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Childhood encephalopathy: A prospective study
128. CHILDHOOD ENCEPHALOPATHY: A PROSPECTIVE STUDY Hussain I.H.M. Ismail, Sofiah Ali, and Ayesha Tajuddin, Kuala Lumpur, Malaysia A prospective study to determine the etiology and outcome of acute encephalopathy in children was undertaken at our institute from March to October, 1992. A total of 116 patients were enrolled and were classified as follows: infection 80 (68.9%), toxic solidus metabolic 15 (13%), hypoxic 6 (5.2%), hemorrhagic 4 (3.4%), and others 11 (9.5%). Within the infection group, 42 patients (51%) were affected by bacterial meningoencephalitis and 23 (28.7%) by viral encephalitis. The overall sex ratio of boys to girls was 2:1. Fifty percent of patients were younger than 1 year, 13% 1-2 years, and only 13.8% older than 6 years. Thirty-nine patients (33.6%) died during acute illness-26 from the infection group. Eighteen months later, 39 patients remained well and 31 (26.7%) had persistent neurologic deficit. Seven patients were lost to follow-up. The best outcome occurred in the toxic/metabolic group with 60% well at discharge, compared to only 35% in the infection group.
129. CLINICAL HETEROGENEITY IN mtDNA 8993 T>c POINT MUTATION Suk-Chun Mak, Filippo M. Santorelli, Marta E. VazquezMemije, Sara Shanske, Pamela Kranz-Eble, Daniel L. Bluestone, Darryl C. De Vivo, and Salvatore DiMauro, New York, New York and San Francisco, California A mitochondrial DNA (mtDNA) point mutation at position nt 8993T>c has been reported in association with neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) [1] and, when present in high percentage (>95%), with maternally inherited Leigh syndrome (MILS) [2]. LS patients bearing this mutation are severely affected and usually die in early infancy. Recently, a novel 8993T>c point mutation has been described in 4 siblings with a juvenile form of LS [3]. We studied 4 unrelated patients with the 8993T>c point mutation who demonstrated diverse clinical manifestations. Patient 1 (5-year-old boy) exhibited developmental delay, hypotonia, and ataxia. He had recurrent exacerbations during intercurrent illnesses, and eventually developed respiratory insufficiency and apnea. Patient 2 (13year-old boy) presented with a typical NARP phenotype, with neuropathy, ataxia, progressive visual loss due to retinitis pigmentosa, and mild developmental delay. Family history was suggestive of maternal inheritance. Patient 3 (4-year-old boy) had developmental delay, mild hypotonia, and ataxia. Intercurrent febrile episodes exacerbated the clinical course. MRI revealed bilateral lucencies in the basal ganglia on T2-weighted images. Patient 4 (19-year-old woman) demonstrated progressive muscle weakness, generalized seizures, and received a diagnosis of spinocerebellar ataxia. MRI disclosed bilateral abnormalities in the anterior aspect of the putamen. Total genomic DNA was extracted either from blood or muscle, and a 641 bp fragment encompassing the region of the NARP mutation was amplified by PCR, then purified. Both RFLP and sequencing analysis demonstrated a T > C point mutation at position nt 8993 of the mtDNA. The mutation was present in high percentage (>90%) in all 4 patients and was heteroplasmic in 20 maternal relatives. These findings suggest high phenotypic variability for the nt 8993T>c mutation. In contrast with the T > G change at the
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same position, the T > C mutation appears to cause milder clinical manifestations. References: [1] Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990;46:428-33. [2] Tatuch Y, Christodoulou J, Feigenbaum A, et al. Heteroplasmic mtDNA mutation (T- > G) at 8993 can cause Leigh's disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 1992;50:852-8. [3] de Vries DD, van Engelen BGM, Gabre~ls FJM, et al. A second missense mutation in the mitochondrial ATPase6 gene in Leigh's syndrome. Ann Neurol 1993;34:410-2.
130. PERVASIVE DEVELOPMENTAL DISORDERS AND THE CHILD NEUROLOGIST Roberto F. Tuchman, Miami, Florida Children with pervasive developmental disorders (i.e., autism and pervasive developmental disorders not otherwise specified) present to child neurologists with abnormal language development, behavioral problems, or general developmental delay. Pervasive developmental disorders are behaviorally defined but associated with a variety of neurobiologic abnormalities. The purpose of this study is to determine the types of neurobiologic problems commonly identified by a child neurologist assessing children with pervasive developmental disorders in clinical practice. From July, 1991 to April, 1994, 340 patients with pervasive developmental disorders seen by one child neurologist were entered into an ongoing database. High-functioningindividuals accounted for a total of 14% of these patients. Motor abnormalities occurred in 18% of the total population with hypotonia being the most common motor manifestation. Stereotypies were present in 67%. Regression of language was reported by 25% of all parents. Chromosomal abnormalities were found in 4% of children (1.5% with fragile X and 2.5% with other chromosomal abnormalities). Ten families (3%) had more than 1 child with a pervasive developmental disorder. Seizures occurred in 13% and abnormal EEGs were present in 31%. Of those individuals who underwent MRI, abnormalities were found in 15%. High levels of anxiety were reported by parents in 22% of the children and sleep problems occurred in 19%. This study supports the importance of neurologic assessment of all children with pervasive developmental disorders. The child neurologist in clinical practice needs to be cognizant of the spectrum of behavioral and neurobiologic manifestations of children with pervasive developmental disorders. Neurologic assessment of these individuals is crucial for appropriate management and to provide families with genetic and prognostic information. In addition, the data presented suggest areas in need of further clinical and basic science research.
131. BILATERAL STRIATAL LESIONS Joaquin A. Pefia, Eduardo Mora, and Enoe E. Medrano, Maracaibo, Venezuela Selective lesions of the basal ganglia have been described in children with acute, subacute, and chronic diseases. The diagnosis of acute or persistent neurologic dysfunction associated with bilateral striatal lesions in childhood (BSLC) can be accomplished by serial CT and MRI. Since 1985 we have identified 9
129. CLINICAL HETEROGENEITY IN mtDNA 8993 T>c POINT MUTATION Suk-Chun Mak, Filippo M. Santorelli, Marta E. VazquezMemije, Sara Shanske, Pamela Kranz-Eble, Daniel L. Bluestone, Darryl C. De Vivo, and Salvatore DiMauro, New York, New York and San Francisco, California A mitochondrial DNA (mtDNA) point mutation at position nt 8993T>c has been reported in association with neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) [1] and, when present in high percentage (>95%), with maternally inherited Leigh syndrome (MILS) [2]. LS patients bearing this mutation are severely affected and usually die in early infancy. Recently, a novel 8993T>c point mutation has been described in 4 siblings with a juvenile form of LS [3]. We studied 4 unrelated patients with the 8993T>c point mutation who demonstrated diverse clinical manifestations. Patient 1 (5-year-old boy) exhibited developmental delay, hypotonia, and ataxia. He had recurrent exacerbations during intercurrent illnesses, and eventually developed respiratory insufficiency and apnea. Patient 2 (13year-old boy) presented with a typical NARP phenotype, with neuropathy, ataxia, progressive visual loss due to retinitis pigmentosa, and mild developmental delay. Family history was suggestive of maternal inheritance. Patient 3 (4-year-old boy) had developmental delay, mild hypotonia, and ataxia. Intercurrent febrile episodes exacerbated the clinical course. MRI revealed bilateral lucencies in the basal ganglia on T2-weighted images. Patient 4 (19-year-old woman) demonstrated progressive muscle weakness, generalized seizures, and received a diagnosis of spinocerebellar ataxia. MRI disclosed bilateral abnormalities in the anterior aspect of the putamen. Total genomic DNA was extracted either from blood or muscle, and a 641 bp fragment encompassing the region of the NARP mutation was amplified by PCR, then purified. Both RFLP and sequencing analysis demonstrated a T > C point mutation at position nt 8993 of the mtDNA. The mutation was present in high percentage (>90%) in all 4 patients and was heteroplasmic in 20 maternal relatives. These findings suggest high phenotypic variability for the nt 8993T>c mutation. In contrast with the T > G change at the
118 PEDIATRICNEUROLOGY Vol. 11 No. 2
same position, the T > C mutation appears to cause milder clinical manifestations. References: [1] Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet 1990;46:428-33. [2] Tatuch Y, Christodoulou J, Feigenbaum A, et al. Heteroplasmic mtDNA mutation (T- > G) at 8993 can cause Leigh's disease when the percentage of abnormal mtDNA is high. Am J Hum Genet 1992;50:852-8. [3] de Vries DD, van Engelen BGM, Gabre~ls FJM, et al. A second missense mutation in the mitochondrial ATPase6 gene in Leigh's syndrome. Ann Neurol 1993;34:410-2.
130. PERVASIVE DEVELOPMENTAL DISORDERS AND THE CHILD NEUROLOGIST Roberto F. Tuchman, Miami, Florida Children with pervasive developmental disorders (i.e., autism and pervasive developmental disorders not otherwise specified) present to child neurologists with abnormal language development, behavioral problems, or general developmental delay. Pervasive developmental disorders are behaviorally defined but associated with a variety of neurobiologic abnormalities. The purpose of this study is to determine the types of neurobiologic problems commonly identified by a child neurologist assessing children with pervasive developmental disorders in clinical practice. From July, 1991 to April, 1994, 340 patients with pervasive developmental disorders seen by one child neurologist were entered into an ongoing database. High-functioningindividuals accounted for a total of 14% of these patients. Motor abnormalities occurred in 18% of the total population with hypotonia being the most common motor manifestation. Stereotypies were present in 67%. Regression of language was reported by 25% of all parents. Chromosomal abnormalities were found in 4% of children (1.5% with fragile X and 2.5% with other chromosomal abnormalities). Ten families (3%) had more than 1 child with a pervasive developmental disorder. Seizures occurred in 13% and abnormal EEGs were present in 31%. Of those individuals who underwent MRI, abnormalities were found in 15%. High levels of anxiety were reported by parents in 22% of the children and sleep problems occurred in 19%. This study supports the importance of neurologic assessment of all children with pervasive developmental disorders. The child neurologist in clinical practice needs to be cognizant of the spectrum of behavioral and neurobiologic manifestations of children with pervasive developmental disorders. Neurologic assessment of these individuals is crucial for appropriate management and to provide families with genetic and prognostic information. In addition, the data presented suggest areas in need of further clinical and basic science research.
131. BILATERAL STRIATAL LESIONS Joaquin A. Pefia, Eduardo Mora, and Enoe E. Medrano, Maracaibo, Venezuela Selective lesions of the basal ganglia have been described in children with acute, subacute, and chronic diseases. The diagnosis of acute or persistent neurologic dysfunction associated with bilateral striatal lesions in childhood (BSLC) can be accomplished by serial CT and MRI. Since 1985 we have identified 9