- Email: [email protected]
Door syndrome: Deafness, onychoosteodystrophy and mental retardation
medullary compression due to the small size of the foramen magnum, and the second is a communicating hydrocephalus that may be responsible in part for psychomotor delay. There is now some evidence that intracranial venous sinus hypertension due to narrowing of the jugular foramina plays a major role in the genesis of hydrocephalus. A 1-year-old achondroplastic boy was admitted for head enlargement (52.5 cm) and psychomotor delay. Head circumference followed the curve of 1 S.D. above the mean for archondroplastic males; the fontanel was tense and the scalp veins were distended. In the sitting position, which was not acquired without support, the head was not fully controlled. The spontaneous motricity of the limbs was poor but the voluntary prehension was normal and symmetric and no pyramidal signs were found. Language was limited to babbling sounds. Eye fundus was normal. Median nerve stimulation did not induce evoked potentials on the somatosensory pathways at a supracervical level. The foramen magnum diameter was 16 mm and crosssectional surface was 208 mlYl2, both measured by CT. Cranial MRI revealed moderate enlargement of the ventricles as well as the subarachnoidal spaces and compression of the cervicomedullary junction. MR angiography performed to evaluate the intracranial venous hemodynamics revealed stenosis of both internal jugular veins at the jugular foramina and the presence of highly developed venous collaterals in the posterior and middle crania fossa, in the orbits with inversion of the flow in the superior ophthalmic veins. Because the foramen magnum was very small, it was decided to operate to prevent compression of the spinal cord and because hydrocephalus could interfere with psychomotor development, to open one jugular foramen in the same procedure. Unfortunately, postoperative MR angiography demonstrated no modification of the venous hemodynamics and head circumference remained at the same percentile 3 months later. At present, no real improvement has been observed at the psychomotor level. The widening of the jugular foramen did not appear to be useful for our patient, which conflicts with the experiences of others. Therefore, the comprehension of the mechanisms of hydrocephalus and psychomotor delay in achondroplastic children is far from complete.
337. ENLARGING CLINICAL SPECTRUM OF DOPARESPONSIVE DYSTONIA Carlo Cianchetti, Alessandro Zuddas, Anna Lisa Fratta, Francesco Muntoni, and Mafia Giovanna Marrosu, Cagliafi, Italy Childhood-onset parkinsonism and dopa-responsive dystonia share several clinical features: rigidity and bradykinesia are often present in dystonia and foot dystonia is common in parkinsonism. The diurnal variation, the response to long-term levodopa treatment, and low levels of biopterin in the CSF are considered to be crucial for the differential diagnosis between the 2 syndromes; prognoses of the 2 diseases are quite different. We report a girl with progressive motor impairment evolving to akinesia and rigidity since age 18 months. At age 12, the postural instability with "atonic" neck and trunk, and the extension hypertonia with crossing legs made standing impossible without support; dramatic akinesia and marked rigidity with cogwheel at both arms and legs were also present. Dystonic postures, muscular spasms, or abnormal involuntary movements were never observed. Facial mimic and intelligence were normal. Symptoms were improved by tetraydrobiopterine (BH4, 10 mg/kg per os).
Complete head control, unassisted walking with slightly wider base, normal hand dexterity, and complete disappearance of akinesia or rigidity were observed after levodopa/carbidopa (125/ 12.5 mg/day). Anticholinergic drugs, dopamine agonists (i.e., apomorphine, bromocriptine, and lisuride) and slow-release levodopa formulations induced minimal to moderate improvement; selegiline and amantadine were ineffective. Continued smooth clinical response was observed after chronic treatment with the same daily dose administered in 2 sessions. No loss of efficacy or peak-dose dyskinesia appeared after 8 years of therapy. The dramatic and sustained improvement with low doses of levodopa and the clinical response to BH4, strongly suggest a deficit in neuronal synthesis of levodopa, probably due to altered metabolism of biopterins, as observed in levodopa-responsive dystonia. This indicates that the clinical spectrum of altered metabolism of biopterins could include a pure parkinsonian syndrome without dystonia.
338. NATIONAL SURVEY ON CHRONIC VENTILATOR-ASSISTED CHILDREN IN JAPAN Y. Sakakihara, T. Yamanaka, N. Kajii, and S. Kamoshita, Yaizu and Hokkaido, Japan Because of the improved technology and care for patients who need mechanical ventilation, quality of life and the prognoses for chronic ventilator-assisted patients have improved significantly in recent years. However, the increased number of these patients has raised economic, ethical, as well as medical problems. In order to assess the magnitude of these problems, we conducted the first nationwide survey on the status of chronic ventilatorassisted children in Japan. Questionnaires were mailed to 2,524 pediatric departments in hospitals with more than 100 beds. Two hundred eighty-two hospitals had 567 patients who had been ventilated for more than 1 month at the time of the survey. Among these patients, 434 were younger than 20 years and had been ventilated for more than 3 months. The most common basic disorders were hypoxic-ischemic encephalopathy (n = 60), spinal muscular atrophy, type 1 (i.e., Werdnig-Hoffmarm disease, 55), various congenital myopathies (44), chronic lung disorders of prematurity (21), Ondine's curse (22), drowning (17), congenital heart diseases (16), and Duchenne muscular dystrophy (15). Of 434 patients, only 55 were ventilated at home. Although home care has been considered suitable for chronic ventilatorassisted patients by many pediatricians who responded to the survey, its realization has been hampered by the lack of systems and regulations that support home ventilator care. The fact that many pediatricians in Japan have actively prolonged the lives of those with Werdnig-Hoffmann disease, whereas aggressive lifesaving measures have been withheld in most Western countries, has raised serious ethical and medical issues.
339. DOOR SYNDROME: DEAFNESS, ONYCHOOSTEODYSTROPHY AND MENTAL RETARDATION Kiyoshi Hashimoto, Takehisa Fujita, Hiroko Shibui, Tsunenori Hirayama, and Kentaro Kuwabara, Kawasaki, Japan The association of sensori-neural deafness with onychodystrophy, osteodystrophy, and mental retardation was first reported
PEDIATRIC NEUROLOGY Vol. 11 No. 2 173
under an acronym DOOR by Cantwell in 1975 [1-3]. This is a rare, autosomal-recessive, inherited disorder. We report the first family case report of this syndrome in Japan. The patients were siblings born to healthy, unrelated Japanese parents. The first child is now 5 years old. He was born at 38 weeks gestation after an uncomplicated pregnancy and normal delivery, weighing 2,280 gm. At birth, the nails of his fingers and toes were hypoplastic or absent. At 4 weeks, he was referred to our hospital for evaluation of possible deafness. Hypoplasia of bilateral finger I-IV nails, absence of bilateral finger V nails, and extreme hypoplasia of bilateral great toe nails and absence of toe nails II-V were noted. His thumbs and great toes were long and had 2 flexion creases. Radiologic examination demonstrated 3 bony phalanges of both thumbs and dysplasia of distal bony phalanges of bilateral fingers II-IV and absence of distal bony phalanges in bilateral fingers V and in bilateral toes II-V. ABR showed no differentiated waves, which confirmed bilateral sensori-neural deafness. Teeth and hair were normal. Cranial MRI and CT were not remarkable. Chromosomes were normal. Analysis of both amino acid and organic acid in urine were normal. He had his first seizure at age 2 years, 7 months, and has continued to have frequent seizures consisting of left hemiconvulsion, focal motor seizures of the left side, which have been resistant to antiepileptic drugs. His developmental milestones were retarded; head control was at 5 months, sitting at 9 months, and walking at 26 months. He is now severely mentally retarded. The second child, born recently, has quite similar findings to his older brother. [1] Cantwell RJ. Congenital sensorineural deafness associated with onycho-osteo dystrophy and mental retardation (DOOR syndrome). Humangenetik 1975;26:261-5. [2] Navin NC, Thomas PS, Calvert J, Reid M McC. Deafness, onycho-osteodystrophy, and mental retardation (DOOR) syndrome. Am J Med Genet 1982;13:325-32. [3] Patton MA, Krywawych S, Winter RM, Brenton DP, Baraitser M. DOOR syndrome (deafness, onychoosteodystrophy, and mental retardation): Elevated plasma and urinary 2-oxyoglutarate in three unrelated patients. 1987;26: 207-15.
340. PREDICTION OF OUTCOME FOR COMPLEX PARTIAL SEIZURES WITHOUT STRUCTURAL BRAIN LESIONS BY MULTIVARIATE ANALYSIS Kenji Sugai, Mohamad A. Mikati, James J. R i v i e l l o , Sandra L. Helmers, and Gregory L. Holmes, Boston, Massachusetts
We retrospectively evaluated seizure outcome of complex partial seizures (CPSs) by comparing 44 good responders (G-R) with 44 nonresponders (N-R), both without cranial MRFCT abnormalities. N-R failed on at least both carbamazepine and phenytoin, and their CPSs were confirmed by long-term video-EEG monitoring. G-R were seizure-free over at least 1 year, and patients with benign partial epilepsy with centrotemporal spikes or occipital paroxysms were excluded. Interictal EEGs were obtained. The poor prognostic factors included: (1) cluster/flurries of seizures, frequent seizures (>1 per week), positive underlying cause or febrile convulsions (P < .0001); (2) abnormal background activity on EEG, absence of staring (P < .001); (3) status epilepticus, more seizure types (P < .01); and (4) younger onset, abnormal neurologic signs, burst discharges on EEG, and anterior focus on EEG (P < .05) (Fisher's exact probability test, or chi square test). The outcome was well predicted by Hayashi
174 PEDIATRIC NEUROLOGY Vol. 11 No. 2
discriminant method for categorical data, type II. Correct classification rates for outcome were 87% by using factors 1 and 2, 87% by 1-3, and 92% by 1-4.
341. GENERALIZED NONCONVULSIVE STATUS EPILEPTICUS IN ANGELMAN SYNDROME J. Campistol, F. X. Sanmarti, P. Poo, J. Conill, and E. Fernandez-Alvarez, Barcelona, Spain Angelman syndrome (AS) is characterized by severe mental retardation, inappropriate laughter, happy disposition, ataxic gait, and peculiar jerky movements. EEG abnormalities and seizures are also characteristic features. Deletions of chromosome 15q have been shown to occur in 60% of AS patients. In our series of 18 patients with AS, we found 9 with nonconvulsive status epilepticus: disappearance of laughter, diurnal sleepiness, episodic palpebral myoclonus, or atypical absence status. Initially, this situation was not clearly identified and secondary effects of antiepileptic drugs used to treat their seizures were suspected. EEG demonstrated continuous and diffuse 2-3 Hz spike-and-wave activity. There was a rapid, positive response within 24-48 hours to endovenous benzodiazepines (clonazepam) and the patients returned to their previous states (e.g., disappearance of diurnal sleepiness, smile reappeared). The very similar characteristic features of our patients are rarely reported in the literature. We believe that a prompt diagnosis of this situation is important for effective treatment.
342. GANGLIOSIDES IN CSF IN AUTISTIC CHILDREN Ola H. Skjeldal, Eili Sponheim, Anniken Lekman, and Lars Svennerholm, Oslo, Norway and G6teburg, Sweden
The concentration of the 4 major brain gangliosides--GMl, GDla, GDIb, and GTlb---were determined in 20 children who fulfilled the criteria of having an autistic disorder according to ICD-10 and DSM-III-R. In addition, the gangliosides were determined in CSF of children with different types of nonprogressive neurologic disorders not including any clinical features of autism and in 10 controls. All major brain gangliosides, but especially GM1, were significantly increased in patients with autism compared with age-matched controls and those children with nonprogressive neurologic disorders. A particular enrichment of GM1 gangliosides in the synaptic junctions has been demonstrated. Thus, we interpreted the findings of increased CSF gangliosides to indicate enhanced activity mainly of the inhibitory synapses.
343. IS-GALACTOSIDASE GENE MUTATIONS IN PATIENTS WITH I~-GALACTOSIDOSIS N. Ishii, A. Oshima, H. Sakuraba, Y. Fukuyama, and Y. Suzuki, Tokyo, Japan Nineteen 13-galactosidase gene mutations were previously identified in patients with 13-galactosidosis (hereditary 13-galactosidase deficiency). Some of them are common in specific clinical phenotypes: 482Arg ~ His for infantile GM 1-gangliosidosis with severe generalized neurosomatic manifestations (Italian); 2°~Arg ---> Cys for juvenile GMl-gangliosidosis with generalized
337. ENLARGING CLINICAL SPECTRUM OF DOPARESPONSIVE DYSTONIA Carlo Cianchetti, Alessandro Zuddas, Anna Lisa Fratta, Francesco Muntoni, and Mafia Giovanna Marrosu, Cagliafi, Italy Childhood-onset parkinsonism and dopa-responsive dystonia share several clinical features: rigidity and bradykinesia are often present in dystonia and foot dystonia is common in parkinsonism. The diurnal variation, the response to long-term levodopa treatment, and low levels of biopterin in the CSF are considered to be crucial for the differential diagnosis between the 2 syndromes; prognoses of the 2 diseases are quite different. We report a girl with progressive motor impairment evolving to akinesia and rigidity since age 18 months. At age 12, the postural instability with "atonic" neck and trunk, and the extension hypertonia with crossing legs made standing impossible without support; dramatic akinesia and marked rigidity with cogwheel at both arms and legs were also present. Dystonic postures, muscular spasms, or abnormal involuntary movements were never observed. Facial mimic and intelligence were normal. Symptoms were improved by tetraydrobiopterine (BH4, 10 mg/kg per os).
Complete head control, unassisted walking with slightly wider base, normal hand dexterity, and complete disappearance of akinesia or rigidity were observed after levodopa/carbidopa (125/ 12.5 mg/day). Anticholinergic drugs, dopamine agonists (i.e., apomorphine, bromocriptine, and lisuride) and slow-release levodopa formulations induced minimal to moderate improvement; selegiline and amantadine were ineffective. Continued smooth clinical response was observed after chronic treatment with the same daily dose administered in 2 sessions. No loss of efficacy or peak-dose dyskinesia appeared after 8 years of therapy. The dramatic and sustained improvement with low doses of levodopa and the clinical response to BH4, strongly suggest a deficit in neuronal synthesis of levodopa, probably due to altered metabolism of biopterins, as observed in levodopa-responsive dystonia. This indicates that the clinical spectrum of altered metabolism of biopterins could include a pure parkinsonian syndrome without dystonia.
338. NATIONAL SURVEY ON CHRONIC VENTILATOR-ASSISTED CHILDREN IN JAPAN Y. Sakakihara, T. Yamanaka, N. Kajii, and S. Kamoshita, Yaizu and Hokkaido, Japan Because of the improved technology and care for patients who need mechanical ventilation, quality of life and the prognoses for chronic ventilator-assisted patients have improved significantly in recent years. However, the increased number of these patients has raised economic, ethical, as well as medical problems. In order to assess the magnitude of these problems, we conducted the first nationwide survey on the status of chronic ventilatorassisted children in Japan. Questionnaires were mailed to 2,524 pediatric departments in hospitals with more than 100 beds. Two hundred eighty-two hospitals had 567 patients who had been ventilated for more than 1 month at the time of the survey. Among these patients, 434 were younger than 20 years and had been ventilated for more than 3 months. The most common basic disorders were hypoxic-ischemic encephalopathy (n = 60), spinal muscular atrophy, type 1 (i.e., Werdnig-Hoffmarm disease, 55), various congenital myopathies (44), chronic lung disorders of prematurity (21), Ondine's curse (22), drowning (17), congenital heart diseases (16), and Duchenne muscular dystrophy (15). Of 434 patients, only 55 were ventilated at home. Although home care has been considered suitable for chronic ventilatorassisted patients by many pediatricians who responded to the survey, its realization has been hampered by the lack of systems and regulations that support home ventilator care. The fact that many pediatricians in Japan have actively prolonged the lives of those with Werdnig-Hoffmann disease, whereas aggressive lifesaving measures have been withheld in most Western countries, has raised serious ethical and medical issues.
339. DOOR SYNDROME: DEAFNESS, ONYCHOOSTEODYSTROPHY AND MENTAL RETARDATION Kiyoshi Hashimoto, Takehisa Fujita, Hiroko Shibui, Tsunenori Hirayama, and Kentaro Kuwabara, Kawasaki, Japan The association of sensori-neural deafness with onychodystrophy, osteodystrophy, and mental retardation was first reported
PEDIATRIC NEUROLOGY Vol. 11 No. 2 173
under an acronym DOOR by Cantwell in 1975 [1-3]. This is a rare, autosomal-recessive, inherited disorder. We report the first family case report of this syndrome in Japan. The patients were siblings born to healthy, unrelated Japanese parents. The first child is now 5 years old. He was born at 38 weeks gestation after an uncomplicated pregnancy and normal delivery, weighing 2,280 gm. At birth, the nails of his fingers and toes were hypoplastic or absent. At 4 weeks, he was referred to our hospital for evaluation of possible deafness. Hypoplasia of bilateral finger I-IV nails, absence of bilateral finger V nails, and extreme hypoplasia of bilateral great toe nails and absence of toe nails II-V were noted. His thumbs and great toes were long and had 2 flexion creases. Radiologic examination demonstrated 3 bony phalanges of both thumbs and dysplasia of distal bony phalanges of bilateral fingers II-IV and absence of distal bony phalanges in bilateral fingers V and in bilateral toes II-V. ABR showed no differentiated waves, which confirmed bilateral sensori-neural deafness. Teeth and hair were normal. Cranial MRI and CT were not remarkable. Chromosomes were normal. Analysis of both amino acid and organic acid in urine were normal. He had his first seizure at age 2 years, 7 months, and has continued to have frequent seizures consisting of left hemiconvulsion, focal motor seizures of the left side, which have been resistant to antiepileptic drugs. His developmental milestones were retarded; head control was at 5 months, sitting at 9 months, and walking at 26 months. He is now severely mentally retarded. The second child, born recently, has quite similar findings to his older brother. [1] Cantwell RJ. Congenital sensorineural deafness associated with onycho-osteo dystrophy and mental retardation (DOOR syndrome). Humangenetik 1975;26:261-5. [2] Navin NC, Thomas PS, Calvert J, Reid M McC. Deafness, onycho-osteodystrophy, and mental retardation (DOOR) syndrome. Am J Med Genet 1982;13:325-32. [3] Patton MA, Krywawych S, Winter RM, Brenton DP, Baraitser M. DOOR syndrome (deafness, onychoosteodystrophy, and mental retardation): Elevated plasma and urinary 2-oxyoglutarate in three unrelated patients. 1987;26: 207-15.
340. PREDICTION OF OUTCOME FOR COMPLEX PARTIAL SEIZURES WITHOUT STRUCTURAL BRAIN LESIONS BY MULTIVARIATE ANALYSIS Kenji Sugai, Mohamad A. Mikati, James J. R i v i e l l o , Sandra L. Helmers, and Gregory L. Holmes, Boston, Massachusetts
We retrospectively evaluated seizure outcome of complex partial seizures (CPSs) by comparing 44 good responders (G-R) with 44 nonresponders (N-R), both without cranial MRFCT abnormalities. N-R failed on at least both carbamazepine and phenytoin, and their CPSs were confirmed by long-term video-EEG monitoring. G-R were seizure-free over at least 1 year, and patients with benign partial epilepsy with centrotemporal spikes or occipital paroxysms were excluded. Interictal EEGs were obtained. The poor prognostic factors included: (1) cluster/flurries of seizures, frequent seizures (>1 per week), positive underlying cause or febrile convulsions (P < .0001); (2) abnormal background activity on EEG, absence of staring (P < .001); (3) status epilepticus, more seizure types (P < .01); and (4) younger onset, abnormal neurologic signs, burst discharges on EEG, and anterior focus on EEG (P < .05) (Fisher's exact probability test, or chi square test). The outcome was well predicted by Hayashi
174 PEDIATRIC NEUROLOGY Vol. 11 No. 2
discriminant method for categorical data, type II. Correct classification rates for outcome were 87% by using factors 1 and 2, 87% by 1-3, and 92% by 1-4.
341. GENERALIZED NONCONVULSIVE STATUS EPILEPTICUS IN ANGELMAN SYNDROME J. Campistol, F. X. Sanmarti, P. Poo, J. Conill, and E. Fernandez-Alvarez, Barcelona, Spain Angelman syndrome (AS) is characterized by severe mental retardation, inappropriate laughter, happy disposition, ataxic gait, and peculiar jerky movements. EEG abnormalities and seizures are also characteristic features. Deletions of chromosome 15q have been shown to occur in 60% of AS patients. In our series of 18 patients with AS, we found 9 with nonconvulsive status epilepticus: disappearance of laughter, diurnal sleepiness, episodic palpebral myoclonus, or atypical absence status. Initially, this situation was not clearly identified and secondary effects of antiepileptic drugs used to treat their seizures were suspected. EEG demonstrated continuous and diffuse 2-3 Hz spike-and-wave activity. There was a rapid, positive response within 24-48 hours to endovenous benzodiazepines (clonazepam) and the patients returned to their previous states (e.g., disappearance of diurnal sleepiness, smile reappeared). The very similar characteristic features of our patients are rarely reported in the literature. We believe that a prompt diagnosis of this situation is important for effective treatment.
342. GANGLIOSIDES IN CSF IN AUTISTIC CHILDREN Ola H. Skjeldal, Eili Sponheim, Anniken Lekman, and Lars Svennerholm, Oslo, Norway and G6teburg, Sweden
The concentration of the 4 major brain gangliosides--GMl, GDla, GDIb, and GTlb---were determined in 20 children who fulfilled the criteria of having an autistic disorder according to ICD-10 and DSM-III-R. In addition, the gangliosides were determined in CSF of children with different types of nonprogressive neurologic disorders not including any clinical features of autism and in 10 controls. All major brain gangliosides, but especially GM1, were significantly increased in patients with autism compared with age-matched controls and those children with nonprogressive neurologic disorders. A particular enrichment of GM1 gangliosides in the synaptic junctions has been demonstrated. Thus, we interpreted the findings of increased CSF gangliosides to indicate enhanced activity mainly of the inhibitory synapses.
343. IS-GALACTOSIDASE GENE MUTATIONS IN PATIENTS WITH I~-GALACTOSIDOSIS N. Ishii, A. Oshima, H. Sakuraba, Y. Fukuyama, and Y. Suzuki, Tokyo, Japan Nineteen 13-galactosidase gene mutations were previously identified in patients with 13-galactosidosis (hereditary 13-galactosidase deficiency). Some of them are common in specific clinical phenotypes: 482Arg ~ His for infantile GM 1-gangliosidosis with severe generalized neurosomatic manifestations (Italian); 2°~Arg ---> Cys for juvenile GMl-gangliosidosis with generalized