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The mildest known case of Fukuyama-type congenital muscular dystrophy
Brain & Development 28 (2006) 537–540 www.elsevier.com/locate/braindev
Case report
The mildest known case of Fukuyama-type congenital muscular dystrophy Tomoyuki Akiyama a
a,*
, Yoko Ohtsuka a, Tsutomu Takata a, Junri Hattori a, Yukiko Kawakita b, Kayoko Saito b
Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan b Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan Received 19 November 2005; received in revised form 3 February 2006; accepted 7 February 2006
Abstract We present a 14-year-old boy with Fukuyama-type congenital muscular dystrophy (FCMD) who shows the mildest muscle weakness ever reported with this affliction and exceptionally mild mental retardation, but who has intractable epilepsy. Magnetic resonance imaging showed the typical abnormalities of FCMD. Molecular genetic analyses revealed a 3 kb insertion mutation in the fukutin gene heterozygously. We could find no mutation in the coding region of the fukutin gene in the chromosome without a 3 kb insertion. The most probable mechanism of clinical manifestation in this patient could be either a mutation in the noncoding regions of the fukutin gene on the chromosome without the ancestral founder haplotype of FCMD, or an error in the process of transcription or translation. Another possibility is the abnormalities in other genes involved in the glycosylation of a-dystroglycan, such as Fukutin-related protein and LARGE genes. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Fukuyama-type congenital muscular dystrophy; Epilepsy; Brain malformation; Molecular genetic analysis; West syndrome; Clinical spectrum
1. Introduction
2. Case report
Patients with Fukuyama-type congenital muscular dystrophy (FCMD) generally display severe motor disturbance associated with severe mental retardation. In most cases, epilepsy is mild despite the existence of distinct brain malformation. We report on an FCMD patient who showed exceptionally mild muscle weakness and mild mental retardation with almost no disturbance of daily activities, but who had severe intractable epilepsy.
The patient, a 14-year-old boy, is a product of nonconsanguineous parents. There were no significant perinatal events, and the family history had no record of muscle diseases or epilepsy. At 6 months he began to have epileptic spasms in clusters. The electroencephalogram (EEG) showed hypsarrhythmia (Fig. 1A). He was diagnosed as having West syndrome. Sodium valproate therapy completely suppressed seizures. He was hypotonic, and the serum creatine kinase (CK) was slightly elevated, ranging from 274 to 462 IU/L (normal: 41–258 IU/L). At 1 year, 2 months, CK rose to 1665 IU/L. He had proximally dominant hypotonia and diminished deep tendon reflexes, but no joint contracture, muscular pseudohypertrophy, or atrophy. The facial muscles were
*
Corresponding author. Tel.: +81 86 235 7372, fax: +81 86 235 7377. E-mail address: [email protected] (T. Akiyama). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.02.003
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T. Akiyama et al. / Brain & Development 28 (2006) 537–540
Fig. 1. (A) Interictal waking EEG record at age 7 months shows hypsarrhythmia. (B) Interictal waking EEG record at age 14 years, 9 months shows diffuse bursts of 1.5–2 Hz slow spike-wave discharges.
also unaffected. At 1 year, 5 months, a muscle biopsy from the left biceps brachii showed a dystrophic change: muscle fibers varying in size, necrosing and regenerating fibers, and opaque fibers, but no inflammatory changes. The dystrophin stain demonstrated no deficit of dystrophin. Although he started to walk independently at 1 year, 2 months and to run at 2 years, 3 months, his mental development was delayed. He began to speak meaningful words at 2 years, 6 months and two-word sentences at 4 years, 8 months. At 5 years, 1 month, he had a 4-min generalized tonic convulsion associated with a common cold. At 6 years, 11 months, magnetic resonance imaging (MRI) revealed polymicrogyria in the bilateral frontal lobes, cerebellar
dysgenesis with small cysts, and abnormal signals in the cerebral white matter (Fig. 2). At 7 years, 10 months, epileptic spasms recurred, and complex partial seizures appeared. Both types of seizures occasionally occurred in combination as a single ictal event. The EEG showed diffuse slow spike-and-wave discharges (Fig. 1B). He showed mild mental retardation (Mental Processing Scale measured by Kaufman Assessment Battery for Children: 58 at age 8 years, 6 months). At age 11 he once became unable to walk because of myalgia in the legs after hard exercises for a few days. At 13 years, 2 months, he showed no muscle atrophy, pseudohypertrophy, or joint contracture. Although he had diminished deep tendon reflexes and mild weakness of
Fig. 2. Axial MRI findings at 13 years, 2 months. (A) The T1-weighted image shows thick and bumpy cortices with shallow sulci and a blurred border between the gray and white matters in the bilateral frontal lobes, suggesting polymicrogyria. (B) This T2-weighted image shows numerous intraparenchymal small cysts in the cerebellar hemispheres. (C) This fluid-attenuated inversion recovery image shows several hyperintense lesions in the deep white matter.
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which is caused by delayed puberty suggested by the endocrinologic studies. Molecular genetic analyses were performed after an informed consent was obtained from his parents. A haplotype analysis [1] revealed that the patient was heterozygous for the ancestral founder (A-F) haplotype of FCMD (Fig. 3A), with a 3 kb insertion mutation (Fig. 3B). Although his chromosome without the A-F haplotype was sequenced twice for the coding regions of the fukutin gene, no mutation was revealed.
3. Discussion
Fig. 3. Haplotype and polymerase chain reaction analyses for detecting 3 kb insertion mutation. (A) A haplotype analysis revealed that the patient and his mother were heterozygous for the ancestral founder haplotype (highlighted with rectangles). (B) The patient showed 375 and 157 bp signals heterozygously, which means that he has a 3 kb insertion mutation heterozygously. The control individual shows a 157 bp signal, and the FCMD patient with the homozygous A-F haplotypes shows a 375 bp signal. The FCMD carrier and the FCMD patient with heterozygous A-F haplotypes show both signals. Lane 1, control; lane 2, FCMD patient with the homozygous A-F haplotypes; lane 3, FCMD carrier; lane 4, father; lane 5, mother; lane 6, the patient’s elder brother; and lane 7, this patient.
the proximal muscles, he was able to run, jump, and stand on one foot normally. Muscle CT demonstrated neither obvious volume loss nor fatty degeneration. He is now 14 years old and shows no definite progressive weakness in muscles, including facial muscles. He walks 3 km to school every day and endures physical exercise without difficulty. CK values have ranged from 300 to 4700 IU/L with a tendency to rise after hard exercise. Ophthalmologic examinations revealed only mild myopia. Despite the intensive antiepileptic drug treatment, he has been having daily epileptic seizures and has displayed diffuse slow spike-and-wave discharges in EEGs since the recurrence of seizures at 7 years, 10 months. He has a short stature and no development of secondary sex characteristics,
This FCMD patient is characterized by exceptionally mild muscle weakness, mild mental retardation, and severe intractable epilepsy. Regarding muscle weakness, this case is the mildest among all previously reported FCMD cases. Generally, ambulatory FCMD cases are rare, and very rarely patients are known to climb stairways [2,3]. Our patient showed no muscle weakness or joint contracture significantly affecting daily life. He had mild mental retardation with little difficulty in daily life except for poor grades at school. Generally, mental retardation in FCMD is moderate or severe. More than half the patients cannot speak intelligibly [2,3]. Although this patient’s MRI displayed the typical findings of FCMD, the cerebral cortical dysplasia was restricted to the frontal lobes. In FCMD patients, cortical dysplasia is most commonly observed in the frontal lobes, followed by the temporooccipital lobes [4]. In some cases, a more severe abnormality or lissencephaly has been reported [5]. Thus also from the radiological point of view, our patient’s cerebral malformation was relatively mild. The fukutin gene abnormality causes a deficiency of a-dystroglycan, resulting in the disturbance of muscle integrity, cortical histiogenesis, and normal eye development [6]. Our patient is characterized by mild muscle weakness and mild mental retardation, besides a relatively mild cerebral malformation. These findings are compatible with the issue that common mechanisms lie in cerebral malformation and muscular dystrophy in FCMD. Our patient had severe epilepsy with refractory daily seizures. Although 50–80% of FCMD patients show febrile convulsions or epileptic seizures [7,8], they are infrequent, and the severity of epilepsy is milder than expected from that of brain malformation. Among the 46 FCMD patients reported by Yoshioka and Higuchi [8], only 9 had intractable seizures, including Lennox– Gastaut syndrome. The reason for this discrepancy has not been clarified. Apart from FCMD, focal cortical
540
T. Akiyama et al. / Brain & Development 28 (2006) 537–540
malformations can cause intractable epilepsies with epileptic spasms associated with partial seizures [9,10]. The underlying brain malformations in this patient might well explain the occurrence of the severe intractable epilepsy. Our patient had mild mental retardation despite the severe epilepsy. Both the severity of brain malformation and that of epilepsy usually determine the severity of mental retardation. He seemingly followed the clinical course from West syndrome to Lennox–Gastaut syndrome, since he has more than one type of seizure, including epileptic spasms, and his EEGs showed diffuse slow spike-and-wave discharges. However, because of the existence of the combined seizures with spasms in clusters and complex partial seizures, and because of focal cortical malformation, this patient might be having a peculiar type of frontal lobe epilepsy rather than symptomatic generalized epilepsy. This may account for the reason why he shows no marked mental deterioration, which is usually observed in Lennox–Gastaut syndrome. Molecular genetic analyses of this patient revealed that he was heterozygous for the A-F haplotype of FCMD, and no mutation was found in the coding regions of the fukutin gene on the chromosome without the A-F haplotype. No symptomatic carrier of FCMD has ever been reported. Therefore the most probable mechanisms of clinical manifestation in our patient could be either a mutation in the noncoding regions of the fukutin gene, or an error in the process of transcription or translation. Another possibility is the abnormalities in other genes involved in the glycosylation of adystroglycan, such as Fukutin-related protein and LARGE genes.
Acknowledgement We thank Dr. Mieko Yoshioka for her helpful suggestions. References [1] Saito K, Osawa M, Wang ZP, Ikeya K, Fukuyama Y, KondoIida E, et al. Haplotype–phenotype correlation in Fukuyama congenital muscular dystrophy. Am J Med Genet 2000;92:184–90. [2] Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of Fukuyama type: clinical, genetic, and pathological considerations. Brain Dev 1981;3:1–29. [3] Yoshioka M, Kuroki S. Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy. Am J Med Genet 1994;53:245–50. [4] Aida N, Tamagawa K, Takada K, Yagishita A, Kobayashi N, Chikumaru K, et al. Brain MR in Fukuyama congenital muscular dystrophy. AJNR Am J Neuroradiol 1996;17:605–13. [5] Murasugi H. Neuroimaging study of Fukuyama type congenital muscular dystrophy (in Japanese). J Tokyo Wom Med Coll 1992;62:1155–74. [6] Takeda S, Kondo M, Sasaki J, Kurahashi H, Kano H, Arai K, et al. Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development. Hum Mol Genet 2003;12:1449–59. [7] Fukuyama Y, Osawa M, Saito K. Congenital muscular dystrophies: an overview. In: Arzimanoglou A, Goutie`res F, editors. Trends in child neurology. Paris: John Libbey Eurotext; 1996. p. 107–35. [8] Yoshioka M, Higuchi Y. Long-term prognosis of epilepsies and related seizure disorders in Fukuyama-type congenital muscular dystrophy. J Child Neurol 2005;20:385–91. [9] Ohtsuka Y, Kobayashi K, Ogino T, Oka E. Spasms in clusters in epilepsies other than typical West syndrome. Brain Dev 2001;23:473–81. [10] Kobayashi K, Ohtsuka Y, Ohno S, Ohmori I, Ogino T, Yoshinaga H, et al. Clinical spectrum of epileptic spasms associated with cortical malformation. Neuropediatrics 2001;32:236–44.
Case report
The mildest known case of Fukuyama-type congenital muscular dystrophy Tomoyuki Akiyama a
a,*
, Yoko Ohtsuka a, Tsutomu Takata a, Junri Hattori a, Yukiko Kawakita b, Kayoko Saito b
Department of Child Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan b Institute of Medical Genetics, Tokyo Women’s Medical University, Tokyo, Japan Received 19 November 2005; received in revised form 3 February 2006; accepted 7 February 2006
Abstract We present a 14-year-old boy with Fukuyama-type congenital muscular dystrophy (FCMD) who shows the mildest muscle weakness ever reported with this affliction and exceptionally mild mental retardation, but who has intractable epilepsy. Magnetic resonance imaging showed the typical abnormalities of FCMD. Molecular genetic analyses revealed a 3 kb insertion mutation in the fukutin gene heterozygously. We could find no mutation in the coding region of the fukutin gene in the chromosome without a 3 kb insertion. The most probable mechanism of clinical manifestation in this patient could be either a mutation in the noncoding regions of the fukutin gene on the chromosome without the ancestral founder haplotype of FCMD, or an error in the process of transcription or translation. Another possibility is the abnormalities in other genes involved in the glycosylation of a-dystroglycan, such as Fukutin-related protein and LARGE genes. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Fukuyama-type congenital muscular dystrophy; Epilepsy; Brain malformation; Molecular genetic analysis; West syndrome; Clinical spectrum
1. Introduction
2. Case report
Patients with Fukuyama-type congenital muscular dystrophy (FCMD) generally display severe motor disturbance associated with severe mental retardation. In most cases, epilepsy is mild despite the existence of distinct brain malformation. We report on an FCMD patient who showed exceptionally mild muscle weakness and mild mental retardation with almost no disturbance of daily activities, but who had severe intractable epilepsy.
The patient, a 14-year-old boy, is a product of nonconsanguineous parents. There were no significant perinatal events, and the family history had no record of muscle diseases or epilepsy. At 6 months he began to have epileptic spasms in clusters. The electroencephalogram (EEG) showed hypsarrhythmia (Fig. 1A). He was diagnosed as having West syndrome. Sodium valproate therapy completely suppressed seizures. He was hypotonic, and the serum creatine kinase (CK) was slightly elevated, ranging from 274 to 462 IU/L (normal: 41–258 IU/L). At 1 year, 2 months, CK rose to 1665 IU/L. He had proximally dominant hypotonia and diminished deep tendon reflexes, but no joint contracture, muscular pseudohypertrophy, or atrophy. The facial muscles were
*
Corresponding author. Tel.: +81 86 235 7372, fax: +81 86 235 7377. E-mail address: [email protected] (T. Akiyama). 0387-7604/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.braindev.2006.02.003
538
T. Akiyama et al. / Brain & Development 28 (2006) 537–540
Fig. 1. (A) Interictal waking EEG record at age 7 months shows hypsarrhythmia. (B) Interictal waking EEG record at age 14 years, 9 months shows diffuse bursts of 1.5–2 Hz slow spike-wave discharges.
also unaffected. At 1 year, 5 months, a muscle biopsy from the left biceps brachii showed a dystrophic change: muscle fibers varying in size, necrosing and regenerating fibers, and opaque fibers, but no inflammatory changes. The dystrophin stain demonstrated no deficit of dystrophin. Although he started to walk independently at 1 year, 2 months and to run at 2 years, 3 months, his mental development was delayed. He began to speak meaningful words at 2 years, 6 months and two-word sentences at 4 years, 8 months. At 5 years, 1 month, he had a 4-min generalized tonic convulsion associated with a common cold. At 6 years, 11 months, magnetic resonance imaging (MRI) revealed polymicrogyria in the bilateral frontal lobes, cerebellar
dysgenesis with small cysts, and abnormal signals in the cerebral white matter (Fig. 2). At 7 years, 10 months, epileptic spasms recurred, and complex partial seizures appeared. Both types of seizures occasionally occurred in combination as a single ictal event. The EEG showed diffuse slow spike-and-wave discharges (Fig. 1B). He showed mild mental retardation (Mental Processing Scale measured by Kaufman Assessment Battery for Children: 58 at age 8 years, 6 months). At age 11 he once became unable to walk because of myalgia in the legs after hard exercises for a few days. At 13 years, 2 months, he showed no muscle atrophy, pseudohypertrophy, or joint contracture. Although he had diminished deep tendon reflexes and mild weakness of
Fig. 2. Axial MRI findings at 13 years, 2 months. (A) The T1-weighted image shows thick and bumpy cortices with shallow sulci and a blurred border between the gray and white matters in the bilateral frontal lobes, suggesting polymicrogyria. (B) This T2-weighted image shows numerous intraparenchymal small cysts in the cerebellar hemispheres. (C) This fluid-attenuated inversion recovery image shows several hyperintense lesions in the deep white matter.
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which is caused by delayed puberty suggested by the endocrinologic studies. Molecular genetic analyses were performed after an informed consent was obtained from his parents. A haplotype analysis [1] revealed that the patient was heterozygous for the ancestral founder (A-F) haplotype of FCMD (Fig. 3A), with a 3 kb insertion mutation (Fig. 3B). Although his chromosome without the A-F haplotype was sequenced twice for the coding regions of the fukutin gene, no mutation was revealed.
3. Discussion
Fig. 3. Haplotype and polymerase chain reaction analyses for detecting 3 kb insertion mutation. (A) A haplotype analysis revealed that the patient and his mother were heterozygous for the ancestral founder haplotype (highlighted with rectangles). (B) The patient showed 375 and 157 bp signals heterozygously, which means that he has a 3 kb insertion mutation heterozygously. The control individual shows a 157 bp signal, and the FCMD patient with the homozygous A-F haplotypes shows a 375 bp signal. The FCMD carrier and the FCMD patient with heterozygous A-F haplotypes show both signals. Lane 1, control; lane 2, FCMD patient with the homozygous A-F haplotypes; lane 3, FCMD carrier; lane 4, father; lane 5, mother; lane 6, the patient’s elder brother; and lane 7, this patient.
the proximal muscles, he was able to run, jump, and stand on one foot normally. Muscle CT demonstrated neither obvious volume loss nor fatty degeneration. He is now 14 years old and shows no definite progressive weakness in muscles, including facial muscles. He walks 3 km to school every day and endures physical exercise without difficulty. CK values have ranged from 300 to 4700 IU/L with a tendency to rise after hard exercise. Ophthalmologic examinations revealed only mild myopia. Despite the intensive antiepileptic drug treatment, he has been having daily epileptic seizures and has displayed diffuse slow spike-and-wave discharges in EEGs since the recurrence of seizures at 7 years, 10 months. He has a short stature and no development of secondary sex characteristics,
This FCMD patient is characterized by exceptionally mild muscle weakness, mild mental retardation, and severe intractable epilepsy. Regarding muscle weakness, this case is the mildest among all previously reported FCMD cases. Generally, ambulatory FCMD cases are rare, and very rarely patients are known to climb stairways [2,3]. Our patient showed no muscle weakness or joint contracture significantly affecting daily life. He had mild mental retardation with little difficulty in daily life except for poor grades at school. Generally, mental retardation in FCMD is moderate or severe. More than half the patients cannot speak intelligibly [2,3]. Although this patient’s MRI displayed the typical findings of FCMD, the cerebral cortical dysplasia was restricted to the frontal lobes. In FCMD patients, cortical dysplasia is most commonly observed in the frontal lobes, followed by the temporooccipital lobes [4]. In some cases, a more severe abnormality or lissencephaly has been reported [5]. Thus also from the radiological point of view, our patient’s cerebral malformation was relatively mild. The fukutin gene abnormality causes a deficiency of a-dystroglycan, resulting in the disturbance of muscle integrity, cortical histiogenesis, and normal eye development [6]. Our patient is characterized by mild muscle weakness and mild mental retardation, besides a relatively mild cerebral malformation. These findings are compatible with the issue that common mechanisms lie in cerebral malformation and muscular dystrophy in FCMD. Our patient had severe epilepsy with refractory daily seizures. Although 50–80% of FCMD patients show febrile convulsions or epileptic seizures [7,8], they are infrequent, and the severity of epilepsy is milder than expected from that of brain malformation. Among the 46 FCMD patients reported by Yoshioka and Higuchi [8], only 9 had intractable seizures, including Lennox– Gastaut syndrome. The reason for this discrepancy has not been clarified. Apart from FCMD, focal cortical
540
T. Akiyama et al. / Brain & Development 28 (2006) 537–540
malformations can cause intractable epilepsies with epileptic spasms associated with partial seizures [9,10]. The underlying brain malformations in this patient might well explain the occurrence of the severe intractable epilepsy. Our patient had mild mental retardation despite the severe epilepsy. Both the severity of brain malformation and that of epilepsy usually determine the severity of mental retardation. He seemingly followed the clinical course from West syndrome to Lennox–Gastaut syndrome, since he has more than one type of seizure, including epileptic spasms, and his EEGs showed diffuse slow spike-and-wave discharges. However, because of the existence of the combined seizures with spasms in clusters and complex partial seizures, and because of focal cortical malformation, this patient might be having a peculiar type of frontal lobe epilepsy rather than symptomatic generalized epilepsy. This may account for the reason why he shows no marked mental deterioration, which is usually observed in Lennox–Gastaut syndrome. Molecular genetic analyses of this patient revealed that he was heterozygous for the A-F haplotype of FCMD, and no mutation was found in the coding regions of the fukutin gene on the chromosome without the A-F haplotype. No symptomatic carrier of FCMD has ever been reported. Therefore the most probable mechanisms of clinical manifestation in our patient could be either a mutation in the noncoding regions of the fukutin gene, or an error in the process of transcription or translation. Another possibility is the abnormalities in other genes involved in the glycosylation of adystroglycan, such as Fukutin-related protein and LARGE genes.
Acknowledgement We thank Dr. Mieko Yoshioka for her helpful suggestions. References [1] Saito K, Osawa M, Wang ZP, Ikeya K, Fukuyama Y, KondoIida E, et al. Haplotype–phenotype correlation in Fukuyama congenital muscular dystrophy. Am J Med Genet 2000;92:184–90. [2] Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of Fukuyama type: clinical, genetic, and pathological considerations. Brain Dev 1981;3:1–29. [3] Yoshioka M, Kuroki S. Clinical spectrum and genetic studies of Fukuyama congenital muscular dystrophy. Am J Med Genet 1994;53:245–50. [4] Aida N, Tamagawa K, Takada K, Yagishita A, Kobayashi N, Chikumaru K, et al. Brain MR in Fukuyama congenital muscular dystrophy. AJNR Am J Neuroradiol 1996;17:605–13. [5] Murasugi H. Neuroimaging study of Fukuyama type congenital muscular dystrophy (in Japanese). J Tokyo Wom Med Coll 1992;62:1155–74. [6] Takeda S, Kondo M, Sasaki J, Kurahashi H, Kano H, Arai K, et al. Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development. Hum Mol Genet 2003;12:1449–59. [7] Fukuyama Y, Osawa M, Saito K. Congenital muscular dystrophies: an overview. In: Arzimanoglou A, Goutie`res F, editors. Trends in child neurology. Paris: John Libbey Eurotext; 1996. p. 107–35. [8] Yoshioka M, Higuchi Y. Long-term prognosis of epilepsies and related seizure disorders in Fukuyama-type congenital muscular dystrophy. J Child Neurol 2005;20:385–91. [9] Ohtsuka Y, Kobayashi K, Ogino T, Oka E. Spasms in clusters in epilepsies other than typical West syndrome. Brain Dev 2001;23:473–81. [10] Kobayashi K, Ohtsuka Y, Ohno S, Ohmori I, Ogino T, Yoshinaga H, et al. Clinical spectrum of epileptic spasms associated with cortical malformation. Neuropediatrics 2001;32:236–44.