A novel mutation in the GDAP1 gene is associated with autosomal recessive Charcot-Marie-Tooth disease in an Amish family.

Charcot-Marie-Tooth disease (CMT) constitutes a large group of genetically heterogeneous disorders of the peripheral nervous system. Autosomal recessive forms of CMT are less common in the general population but account for the vast majority of CMT phenotypes in communities with a high prevalence of consanguinity. At least 10 genetic loci cause autosomal recessive forms of CMT. Mutations in the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene are among the most frequent genetic causes of autosomal recessive forms of CMT. To date, 28 mutations in GDAP1 gene have been linked with the disease. Here, we report a novel GDAP1 mutation in an Old Order Amish family with CMT. To ascertain the Amish CMT locus, we performed a genome-wide single nucleotide polymorphism (SNP) analysis on one of three patients from a consanguineous pedigree. Assuming mutation homogeneity, the analysis sought large homozygous SNP blocks that also contained known CMT loci. The largest homozygous SNP block in the patient was localized to chromosome 8q13.1-21.3 and contained the GDAP1 gene. Sequence analysis revealed a novel homozygous mutation, c.692C>T, at codon 231 (p.P231L) in exon 5 of GDAP1 in all patients. Neither the unaffected individuals in the family nor the healthy control samples were homozygous for this mutation. Our findings suggested that this novel mutation in GDAP1 gene is associated with an autosomal recessive form of CMT in Ohio Old Order Amish community.

Autosomal dominant acute necrotizing encephalopathy.

OBJECTIVE: To define the clinical and biochemical abnormalities of an autosomal dominant form of acute encephalopathy. METHODS: The clinical details of 11 affected family members in comparison with 63 unaffected relatives were analyzed. RESULTS: Affected children become comatose after onset of a febrile illness. Outcomes include full recovery, permanent neurologic impairment, and death. Recurrences produce more severe impairments. Lesions of necrotizing encephalopathy of the thalamus and brainstem are present on autopsy and MRI. Oxidative phosphorylation of intact mitochondria from a muscle biopsy shows loose coupling. Unaffected family members, including obligate carriers, share no clinical characteristics, demonstrating incomplete penetrance. CONCLUSIONS: Characteristic pathology and MRI findings define this disorder of autosomal dominant acute encephalopathy. Leigh syndrome and sporadic acute necrotizing encephalopathy share similarities but are distinct.

A 13-year-old boy with cognitive impairment, retinoblastoma, and Wilson disease.

A developmentally delayed child manifested retinoblastoma at age 4 years and Wilson disease at age 11, a previously unreported association. Cytogenetic and molecular analysis showed an interstitial deletion in the long arm of the paternally derived homologue of chromosome 13 (13q14.2-13q22.2), which encompasses the retinoblastoma and Wilson disease loci. The authors postulate that the co-occurrence of retinoblastoma and Wilson disease was the consequence of an acquired somatic mutation at the retinoblastoma locus and an inherited mutation at the Wilson disease locus of the maternally derived chromosome 13, superimposed on the hemizygosity associated with the paternally derived deletion.

Stroke in children: recognition, treatment, and future directions.

Childhood stoke is increasingly recognized, but studies remain largely descriptive. Important differences from adult stroke include the following: (1) frequently delayed or missed diagnosis, (2) heterogenous and overlapping risk factors, and (3) developmental differences in the cerebrovascular, neurologic, and coagulation systems. These aspects limit the extrapolation of the results of adult stroke research and present challenges in caring for children with stroke. The incidence of childhood ischemic stroke exceeds 3.3 in 100,000 children per year, more than double the estimates from past decades. The increased incidence reflects, in part, increased survival in previously fatal conditions predisposing to stroke, including congenital heart disease, sickle cell anemia, and leukemia. Risk factors for stroke are recognized in more than 75% of children. Common risk factors include congenital heart disease and sickle cell disease. Progressive arteriopathies, including vasculitis and moyamoya syndrome, are rare in children with stroke; however, transient arteriopathies including post-varicella angiopathy are increasingly recognized. Prothrombotic abnormalities are frequently present but of unclear significance. Adverse outcomes after childhood stroke, including death in 10%, recurrence in 20%, and neurologic deficits in two thirds of survivors could be reduced with available stroke treatments. Aggressive prehospital emergency care and transfer could improve access to hyperacute stroke therapies including tPA. Currently, the diagnosis is delayed by more than 24 hours from onset in most children. As in adults, tPA will likely produce unacceptable rates of intracerebral hemmorrhage unless given within 3 hours of stroke symptom onset. The appropriate choices for in hospital treatment and secondary preventative strategies, including aspirin and anticoagulants, are controversial. Empiric recommendations are published; however, age-appropriate clinical trials are urgently needed. The large multinational networks of investigators necessary for designing and conducting these future trials are now being formed.

Risperidone-induced hepatotoxicity in children and adolescents? A chart review study.

Risperidone is an atypical antipsychotic drug that has been used in the treatment of numerous psychiatric disorders in children and adolescents. The question of whether risperidone-induced weight gain is associated with steatohepatitis has recently been raised. The purpose of this chart review was to ascertain: (1) the rate of liver dysfunction observed during risperidone treatment in children and adolescents; and (2) the clinical factors associated with liver dysfunction. For purposes of this chart review study, abnormal liver function was defined by serum transaminase or bilirubin values falling outside the normal laboratory ranges. Chart reviews were completed on 38 youths with ages ranging from 5-17 years with a variety of psychiatric diagnoses. The mean length of risperidone treatment was 15.2 months at a mean dose of 2.5 mg/day. It was found that 37 of the 38 youths treated with risperidone had no liver enzyme abnormalities at the end of study. One subject had an alanine aminotransferase (ALT) level of 46 U/L which was 7 U/L above the upper limit of normal for this laboratory test. This isolated value was not considered clinically significant. These data were noted in spite of weight gain and the use of numerous concomitant psychotropic medications. These findings suggest that risperidone in short term treatment does not commonly lead to evidence of abnormal liver function at therapeutic doses in children and adolescents. Larger-scale, prospective studies are needed in order to confirm these findings.

Neurodevelopmental outcomes of Ugandan infants with HIV infection: an application of growth curve analysis.

Neurodevelopmental outcomes of human immunodeficiency virus Type 1 (HIV-1)-infected infants of non-drug-using mothers were assessed in a controlled, prospective study from birth to 24 months with 3 groups: 61 infants of HIV-infected mothers, 234 uninfected infants of HIV-infected mothers (seroreverters), and 115 uninfected infants of uninfected mothers. Compared with seroreverters and uninfected infants, HIV-infected infants demonstrated lower mental and motor development on the Bayley Scales and greater deceleration in their rate of motor development. HIV-infected infants with abnormal neurologic exams had lower motor and mental test scores and lower rates of motor Bayley Scales scores than their HIV-infected counterparts with normal neurologic exams. Contrary to prediction, no group differences in mean performance or growth rates were found on visual information processing on the Fagan Test of Infant Intelligence.

High-dose pyridoxine and magnesium administration in children with autistic disorder: an absence of salutary effects in a double-blind, placebo-controlled study.

Several reports have described salutary effects such as decreased physical aggression and improved social responsiveness being associated with the administration of high doses of pyridoxine and magnesium (HDPM) in open-labeled and controlled studies of patients with autism. Despite this fact, this intervention remains controversial. A 10-week double-blind, placebo-controlled trial was undertaken to examine both the efficacy and safety of HDPM in autism. Twelve patients were enrolled, and 10 patients (mean age 6 years 3 months) were able to complete the study. HDPM at an average dose of 638.9 mg of pyridoxine and 216.3 mg of magnesium oxide was ineffective in ameliorating autistic behaviors as assessed by the Children's Psychiatric Rating Scale (CPRS), the Clinical Global Impression Scale, and the NIMH Global Obsessive Compulsive Scale. Furthermore, no clinically significant side effects were noted during HDPM administration. A trend for a transient change on the CPRS was found that was possibly due to a placebo response. This study raises doubts about the clinical effectiveness of HDPM in autistic disorder.

Neurodevelopmental outcomes of Ugandan infants with human immunodeficiency virus type 1 infection.

BACKGROUND: The neurodevelopmental outcomes of human immunodeficiency virus type 1 (HIV-1)-infected Ugandan infants of nondrug-using mothers were studied using controlled, prospective methodology. METHOD: The sample of 436 full-term infants included 79 HIV-infected infants of HIV-1-infected mothers, 241 uninfected infants of HIV-1-infected mothers (seroreverters), and 116 uninfected infants born to HIV-negative mothers. Neurologic status, information processing ability, and motor and mental development were assessed from 6 to 24 months of age. Observations of caretaker-child interaction and home environments were made at 6 and 12 months. All evaluators were blinded to the HIV status of the child and family. RESULTS: Compared with seroreverters and uninfected infants, HIV-infected infants demonstrated greater deficits in motor development and neurologic status, and more frequent and earlier onset of motor and neurologic abnormalities. Compared with controls, HIV-infected infants had more abnormalities in mental development at 6 and 18 months and an earlier onset of abnormalities. By 12 months, 30% of HIV-infected infants demonstrated motor abnormalities and 26% cognitive abnormalities as compared with 11% and 6% among seroreverters and 5% and 6% among seronegative infants. HIV-infected infants (62%) demonstrated a higher probability of developing an abnormal neurologic examination by 12 months, compared with seroreverters (17%) or seronegative infants (15%). Information-processing abilities did not differ as a function of HIV infection. Home environments and infants' interactions with caretakers were similar across groups. CONCLUSION: We conclude that HIV infection results in more frequent and earlier abnormalities in infants' neurologic status and motor development that are not attributable to other biological and environmental risk factors. More frequent mental developmental abnormalities were evident at several ages. However, information-processing abilities, such as recognition memory, may be spared from HIV-related deficits.

An open clinical trial of risperidone monotherapy in young children with autistic disorder.

Autistic disorder (AD) may be associated with dysfunctional behaviors which significantly interfere with a child's functioning. Risperidone has been described as having salutary effects as an adjunctive pharmacotherapy in adult and pediatric patients with AD. The purpose of this 8-week, open-label study was to examine the effectiveness and tolerability of risperidone monotherapy in young patients with AD. Doses of risperidone were to be started at 0.25 mg qhs and were titrated to maximize clinical efficacy. Six patients (ages 5 to 9 years) were enrolled in this protocol, and all completed it. After 8 weeks of treatment, with a mean risperidone dose of 1.1 mg, improvement in symptomatology was demonstrated by reduced scores on both the Children's Psychiatric Rating Scale (p < .005) and the Clinical Global Impressions Scale (p < .001). The most common side effect were weight gain and sedation. This study provides preliminary evidence that risperidone monotherapy may be safe and effective in ameliorating dysfunctional behaviors in children with AD.

Continuity and change of self-reported problem behaviors from adolescence into young adulthood.

OBJECTIVE: To investigate the 4-year course of behavioral and emotional problems from adolescence into young adulthood in a general population sample. METHOD: The population consisted of 364 individuals, aged 15 to 18 years at the beginning of the study. Subjects filled out the Youth Self-Report at the first time of assessment. At follow-up, 2 and 4 years later, subjects aged 19 or older completed the Young Adult Self-Report, which was derived from the Youth Self-Report. RESULTS: Almost 40% of the adolescents who were classified as deviant initially were still deviant 4 years later. There was no significant difference in the continuity of internalizing problems versus externalizing problems in this sample. CONCLUSIONS: All types of problems tended to persist to a similar degree. This holds also for problems that are often regarded as typical childhood problems, such as attention problems and hyperactivity. Because adolescent problems are likely to continue, we need more knowledge on the efficacy of interventions.

Short versus long echo time for cranial MR angiography in children and adults.

PURPOSE: To evaluate the ability of short-echo-time (TE) versus long-TE three-dimensional time-of-flight MR angiography sequences to decrease phase-related signal loss and refocus signal from blood in intracranial MR angiography of adults and children. METHODS: We evaluated 3-D time-of-flight cranial MR angiography in 33 cases (18 children and 15 adults) using two sequences. The longer-echo reference sequence had a TE of 8.0 milliseconds and a field echo of 6.5 milliseconds; the shorter-echo sequence had a TE of 5.1 and a field echo of 4.2 milliseconds. Repetition time, flip angle, and matrix were constant. The bandwidth for the longer-echo sequence was 130 Hz, 195 Hz for the shorter-echo sequence. RESULTS: The greatest improvement in diagnostic images was for children; significant and mildly improved signal recovery was demonstrated in 15 and 2 cases, respectively, of a total of 18 studies. This allowed improved diagnostic assessment. However, in the adult group significantly and mildly improved signal recovery were present in only 2 and 6 cases, respectively, of a total of 15 studies. In the group of children and adults combined, decreased lumen definition and peripheral vessel visibility were present in 24 and 30 of 33 cases, respectively, because of higher signal from background tissue when the shorter-TE field-echo sequence was used and, hence, reduced vascular contrast. CONCLUSION: The use of a short-field-echo/TE sequence is therefore recommended as the initial study in children but as a secondary examination in areas of abnormality in adults. This study illustrates the improved signal recovery from phase-related sources and improved visibility of intracranial stenosis in children with the use of a short-echo sequence. In adults, the short-echo sequence should not be used for the initial screening but reserved for secondary evaluation.

Assessment of the effects of ciprofloxacin and nalidixic acid on cerebral blood flow and metabolism in healthy subjects by positron emission tomography.

STUDY OBJECTIVES: The mechanism by which the fluorinated quinolones produce central nervous system effects is unknown. Using positron emission tomography (PET), we evaluated the effects of two quinolones on brain blood flow as well as on oxygen and glucose metabolism. These determinations were done in conjunction with ophthalmologic and neuro-ophthalmologic testing. DESIGN: Randomized, double-blind, placebo-controlled, 7-day course of ciprofloxacin 750 mg (C750) or 500 mg (C500) every 12 hours, or nalidixic acid (NA) 1 g every 6 hours. POPULATION: Twenty-four healthy male volunteers, six in each treatment arm. RESULTS: [table: see text] CONCLUSIONS: Compared with baseline values, NA significantly reduced brain glucose uptake, whereas C500, C750, and placebo produced no detectable effect. No compound significantly altered brain blood flow or oxygen metabolism compared with baseline or other treatments. No significant effect on electroretinographic, electro-oculographic, or other neuro-ophthalmologic tests was observed.

Menkes kinky hair disease: characteristic MR angiographic findings.

We report two cases of Menkes kinky hair disease in which MR and MR angiography were performed. The clinical and imaging features are reviewed. MR demonstrated characteristic cerebrovascular tortuousity and thus may be a valuable aid in diagnosis and follow-up.

MRA detection of vascular occlusion in a child with progeria.

We report a case of progeria and the utility of visualizing the cerebrovascular anatomy by using MR angiography. A 4-year-old child with Hutchinson-Guilford syndrome developed symptoms of ischemia and MR angiography showed bilateral occlusion of internal carotid and vertebral artery origins; the anterior spinal artery was prominent.

Detecting psychopathology in young adults: the Young Adult Self Report, the General Health Questionnaire and the Symptom Checklist as screening instruments.

This study compares the screening capacity of an age-adjusted child-oriented questionnaire, the Young Adult Self Report (YASR) with two adult-oriented questionnaires, the General Health Questionnaire-28 (GHQ-28) and Symptom Checklist-90 (SCL-90) in a sample of young adults (18-25 years). The YASR performed just as well as the SCL-90 and both performed better than the GHQ-28. The relatively poor performance of the GHQ-28 compared with the YASR and SCL-90 could not be attributed to instrument characteristics or to the use of referral status as indicator of psychopathology. In assessing psychopathology in young adults an age-adjusted child-oriented instrument might be a good alternative to the existing adult-oriented instruments, especially when one takes into account the problem of data comparability over time in longitudinal studies in which children are followed into adulthood.

Cerebrovascular abnormalities in pediatric stroke: assessment using parenchymal and angiographic magnetic resonance imaging.

Three-dimensional (volume) magnetic resonance angiography is a noninvasive technique that images the intracranial and cervical arterial vasculature without contrast agents. Twenty-four children with strokes had combined parenchymal magnetic resonance imaging and magnetic resonance angiography 1 day to 4 years after acute presentation. Eight had had prior intra-arterial angiography. Eighteen magnetic resonance angiographic studies showed arterial stenosis or occlusion in the vascular distribution of magnetic resonance image-defined brain infarction and, in 7 children, in the same location as previously defined abnormalities on intra-arterial angiography. One child had a normal intra-arterial angiogram and magnetic resonance angiogram. The other 5 children with normal magnetic resonance angiographic studies included 3 with presumed embolic disease, 1 with meningitis, and 1 with Crohn's disease-related vasculitis. Collateral flow patterns could be determined in 4 children. Artifact presenting as filling defects in vessels was present in 10 studies, but did not interfere with interpretation of 8 studies. Combined magnetic resonance imaging/magnetic resonance angiography provides a screening technique to evaluate noninvasively brain parenchyma and vasculature in children with suspected large-vessel abnormalities, allowing selection for intra-arterial angiography and serial monitoring of vascular abnormalities over time and during therapeutic intervention.

Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity.

The gene for autosomal dominant "benign" familial neonatal convulsions, a transient, primary epilepsy of infancy, has recently been assigned to chromosome 20q. To determine whether this disorder is genetically heterogeneous, we performed linkage analysis in two previously unreported pedigrees with benign familial neonatal convulsions in which clinical heterogeneity was evident. There were 14 affected persons in the first family, and none had seizures (febrile or afebrile) after the age of 2 months. The second family had 13 affected individuals and 2 obligate carriers; seizures frequently did not remit until 6 to 24 months, febrile convulsions occurred in at least 2 patients, apparent audiogenic seizures occurred in 4 patients, and 1 individual had refractory epilepsy until late adolescence. Linkage studies with the chromosome 20 markers D20S19 and D20S20 were performed in both families. The resulting data favored linkage of the disease and marker loci in Family 2 by a maximum odds ratio of 45:1 at 6% recombination. In Family 1, however, the odds were greater than 20,000:1 against linkage at 10% recombination or less. We conclude that the syndrome of benign familial neonatal convulsions is clinically and genetically heterogeneous. Further study will be necessary to clarify the relationship between phenotype and genotype in this disorder.

Carotid reconstruction in the neonate following ECMO.

Permanent ligation of the carotid artery remains a major objection to the use of extra corporeal membrane oxygenation (ECMO) in infants with severe cardiorespiratory disorders. Because reconstruction of the carotid artery is highly desirable, we began a study to evaluate the feasibility and risks of carotid artery repair following decannulation. All infants placed on ECMO from December 1988 to January 1990 were evaluated for carotid artery reconstruction. During this period 18 infants underwent carotid reconstruction and 8 infants were deemed unsuitable candidates. Patency of the right common carotid artery was demonstrated in 14 of the 18 infants with good bilateral anterior and middle cerebral artery flow. Seven infants have had MRA evaluation at 6 months and have demonstrated no significant change from their discharge study. These preliminary findings suggest that carotid reconstruction can be performed safely with no apparent morbidity in the majority of infants placed on ECMO, but long-term follow-up data concerning patency rate and neurological status must be obtained before this technique is applied to all infants with this problem.

Parenchymal and vascular magnetic resonance imaging of the brain after extracorporeal membrane oxygenation.

Three-dimensional (volume) magnetic resonance angiography is a new and noninvasive method for imaging the intracranial vasculature. The combination of magnetic resonance angiography and conventional magnetic resonance imaging was used to evaluate brain parenchyma and vessels in 30 survivors of extracorporeal membrane oxygenation. Magnetic resonance imaging findings were abnormal in 33% of the patients, with no increased frequency of right hemispheric lesions. Magnetic resonance angiography demonstrated good intracranial flow in all infants and demonstrable right internal carotid arterial flow in 35% of those patients with permanent carotid ligation. An abnormal magnetic resonance imaging study was found more often in infants with abnormal predischarge neurologic examination results. These techniques have several advantages over other neuroimaging modalities, including better definition of deep structures, myelin formation, and intracranial vasculature, the absence of bone artifact, and the elimination of catheter or contrast use.