a developmental quotient of 78 to 85 ac-
Fig 1 A: CT scan on admission. Plagiocephaly, slight frontal cor· tical atrophy, and low density area anterior to left temporal lobe are shown (arrow). B: MRI on admission. (Upper) T, weighted image (TR 2,500 msec, TE 80 msec) shows plagio· cephaly, slight cortical atrophy and a high intensity area anterior to left temporal lobe (arrow). (Lower) Proton density image (TR 2,500 msec, TE 30 msec) shows low intensity area medial and inferior to left temporal lobe (arrow).
cen
P13 (
~ q323 ~ r (14
)
14
Fig 2 Ring 14 chromosome of this patient. The karyotype is 46, XX, r(14) (PJ3,q32.3).
cording to the Kyoto Scale of Psychological Development (a modification of Gessell's developmental scale). This retardation was especially noted with respect to language development. There were no abnormalities of consciousness, cranial, motor or sensory nerves nor was there any cerebellar or motor dysfunction. CT scan (Fig 1A) re-
258 Brain & Development, Vol 14, No 4,1992
vealed plagiocephaly, slight frontal cortical atrophy, and a low density area anterior to the left temporal lobe. A metrizamide CT scan showed that this low density area communicated with the subarachnoid space and seemed to be an area of atrophy in the temporal lobe or a cyst. MRI (Fig 1B) showed the same findings as the CT scan. 123I·IMP-SPECT showed a low uptake of IMP only in the area of low density as seen in the CT scan. Auditory, visual, and sensory evoked potentials were all within the normal range. Chromosomal analysis revealed, 46, XX, r(14) (P13 q32.3) in the patient (Fig 2), but normal karyotypes in her parents. All other laboratory examination results were normal, including serum immunoglobulins. Interictal EEGs showed multiple sporadic focal discharges: single spikes, spikes and waves, and polyspikes and waves in the bilateral anterior and middle temporal, and right occipital regions. Her medications (phenytoin, phenobarbital, valproate) were continued, and two weeks after admission an attack occurred early in the morning during sleep. Both arms were convulsed at 2-3Hz and were raised above the head, and, at the same time, the lower extremities convulsed in extension. The muscle tone increased in all extremities equally, but they could easily be moved, i.e., they were
A 0.- P, PJ -e.
e
l -
T,
T, - F, F, - F.. F. - F. F.,- F,
F, - T.
T.
-c.
C. - p.
P. -0, 0, -0. ECG
c
o
1'HC"""" l00),Y
Fig 3 A: EEG before the attack with hypertonicity. Diffuse high voltage slow wave and focal spikes are seen in the right anterior and middle temporal regions. B: At the beginning of the attack. 2 Hz slow waves are dominant in the right middle temporal region and gradually change to 2.5 Hz spike-polyspike and waves. C: During the attack. Diffuse 2.5 Hz spike-polyspike and wave complexes are seen. D: At the end ofthe attack. Spike-polyspike and wave complexes gradually decrease in frequency to 1.5 Hz and cease abrnptly and spontaneously.
not rigid. Both eyes were wide open and staring. This attack continued for 3-4 seconds, then all extremities became flaccid. Consciousness remained disturbed between the attacks, which recurred every 30-60 seconds for 45 minutes, after which she fell asleep again. The same episodes occurred 1-2 times per week, usually in groups, and the duration of attacks varied from several seconds to several minutes. EEG recordings showed that before the seizures with hypertonicity there were diffuse high voltage slow waves and sporadic spikes in the right anterior and middle temporal regions (Fig 3A). At the beginning of the seizures, 2 Hz slow waves were dominant in the right temporal region, and these gradually changed to 2.5 Hz spike-polyspike and waves (Fig 3B). During seizures, 2.5 Hz spike-polyspike and wave complexes were
spread diffusely and continued throughout the seizure, with relative sparing of the frontal region (Fig 3C). These complexes decreased gradually in frequency and ceased abruptly and spontaneously 30 seconds after the beginning of the attack (Fig 3D). From the above noted clinical manifestations and EEG findings we diagnosed complex partial seizures (CPS), and the medication was changed to carbamazepine and c1onazepam. The frequency of the seizures decreased to approximately once a month.
DISCUSSION Patients with abnormal chromosome 14 often have epileptic seizures [3]. These chromosomal abnormalities
Shirasaka etal: Ring 14 chromosome with CPS 259
involve partial trisomy [4], deletion with pericentric inversion [5], reciprocal translocation [6], and ring chromosome [7, 8]. The incidence of epileptic seizures in patients with ring 14 chromosome is reported to be 100% [3]. Seizures in patients with chromosomal abnormalities tend to be considered as primary generalized ones, and the seizures described in the literature are mainly of the primary generalized type including the ones in patients with ring 14 chromosome [7,9]. However, Lippe and Sparkes noted that seizures might also be associated with focal cerebral atrophy in ring 14 chromosome patients [8] ; in addition, some patients actually exhibited partial onset seizures [8, 10] and unbalanced developmental subnormality [7,9] indicating the presence of a focal disturbance in the CNS. Thus, in ring 14 chromosome patients, focal CNS disturbances can be present. In our patient, complex partial seizures were diagnosed on the basis of EEG findings and clinical manifestations, and the CPS were considered to be a symptom of the focal lesions in the CNS. There remains the possibility that her seizures were caused not only by genetic factors, but by some disturbances during pregnancy, however, it is likely that the genetic defect does enhance the appearance of CPS. Reviewing the reports of 25 patients with ring 14 chromosome, our case report is the first one involving a patient with ring 14 chromosome and CPS and shows that focal CNS lesions can also occur in ring 14 chromosome patients.
REFERENCES 1. Doose H, Baier W. Genetic aspects of chidhood epilepsy. Clev Clin J Med 1989;56(suppl1):S105-1O. 2. Delgado-Escueta AV, Greenberg D. The search for epilepsies ideal for clinical and molecular genetic studies. Ann Neural 1984 ;16(suppl):Sl-l1. 3. Ieshima A, Takeshita K. Chromosome abnormalities and epileptic seizures. Jpn J Human Genet (Tokyo) 1988 ;33:49-60. 4. Smith A, Dulk GD, Elliott G. A severely retarded 18-yearold boy with tertiary partial trisomy 14. J Med Genet 1980; 17:230-2. 5. Nielsen J, Homma A, Rasmussen K, Ried E, Sorensen K, Saldana-Garcia P. Deletion 14q and pericentric inversion 14. J Med Genet 1978; 15: 236-8. 6. Hattori H, Hayashi K, Okuno T, et al. De novo reciprocal translocation t(6;14) (q27;q13,3) in a child with infantile spasms. Epilepsia 1985;26:310-3. 7. Howard PJ, Clark D, Dearlove 1. Retinal/macular pigmentation in conjunction with ring 14 chromsome. Hum Genet 1988;80:140-2. 8. Lippe BM, Sparkes RS. Ring 14 chromosome: association with seizures. Am J Med Genet 1981 ;9:301-5. 9. Abe T, Misawa S, Nishioka K, Okuno T, Nakagome Y. Formation of a ring chromosome 14 subsequent to the de novo 13/14 reciprocal translocation: a new cytogenetic evidence obtained by the nucleolus-organizer staining. Ann Genet 1978;21: 109-12. 10. Amarose AP, Dorus E, Huttenlocher PR, Csaszar S. A ring 14 chromsome with deleted short arm. Hum Genet 1980; 54:145-7.
Cortical Reflex Myoclonus Associated with Mitochondrial Myopathy~ Encephalopathy~ Lactic Acidosis and Stroke-like Episodes (MELAS): A Case Report Shinji Saitoh, MD, Shinobu Kohsaka, MD, Susumu Mizukami, MD, and Naofumi Kajii, MD
A 9-year-old female MELAS patient with myoclonus is reported, with emphasis on the results of electrophysiological studies of the myoclonus. At age 5 years she experienced a stroke-like episode, and a diagnosis of MELAS was made at age 6 years on the basis of muscle biopsy findings. At age 9 years spontaneous and segmental myoclonus, predominantly affecting the upper extremities, developed because of complications. Electrophysiological examination, including of somatosensory-evoked potentials (SEPs) and averaged EMG for long loop reflexes, revealed the so-called "giant SEP" and enhanced long loop reflexes reflecting cortical hyperexcitability. Jerk-locked averaging yielded no myoclonus related
260 Brain & Development, Vol 14, No 4,1992
