Ethical issues surrounding the evaluation of oxidative phosphorylation disorders in children.

Genetic testing is becoming increasingly frequent as a part of a pediatric evaluation. Oxidative phosphorylation disorders are likewise becoming part of the differential diagnosis for many children with undiagnosed neurologic problems. The complexity of the oxidative phosphorylation pathway and its dual genetic control by nuclear and mitochondrial DNA raise a number of ethical issues dealing mainly with the informed consent process, the respect for a patient's autonomy, the best interest of the patients and their families, as well as issues of genetic discrimination and genetic privacy laws. Open communication with families in pediatric medicine remains the cornerstone of good ethics, along with the skill needed to avoid having ethical issues arise.

Familial cerebellar ataxia with muscle coenzyme Q10 deficiency.

OBJECTIVE: To describe a clinical syndrome of cerebellar ataxia associated with muscle coenzyme Q10 (CoQ10) deficiency. BACKGROUND: Muscle CoQ10 deficiency has been reported only in a few patients with a mitochondrial encephalomyopathy characterized by 1) recurrent myoglobinuria; 2) brain involvement (seizures, ataxia, mental retardation), and 3) ragged-red fibers and lipid storage in the muscle biopsy. METHODS: Having found decreased CoQ10 levels in muscle from a patient with unclassified familial cerebellar ataxia, the authors measured CoQ10 in muscle biopsies from other patients in whom cerebellar ataxia could not be attributed to known genetic causes. RESULTS: The authors found muscle CoQ10 deficiency (26 to 35% of normal) in six patients with cerebellar ataxia, pyramidal signs, and seizures. All six patients responded to CoQ10 supplementation; strength increased, ataxia improved, and seizures became less frequent. CONCLUSIONS: Primary CoQ10 deficiency is a potentially important cause of familial ataxia and should be considered in the differential diagnosis of this condition because CoQ10 administration seems to improve the clinical picture.

Social problem solving in children with acquired brain injuries.

OBJECTIVES: To assess the performance of children with acquired brain injuries (ABIs) on a measure of social problem solving and to examine the relationships between participant characteristics and performance on the Social Knowledge Interview (SKI) and between parent-reported child behavior and performance on the SKI. DESIGN: Between-group comparisons using correlational analyses, matched pairs t-tests, and analysis of covariance (ANCOVA). PARTICIPANTS: Thirty-one children 6-12 years old with ABI and 31 control participants, matched on age and sex. MAIN OUTCOME MEASURE: The SKI, a measure of social problem-solving skills. RESULTS: Using matched pairs t-tests and ANCOVA, groups were compared on several SKI measures, including the number of unique responses generated for each problem scenario, the quality of those responses, and the ability to select the best response from a set of alternatives. When equated for socioeconomic status (SES), ABI and control participants performed similarly on the SKI; however, a trend for children with ABI to generate more assertive responses was observed. Performance on the SKI was positively correlated with IQ and related to parent-reported adaptive behavior. In children with ABI, performance was also related to primary lesion location and treatment regimen. CONCLUSIONS: Children with ABI are as capable of judging the appropriateness of behavior and generating response options on an analog measure of social problem solving as were their typically developing peers. However, those individual children with ABI who are more likely to have social problems may be identified by the qualitative aspects of their responses on analog tasks. These findings have implications for the identification of children with social skills deficits following ABI and for the development of effective rehabilitation strategies.

Systematic approach for detection of endocrine disorders in children treated for brain tumors.

Endocrine dysfunction can be challenging to diagnose in children treated for brain tumors. Treatments are available for hormonal replacement and when necessary, hormonal suppression. Without these endocrine treatment regimens, life can be unnecessarily difficult or unpleasant. An endocrine survey can be used to screen at-risk neuro-oncology patients once or twice a year to facilitate the recognition of endocrine dysfunction. It is hoped that through the use of a routine screening program, physicians will be able to diagnose and begin treatment of endocrine problems in a time-efficient manner.

Additive impact of in-hospital cardiac arrest on the functioning of children with heart disease.

OBJECTIVE: This study examined the impact of a sudden cardiac arrest (CA) on the neurodevelopmental and adaptive functioning of young children with congenital heart disease (CHD). METHODOLOGY: Sixteen children with CHD who had sustained an in-hospital CA were compared with a medically similar group of children with CHD who had not incurred a CA. The contribution of CA, disease severity, and family socioeconomic status on the prediction of developmental outcome variables was evaluated. RESULTS: Children in the CA group displayed more impairments in general cognitive, motor, and adaptive behavior functioning as well as greater disease severity as measured by a cumulative medical risk index. With respect to all children in the study, a higher socioeconomic status was related to higher scores on cognitive functioning, lower levels of child maladjustment, and lower levels of stress within the parent-child relationship. Although the occurrence of a CA alone did not contribute to the prediction of outcome measures, a significant interactional effect between CA and cumulative medical risk index was found. Specifically, among children who had incurred a CA, as disease severity increased, decrements in abilities were observed. Few significant correlations between specific CA-related variables (eg, length of CA) and outcome indices were found. CONCLUSIONS: Results from this study indicate that the impact of cardiac arrest on neuropsychological functioning may be mediated by the child's overall disease severity. These findings have implications for the identification of CA survivors at greatest risk for developmental difficulties.

Oxidative phosphorylation defect associated with primary adrenal insufficiency.

An 18-month-old girl with an oxidative phosphorylation defect had neonatal onset of chronic lactic acidosis, lipid storage myopathy, bilateral cataracts, and primary adrenal insufficiency. Chronic lactic acidosis responded to treatment with dichloroacetate. Sequential muscle biopsies demonstrated resolution of the lipid storage myopathy associated with the return to normal muscle free carnitine levels. This case demonstrates a new clinical phenotype associated with a defect in oxidative phosphorylation and the need to consider mitochondrial disorders in the differential diagnosis of primary adrenal insufficiency in childhood.

Family and illness predictors of outcome in pediatric brain tumors.

Investigated the prediction of cognitive and behavioral outcomes in 63 children with heterogenous brain tumors. Hierarchical multiple regression analyses were used to determine how family-related variables added to the prediction of children's outcome over and above illness measures. The best predictors of children's behavior problems and adaptive behavior were family and demographic variables, whereas the best predictors of achievement were illness and demographic variables. A combination of family and illness variables, however, was the best predictor of intellectual functioning. In addition to identifying specific predictors of cognitive and behavioral outcome in children with brain tumors, these results lend initial support for the inclusion of contextual factors such as family stress, maternal coping, number of parents in the home, and family SES measures in studies of how disease factors affect outcomes in pediatric brain tumor patients.

Oxidative phosphorylation diseases and cerebellar ataxia.

Oxidative phosphorylation (OXPHOS) diseases can be caused by mutations in nuclear genes or mitochondrial DNA (mtDNA) genes. mtDNA mutations include complex mtDNA rearrangements in which large segments of mtDNA are duplicated or deleted and point mutations in which single nucleotide substitutions occur within transfer RNA (tRNA) genes, ribosomal RNA (rRNA) genes, or mitochondrial genes encoding OXPHOS polypeptides. Although over 30 pathogenic mtDNA point mutations and over 60 different types of mtDNA deletions are known (Shoffner and Wallace, 1995; Wallace et al., 1994), only a subset of these mutations are associated with cerebellar ataxia. This review focuses on the clinical, biochemical, and genetic features of OXPHOS diseases caused by mtDNA mutations in which ataxia is a common manifestation.

Response to neoadjuvant chemotherapy in children with pineoblastoma.

BACKGROUND: The outlook of children with pineoblastoma treated with radiation therapy alone is extremely poor, but neoadjuvant chemotherapy has been tried only in a few cases of this rare childhood brain tumor with poor prognosis. METHODS: Three consecutive children 3 to 7 years of age received neoadjuvant chemotherapy consisting of etoposide 100 mg/m2 days 1 to 3, cisplatin 100 mg/m2 day 1, and vincristine 1.5 mg/m2 day 1, repeated every 4 weeks. After four courses of chemotherapy, patients underwent craniospinal irradiation. The radiation doses to the primary site ranged from 5040 to 5440 cGy and craniospinal axis radiation dose was 2520 to 3060 cGy. RESULTS: After chemotherapy, mild myelosuppression occurred in all three and mild to moderate bilateral high-frequency sensorineural hearing loss occurred in two of the three patients. One patient remains in near complete resolution of the tumor at 2 years after diagnosis and another remains in CR for 5 years. One patient achieved PR for 5 months but eventually died of progressive tumor. CONCLUSIONS: This study suggests that the neoadjuvant chemotherapy as used here is effective and has acceptable toxicity.

Childhood intracranial meningiomas after high-dose irradiation.

BACKGROUND: Irradiation, either alone or in association with other factors, is thought to play a role in the causation of intracranial meningioma. METHODS: The authors report two 15-year-old patients with convexity meningiomas as a result of high-dose irradiation received at a young age and review the English language literature reports of 13 pediatric patients with meningiomas after high-dose irradiation. The clinical characteristics of the 15 patients are presented. RESULTS: There were nine girls and six boys. The mean age at the time of irradiation was 2.5 years (2 months-9 years), and the mean age at diagnosis of meningioma was 13 years (5-15.5 years). The mean radiation dose was 4154 cGy (1500-8000 cGy). In 11 of the 15 patients, the meningioma was located in the calvarial area. Only 1 of 15 had multiple tumors, and only two of the tumors were clearly malignant at diagnosis. In ten patients, gross total resection was recorded, and two patients underwent subtotal resection. Three died of recurrent/disseminated meningiomas. CONCLUSIONS: This study suggests that meningiomas after high-dose radiation in children are mostly calvarial in location, rarely multiple, mostly benign in histologic type, and that complete removal is possible in most patients. The age at the time of radiation is young (mean age, 2.5 years) and the latent period is short (mean, 10.8 years). Although the clinical course of radiation-induced meningiomas in childhood generally is benign, high doses of radiation at a young age are to be avoided, and other means of therapy should be used if possible.

Neuropsychological, academic, and adaptive functioning in children who survive in-hospital cardiac arrest and resuscitation.

Children suffering cardiac arrest (CA) are not uncommon in certain pediatric populations. Due to the increasing survival rates of child CA patients, there is a growing interest in, and concern for, their long-term intellectual, academic, emotional, and adaptive functioning. This article describes the possible neurologic sequelae of CA in children and presents standardized assessment results on 25 children, 2 to 15 years of age, who survived a CA while in the hospital. A majority of these children exhibited low-average to deficient levels of performance on neuropsychologic, achievement, and adaptive behavior measures. Duration of cardiac arrest and a medical risk score were significantly correlated with decreased functioning in child CA patients. Children who suffer a cardiac arrest are at high risk for academic struggles, and many may need special education services.

Subacute necrotizing encephalopathy: oxidative phosphorylation defects and the ATPase 6 point mutation.

Subacute necrotizing encephalopathy (SNE) or Leigh's disease is associated with various defects in oxidative phosphorylation (OXPHOS). However, the relationships between these OXPHOS defects and nuclear DNA or mitochondrial DNA (mtDNA) mutations is still unclear. We evaluated three SNE pedigrees (two singleton cases and a pedigree) biochemically for OXPHOS abnormalities and genetically for four mtDNA point mutations. There was a complex I defect in all three pedigrees that was associated with a complex III defect in two individuals. An mtDNA mutation in the ATPase, subunit 6 gene (np 8993) was present in one SNE pedigree. This mutation was maternally inherited, heteroplasmic, produced marked clinical and biochemical heterogeneity between pedigree members, and varied along the maternal lineage at levels ranging from 0% to > 95% of the total mtDNAs. These mtDNA mutations were not present in the other two pedigrees. These observations emphasize the importance of screening for OXPHOS defects and mtDNA mutations in SNE cases.

Factors related to adherence to medication regimens in pediatric seizure patients.

Factors related to medication adherence were studied in 35 pediatric seizure patients at a public hospital serving primarily low-income minority patients. Adherence ratings by pediatric neurologists were based primarily on three blood assays drawn at monthly intervals and patients were rated as adherent on 1, 2, or 3 visits. Parent and child satisfaction with medical care was associated with greater adherence. Parental worry about the child's health was positively correlated with the number of behavioral restrictions placed on the child, and both variables were negatively related to adherence. The authors hypothesize that anxiety-based denial and perceived threats to patient autonomy may interfere with medication adherence. Implications for the development of intervention strategies for improving adherence among pediatric seizure patients are discussed.

Evidence in a lethal infantile mitochondrial disease for a nuclear mutation affecting respiratory complexes I and IV.

A child died at 4 months of age of a lethal infantile mitochondrial disease associated with cardiomyopathy. Detailed pathologic evaluation of this patient revealed abnormalities in the striated muscle, smooth muscle, heart, and liver, but not the central nervous system. Biochemical analysis revealed a combined complex I and IV deficiency in skeletal muscle, heart, and liver, but not in kidney and brain. Analysis of mitochondrial translation products and mitochondrial DNA failed to detect any abnormality. Parallel studies on both parents were uniformly normal. These data support the hypothesis that this disease was the result of a nuclear DNA mutation in a developmental stage-specific and tissue-specific oxidative phosphorylation-gene.

MR of Leigh's disease (subacute necrotizing encephalomyelopathy).

MR images of three patients with Leigh's disease (subacute necrotizing encephalomyelopathy) were compared with CT findings. In all patients typical lesions in the basal ganglia were identified with both MR and CT. In two patients MR permitted identification of additional lesions not detected with CT. In one patient progression of MR abnormalities over a 4-month period correlated well with clinical deterioration in neurologic status. T2-weighted images with a repetition time (TR) greater than 1950 msec and an echo time (TE) greater than or equal to 60 msec or inversion-recovery images with a 50-msec TE, 1213-msec inversion time, and 3000-msec TR were advantageous in identifying multiple necrotic lesions in the brainstem, deep gray matter, periventricular white matter, and cerebral cortex. In this series MR was more sensitive in detecting and localizing multifocal necrotic lesions of Leigh's disease than CT was, and thus may be a useful diagnostic tool for patients with the appropriate clinical and laboratory abnormalities.

The use of neuropsychological evaluation in the medical management of subdural empyema.

Subdural empyema is in itself an uncommon complication of infection in childhood and localization of the infection to the parafalcine area is rare. This paper presents a case study of a teenager with subdural empyema resulting from paranasal sinusitis, who presented as a parafalcine syndrome and was treated successfully without neurosurgical intervention. Results of repeat neuropsychological evaluation (premorbid, 17 days into treatment, and after six months), correlated with changes seen on serial CT scanning during treatment and follow up. More importantly, the neuropsychological evaluation was clinically more sensitive than the traditional neurological examination in assessing changes in cortical integrity during the course of recovery. Thus, neuropsychological evaluation proved to be a valuable supplement to the neurological examination in exploring morbidity and assisting in treatment decision making in the management of subdural empyema.

The neuropsychological approach to the remediation of dyslexia.

The neuropsychological approach to remediation emphasizes the use of intact areas of higher cortical functioning in the development of remedial strategies while minimizing the emphasis placed upon dysfunctional cortical areas. This investigation was directed towards evaluating the effectiveness of the neuropsychological approach to the remediation of developmental dyslexia in school age children previously placed in self-contained classrooms for the learning disabled due to reading failure. A significant improvement in word recognition skills was demonstrated with a similar, but nonsignificant, trend noted in reading comprehension.

Serum carnosinase deficiency: a non-disabling phenotype?

Serum carnosinase deficiency (McKusick 21220) is a rare condition, described in 13 cases. Ten additional individuals with serum carnosinase deficiency have been identified. All continued to excrete increased amounts of carnosine in their urine despite a meat-free diet for 3 days. Serum carnosinase activity ranged from 0-30% of normal. In four individuals a normal Km for carnosine of 0.12 mM was observed, while in five individuals an increased Km was found. Homocarnosine levels in CSF in three individuals ranged from 3.4 to 15 mM. Clinical symptoms in these individuals were as follows: attention deficit disorder: 4; non progressive developmental delay: 1; neurofibromatosis: 1; absences seizures: 1; severe, but non-progressive mental retardation, seizures and neurosensory hearing loss: 1; progressive childhood dementia; 1; clinically normal: 1. There was no correlation between severity and type of the neurological symptoms and residual serum carnosinase activity. Although a definite conclusion can only be made after a considerably higher number of individuals has been analyzed, the suspicion that serum carnosinase deficiency is unrelated to the neurological symptoms is strengthened by these observations. There may, however, be an association with a predisposition for mental deficiency.

Computed tomography of the brain in subacute sclerosing panencephalitis.

Twenty-four computed tomographic scans of 12 patients with confirmed subacute sclerosing panencephalitis were studied using standardized techniques of radiological assessment. Abnormalities encountered were of four types--(1) lateral ventricular dilatation, (2) cerebral cortical atrophy and sylvian fissure widening, (3) low parenchymal attenuation, and (4) brainstem atrophy and cerebellar atrophy--and of varying degrees. The abnormalities correlated best with the stage and duration of disease, but not necessarily well with the patient's mental state. The fewest radiological abnormalities were encountered in the acute or early stages, whereas more signs of parenchymal disturbances in the form of low attenuations emerged during intermediate periods. Chronic periods were accompanied by atrophic changes in the form of cortical atrophy, ventricular dilatation, and brainstem cerebellar atrophy.

Neurodegenerative diseases of infancy and childhood.

The neurodegenerative diseases of infancy and childhood include disorders in which there is progressive loss of neurological function due to structural abnormalities of the central nervous system. Well over six hundred disorders, many of which are rarely seen, can be included in this category. Yet, the conditions represent collectively over one-fourth of all admissions to pediatric neurology services. Five-year samples of admission characteristics of 1218 patients from two medical centers over twenty-two years permit an estimate of the frequency of the neurodegenerative diseases. The six most-encountered diagnoses, in declining order, were: subacute sclerosing panencephalitis; neuronal ceroid lipofuscinosis; tuberous sclerosis with degeneration; West disease, or idiopathic degenerative encephalopathy associated with infantile spasms; Werdnig-Hoffmann disease, and hereditary spastic paraplegia. A classification is offered grouping the neurodegenerative disorders into five major categories: polioencephalopathies, leukoencephalopathies, corencephalopathies, spinocerebellopathies, and diffuse encephalopathies. Disorders in each subgroup may be either genetic or nongenetic. Neurodegenerative diseases have multiple causes, including metabolic, viral, immunopathic, environmental, and epileptogenic. The cause of many remains unknown.