Dystonia and calcification of the basal ganglia.

We studied a family with dominantly inherited dystonia and intracranial calcification. Thirty-seven members were examined; 13 were affected by dystonia that was segmental in most patients, affecting especially the voice, face, neck, and limbs. Intracranial calcification involved the putamen, pallidum, cerebral white matter and cortex, and cerebellar nuclei. Several patients had both dystonia and calcification, but others had either dystonia or calcification alone.

Krabbe's leukodystrophy without globoid cells.

Krabbe's infantile cerebral sclerosis with a prolonged course was present in a boy who became increasingly hypertonic during infancy and had an increased protein level in the spinal fluid. At 4 years he showed significant growth failure, profound mental retardation, spastic quadriplegia, bilateral optic atrophy, and depressed tendon reflexes. Conduction velocity in motor fibers of the median nerve had become progressively impaired. Autopsy at 5 years 10 months showed severe leukodystrophy with demyelination and gliosis. No stored breakdown products or globoid cells were seen in the brain. Galactosyl ceramide beta-galactosidase was virtually absent, and hardly any myelin was demonstrable on chemical and electron microscopic studies. The presence of globoid cells may not be essential for the pathologic diagnosis of Krabbe's leukodystrophy in the presence of appropriate enzyme deficiency.

Long-term follow-up after cerebral hemispherectomy: neurophysiologic, radiologic, and psychological findings.

Eight patients were studied 3 to 16 years (mean, 10 years) after cerebral hemispherectomy. Seven have infantile hemiplegia, and one had Sturge-Weber disease. Preoperative assessment included EEG responses to intracarotid drug injections. Postoperative complications occurred in seven patients. The operation was followed by a marked reduction in seizure frequency and improvement in behavior, with little change in intellect or hemiplegia. Neuropsychological assessment performed in four patients showed that they were not aphasic, but nonverbal spatial abilities were poor. CT showed marked shift of the remaining hemisphere in five of six patients scanned.

X-linked mental retardation: a study of 7 families.

Seven families with X-linked mental retardation (MR) have been studied clinically and cytogenetically. All affected males in six of the families were found to have a fragile site on Xq in a number of their peripheral lymphocytes. The fragile site was not seen in any of the affected males in the seventh family. The affected males in the six families with the fragile X had a syndrome characterized by a variable degree of MR, macro-orchidism, a characteristic repetitive, jocular speech, normal body proportions, and large jaws and ears. The fragile X chromosome could only be detected in a proportion of female carriers and its frequency in females was found to be correlated with their mental status to be inversely correlated with their age.

Myasthenia gravis with thymoma and pure red blood cell aplasia.

A case of myasthenia gravis with histopathologic confirmation of spindle cell thymoma and pure red blood cell aplasia is reported. This is the twelfth case in the literature in which a simultaneous occurrence of all three disorders, with documented thymic pathology, is noted. Immunologic observations in this patient include an elevated acetylcholine receptor antibody and antinuclear antibody titer, agglutination of mouse red blood cells when combined with the patient's serum, and lack of inhibition of binding of radioactive erythropoietin to mouse red cell receptors when combined with the patient's serum. Although both myasthenia with thymoma and pure red blood cell aplasia may have a common immunologic denominator, our findings in this case indicate that inhibition of erythropoiesis is unrelated to erythropoietin receptor blockade. An alternative hypothesis is offered based on defective T-cell function.

Cytoplasmic body myopathy. Report on a family and review of the literature.

A 15-year-old girl who was seen for scoliosis presented with cardiorespiratory failure associated with a respiratory infection. She was found to have weakness predominant in the face, sternomastoid, proximal limb, respiratory, spinal and cardiac muscles. The serum creatine kinase level was slightly elevated and the electrocardiogram was abnormal. The electromyograph was consistent with a myopathy. The course was malignant. Her 14-year-old brother had similar findings and succumbed at the age of 14 and one-half years from cardiorespiratory failure. The mother had minimal weakness of proximal limb muscles since early life. The tendon reflexes were normal as was the serum creatine kinase level. The course was benign. On light microscopy the muscle biopsy in the girl showed fibre diameter variation, centrally placed nuclei, necrosis, fibrosis and cytoplasmic bodies. The muscle biopsy in the brother and mother had similar findings except that the inclusion bodies were not seen in the mother. On electron microscopy, the girl showed typical cytoplasmic bodies, involving predominantly type 1 fibres. The mother also had these structures. The literature is reviewed and the origin, pathogenesis and aetiology of the cytoplasmic body are discussed.

Reflections on the history of the Canadian Association for Child Neurology.

The Canadian Association for Child Neurology (CACN) was founded in June 1971 to combine neurologists interested in children and paediatricians interested in the nervous system into an organization which would promote the development of this subspecialty. Initially, the members of the Association mostly wished to have a training programme under the combined supervision of University Departments of Paediatrics and Neurology. However, under the influence of the Royal College of Physicians & Surgeons of Canada, and its Committee on Neurology, the training of child neurologists was organized in a manner analogous to that of neurologists for adults, though with an initial one or two years of paediatrics instead of medicine. By 1975, four years within a recognized neurological training programme could lead to the Certification Examination in Neurology, as modified for paediatric neurology. In 1981, the CACN also joined the Canadian Congress of Neurological Sciences. It has played an increasing part in child care and also in a academic studies. However, evidence will be presented to show that the present number of paediatric neurologists in Canada is insufficient. The number of trainees also appears inadequate, and increased funding for training positions is needed. Close cooperation between paediatric neurologists, rehabilitation experts, developmental paediatricians and related subspecialists is required.

Rett syndrome: review of biological abnormalities.

The Rett syndrome (RS) is a peculiar, sporadic, atrophic disorder, almost entirely confined to females. After the first six months of life there is developmental slowing with reduced communication and head growth for about one year. This is followed by a rapid destructive stage with severe dementia and loss of hand skills (with frequent hand wringing), apraxia and ataxia, autistic features and irregular breathing with hyperventilation. Seizures often supervene. Subsequently there is some stabilization in a pseudo-stationary stage during the preschool to school years, associated with more emotional contact but also abnormalities of the autonomic and skeletal systems. After the age of 15-20 years, a late motor deterioration occurs with dystonia and frequent spasticity but seizures become milder. RS has generally been considered an X-linked disorder in which affected females represent a new mutation, with male lethality. Linkage studies suggested a critical region at Xq28. In 1999, mutations in the gene MECP2 encoding X-linked methyl cytosine-binding protein 2 (MeCP2) were found in a proportion of Rett girls. This protein can bind methylated DNA. Analyses are leading to much further investigation of mutants and their effects on genes. Neuropathological and electrophysiological studies of RS are described. Description of neurometabolic factors includes reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. The results of neuroimaging are surveyed, including volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET).

Friedreich's ataxia with dysautonomia and labile hypertension.

An Amerindian girl with Friedreich's ataxia presented at the age of 14 years with intermittent bifrontal headaches and abdominal aching, often associated with nausea and recurrent vomiting and an evanescent pink, blotchy rash on the upper trunk. In these attacks she also had hypertension up to 210/160 mm Hg. Renal function studies, including intravenous pyelogram and angiography, were normal. Plasma renin activity (2.5 ng/ml/hr) was also normal. Total body CT scan was negative for phaeochromocytoma, and repeated estimations of 24-hour excretion of urinary VMA were normal or borderline high. Levels of total catecholamines in 24-hour urine were normal twice, but two random specimens during the paroxysmal episodes contained abnormally high levels of norepinephrine and dopamine. Plasma catecholamine concentrations were increased but not as high as with phaeochromocytoma. Blood pressure monitoring demonstrated marked fluctuations with position and temperature. A clonidine suppression test showed a substantial fall of plasma catecholamine levels, consistent with dysautonomia and not with phaeochromocytoma. It is concluded that the patient has dysautonomia of central origin, probably as a manifestation of Friedreich's ataxia. These findings are discussed in relation to the recent demonstration of increased levels of plasma catecholamines in that disease.

Sex-linked hereditary ataxic deplegia, the borderland between cerebral palsy and Pelizaeus-Merzbacher disease.

After a review of the literature concerning hereditary cases of cerebral palsy, a family is reported in which ataxic diplegia appears to be inherited as a sex-linked and probably recessive condition occurring in 3 males in successive generations. This ataxic diplegia, occurring after an unremarkable perinatal course, is associated with mild to moderate mental retardation, congenitial nystagmus and significantly small stature and prevents the acquisition of free walking. Associated extrapyramidal features may gradually become more marked, while the nystagmus may subside. The condition is similar to that described in three previous reports in the literature. No evidence of linkage with other sex-linked disorders has been found, Xga typing showed that recombination between the Xg locus and the locus for hereditary ataxic deplegia has occurred once out of three possible opportunities. In the absence of neuropathological findings or specific biochemical tests, the differential diagnosis from Pelizaeus-Merzbacher disease cannot be made with certainty. The differentiation from other progressive sex-linked neurological disorders is discussed.

Importance of Rett syndrome in child neurology.

The syndrome of brain atrophy in girls described by Andreas Rett in 1966 [Rett, Wien Klin Wochenschr, 1966;116:723-726] was brought to the attention of the English-speaking world by Hagberg et al. in 1983 [Hagberg et al., Ann Neurol, 1983;14:471-479]. Four clinical stages after the age of 6 months were described in classical cases of Rett syndrome (RS), namely early onset stagnation at 6 months to 1(1/2) years, the rapid destructive stage at 1-3 years, the pseudo-stationary stage from pre-school to school years, and the late motor deterioration stage at 15-30 or more years. The rapid destructive stage causes profound dementia with loss of speech and hand skills, stereotypic movements, ataxia, apraxia, irregular breathing with hyperventilation while awake, and frequently seizures. Most cases are isolated in their families, apart from identical twins. However, linkage studies in rare familial cases suggested a critical region at Xq28. In 1999 American investigators found several mutations in the X-linked gene MECP2 encoding Methyl-CpG-binding protein 2 in a proportion of Rett patients. The protein MeCP2 can bind methylated DNA and when mutated may interfere with transcriptional silencing of other genes and result in abnormal chromatin assembly. Many different mutations of the protein are being studied in humans and in mice. Neuropathological studies have shown decreased brain growth and decreased size of individual neurons, with thinned dendrites in some cortical layers, and abnormalities in substantia nigra, suggestive of deficient synaptogenic development, probably starting before birth. Electrophysiology demonstrates progressively abnormal electroencephalograms (EEG) in the first three stages of the syndrome, with some subsequent improvement and occurrence of pseudoseizures. Neurometabolic factors are discussed in detail, particularly reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. Autonomic dysfunction is described, particularly reduced vagal and overactive sympathetic activity. Neuro-imaging may be required for further investigation, as shown in the differential diagnosis.

Neurons and neuronal systems involved in the pathophysiologies of Rett syndrome.

It has long been suspected that the Rett syndrome (RS) is associated with abnormality of monoaminergic systems, particularly in the brainstem and midbrain, with spread to basal ganglia and cerebral cortex. Early investigators found no significant abnormality in the level of metabolites of noradrenaline, dopamine or serotonin in the spinal fluid, but autopsy brain studies revealed reduced levels of these substances and their metabolites as well as cortical choline acetyltransferase (ChAT) and microtubule-associated proteins (MAP). Levels of Substance P in spinal fluid of RS girls have been reported to be low, while levels of glutamate are raised. Attempts to assess dopaminergic activity by positron emission tomography (PET) in RS have given variable results with different reagents, including [(18)F] 6-fluorodopa. Our group investigated nine RS patients after the age of 12 years and control girls of similar age. Volumetric scans of basal ganglia with Magnetic Resonance Imaging showed a significant reduction in the size of caudate heads and thalami in RS (but not in the size of lentiform nuclei). PET scans with [(11)C] raclopride and with [(18)F] 6-fluorodopa under intravenous propofol anesthesia showed the mean uptake of fluorodopa to be reduced by 13.1% in caudate and by 12.4% in putamen as compared to the controls, whereas dopamine D2 receptor binding, as indicated by raclopride binding, was significantly increased by 9.7% in caudate and by 9.6% in putamen.

Neurological, psychological and educational sequelae of low birth weight.

In a prospective study of 501 infants of low birth weight (LBW) who mostly weighed 2,041 g (4 1/2 lb) or less, and of 203 control infants of full birth weight (FBW > 2,500 g), 335 LBW and 139 FBW children were followed beyond the age of 6 years and 6 months. The incidence of neurological defects was negatively correlated with birth weight, and the mean "global" IQ of different birth weight groups retained a direct relationship. While the relationship of birth weight to IQ gradually became less marked, the effect of social class was increasingly evident from the age of 2 years and 6 months. The preterm children whose birth weight was appropriate for gestational age (AGA) attained a slightly higher mean IQ and significantly better grade placement in the third school year than the children who were unduly light for their gestational age. Details of the neurological and ophthalmological defects are given, and the predictive significance of neonatal variables is analyzed.

Maternal cigarette smoking during pregnancy and the child's subsequent development: I. Physical growth to the age of 6 1/2 years.

PIP: The growth of 81 "small-for-dates" (SFD) and 99 "truly premature" children of low birth weight, and of 146 controls of full birth weight (FBW) was analyzed with respect to maternal smoking during pregnancy. Shortly after birth, a history was obtained from the mother pertaining to factors which could be related to the pregnancy outcome. Physical examination, developmental tests, and psychological tests were performed on the children up to the age of 6 1/2 years. There was a highly significant excess in the percentage of smokers among the mothers of SFD children as compared to FBW control children. At 6 1/2 years, the children of nonsmoking mothers had a slightly greater mean weight and height in all categories. Statistically significant differences in favor of nonsmokers' children were seen only in the FBW children. Mean social class was lower in children of nonsmoking mothers. Other factors influencing growth, such as maternal height and weight, and childrens' sex were not significantly different in the 2 groups of children. Although the trends of the results indicate that cigarette smoking in pregnancy may negatively affect the child's growth, the trends rarely reached statistical significance, and larger numbers are required for detailed factorial analysis.^ieng

Lactic acidosis in childhood.

Children with chronic metabolic acidosis should be investigated to determine the presence of an organic acid, especially when the plasma electrolyte profile shows a deficiency of anion. One of the organic acids that should be looked for in such a patient is lactic acid. Lactic acidosis due to tissue hypoxia is a well-known phenomenon (e.g., in shock and cardiopulmonary disease) and has not been discussed in this essay; nor has lactic acidosis due to exogenous causes like infusion of fructose or sorbitol, or admiministration of phenformin. Chronic lactic acidosis in infancy is a rare condition. It may be associated with glycogen storage disease Type 1, fructose diphosphatase deficiency, methylmalonic acidemia, propionic acidemia, pyruvate carboxylase or dehydrogenase deficiency and Leigh's subacute necrotizing encephalomyelopathy (SNE). Some patients with chronic lactic acidosis do not have nay of these diseases and comprise an "idiopathic" group. This is a heterogeneous group, probably having several different causes for the metabolic error. In Leigh's SNE, a metabolic block in the formation of thiamine triphosphate in brain has been demonstrated and has been attributed to the presence of an inhibitor of thiamine pyrophosphate-adenosine triphosphate (TPP-ATP) phosphoryl transferase in body fluids. The inhibitor has also been encountered in cases of intermittent cerebellar ataxia and of primary hypoventilation (Ondine's curse), which may represent variants of Leigh's disease. Increased blood levels of lactate, pyruvate and alanine frequently are encountered in SNE, but it still is not clear whether they are due to a primary or secondary disturbance in the catabolism of pyruvate. Disturbed lactate and pyruvate metabolism has also been encountered in isolated cases of mental retardation and growth failure, in mitochondrial myopathies and in polyneuropathies, and may be expected to occur in Wernicke's encephalopathy. Finally, it has been noted in malignancy and in association with other rare metabolic disorders.

Interstitial Lung Disease Developing during Treatment with Cyclosporine in a patient with Diffuse Scleroderma, Aplastic Anemia and Crohn's Disease: Implications for Pathogenesis and Treatment.

Systemic sclerosis (scleroderma) is an uncommon disease of as-yet-unknown etiology. The hallmark of scleroderma is proliferation of collagen, particularly types I and III, with associated vascular changes. Visceral involvement, particularly pulmonary interstitial disease, can lead to significant morbidity and mortality.Specific therapy is unavailable to date, but there has been interest in the use of cyclosporine (CSA), because it inhibits interleukin-2 production and affects cytotoxic T cells. We present a case of a patient with a triad of suspected autoimmune diseases, systemic sclerosis and Crohn's. disease on CSA therapy for aplastic anemia. Despite hematologic response and cutaneous improvement on CSA therapy, this patient developed interstitial lung disease consistent with sclerodermatous lung.