Hallervorden-Spatz syndrome.

The historic and current status of Hallervorden-Spatz syndrome diagnosis, classification, and therapies are discussed. A number of symptomatic therapies are available and should be used optimally for each patient. Although one gene locus has been identified, many patients do not manifest linkage to the NBIA1 locus (neurodegeneration with brain iron accumulation). Further investigation is necessary. The lack of understanding of the basic mechanisms that underlie the syndrome have hindered the development of more meaningful classification and definitive therapies. The recent report of a defect in a novel pantothenate kinase gene (PANK2) in Hallervorden-Spatz syndrome will undoubtedly lead the way to future advances in the diagnosis and management of the syndrome. The clarification of the role of oxidative distress in the pathophysiology of the syndrome will fill a large void in the understanding of the condition.

Neurologic characteristics of childhood lupus erythematosus.

Records of 108 patients with lupus erythematosus beginning in childhood (1953-1990) were reviewed; 25 had recorded neurologic findings. This is the largest group of childhood lupus erythematosus patients with neurologic disease that has been reported. The average age of children at the time of diagnosis of lupus was 154 months. There were 22 girls and 3 boys in the group. All patients met at least four of the 1982 American Rheumatism Association criteria for the classification of systemic lupus erythematosus. Average age at onset of neurologic difficulties was 168 months. In 4 patients, the neurologic symptoms preceded the diagnosis: 1 month (spastic diplegia), 1 month (bilateral weakness and spasticity), 24 months (chorea), and 26 months (chorea), respectively. Four patients had neurologic symptoms coincident with the diagnosis of lupus erythematosus. In those patients whose symptoms followed the diagnosis of lupus erythematosus, the average elapsed time until symptoms appeared was 33 months; the single lowest and highest outliers were discounted. Most frequent findings were headache (16/25) and behavioral aberrations (10/25). All behavioral manifestations were depression except in 1 patient. Other prevalent findings included hemichorea or chorea (7/25), cerebrovascular accident with hemiplegia or diplegia (7/25), seizures (5/25), visual loss (3/25), and cranial neuropathy (2/25). Vertigo and myelopathy occurred in 1 patient each. All patients were treated primarily with corticosteroids and azathioprine; in the presence of active disease, the drug dosages were increased with significant improvement in neurologic symptoms. Resolution usually occurred from days to months; most improved in a few days to a few weeks; 3-4 months was the longest period until symptoms subsided.

Effect of ferric nitrilotriacetate on rostral mesencephalic cells.

After murine fetal cells from the rostral mesencephalic tegmentum were isolated, prepared, and cultured; neuronal and glial cells in primary mixed cell cultures were exposed to ferric nitrilotriacetate (Fe-NTA) at varying concentrations. Studies were performed at 23 days in culture after 14 day exposure to Fe-NTA. In addition to morphologic studies, biochemical assays including specific [3H]flunitrazepam (FLU) binding, clonazepam (CLO)-displaceable [3H]-FLU binding, Ro5-4864-displaceable [3H]-FLU binding, [3H]-FLU binding, [3H]dopamine (DA) uptake, [3H]haloperidol (HAL) binding, [3H]spiperone (SP) binding, glutamine synthetase activity (GS), and protein determinations were performed. The data demonstrate that chelated ferric iron has an adverse effect on these cells. The data also demonstrate that increasing concentrations of Fe-NTA resulted in massive neuronal dropout leaving the culture population virtually all glial; however, the specific binding of [3H]HAL and [3H]SP increased. There was a concomitant decrease in both glutamine synthetase activity and overall protein content. The mechanism of enhancement in the presence of Fe-NTA of [3H]HAL and [3H]SP binding is unknown and may be unique, but may be related to the known increase in D2 receptor ligand affinity in the presence of other multivalent cations (Ca2+ and Mg2+).

Hallervorden-Spatz syndrome and brain iron metabolism.

Aberrant iron metabolism in the brain is typified by Hallervorden-Spatz syndrome. In this disorder, large amounts of iron are deposited in the globus pallidus and the pars reticulata of the substantia nigra. It is characterized by extrapyramidal dysfunction, as demonstrated by dystonia, rigidity, and choreoathetosis; onset during the first two decades of life; and progression of signs and symptoms. Corroborative findings include corticospinal tract involvement, ie, spasticity and extensor toe signs, progressive intellectual impairment, retinitis pigmentosa and optic atrophy (usually associated visual evoked response and electroretinogram abnormalities), seizures, familial occurrence, hypointense areas in the basal ganglia on magnetic resonance imaging scans (particularly in the substantia nigra), abnormal cytosomes in circulating lymphocytes, and sea-blue histiocytes in bone marrow. Iron function in normal brain metabolism is manifold, but high concentrations of iron in the basal ganglia area may signal a unique relationship. Data support the likelihood that iron plays a role in the modulation of dopamine binding to postsynaptic receptors. In addition, transferrin receptors and iron are also concentrated in oligodendrocytes in normal brain and, thus, may have a function in myelination. A role of iron also seems likely in oxidation and peroxidation reactions involving membranes and DNA, a capability that becomes uncontrolled when protective biologic mechanisms become inadequate.

Effects of phenobarbital and phenytoin on cortical glial cells in culture.

Studies were undertaken to determine the effects of 7-day phenobarbital and phenytoin exposure on 14-day-old glial cell cultures of fetal murine cortex. Biochemical markers monitored were Ro5-4684-displaceable 3H-flunitrazepam binding, 3H-beta-alanine uptake, glutamine synthetase activity, and protein content. Phenobarbital concentrations were 30, 60, and 120 micrograms/ml and phenytoin concentrations 15, 30, 60 micrograms/ml. There were no discernible phase microscopic changes at any concentration of either drug. Phenobarbital produced no significant changes in the biochemical measures monitored. Exposure to phenytoin produced no biochemical changes at 15 micrograms/ml, but did produce significant changes at 30 and 60 micrograms/ml. There was an increase in Ro5-4684-displaceable 3H-flunitrazepam binding signifying increased binding or an increase in the number of binding sites and perhaps an increased population of glial cells although, the unchanged protein content suggests that the number of glial cells was not increased. There was a decrease with 30 and 60 micrograms/ml phenytoin of 3H-beta-alanine uptake suggesting interference with normal membrane transport of this compound. The latter effect may well mirror changes in GABA uptake in glial cells in the presence of phenytoin.

Effect of ferric nitrilotriacetate on predominantly cortical glial cell cultures.

Cultured glial cells were exposed to ferric nitrilotriacetate (Fe-NTA) at varying concentrations. Studies of the exposed glial cells were performed at days 29 and 36 post-conceptional age (culture days 8 and 15). In addition to morphologic studies, biochemical assays including [3H]-flunitrazepam (FLU) specific binding, Ro5-4864-displaceable 3H-FLU binding, and protein determinations were performed. At day 29 post-conceptional age, significant decreases in 3H-FLU specific binding, Ro5-4864-displaceable 3H-FLU binding, and protein determinations were discernible only in the presence of 100 microM Fe-NTA. At day 36 post-conceptional age 3H-FLU specific binding was significantly decreased at 20, 60, and 100 microM Fe-NTA concentrations, while Ro5-4864-displaceable 3H-FLU binding and protein determinations were significantly reduced at 60 and 100 microM Fe-NTA concentrations. The effects of Fe-NTA exposure appear to be both concentration and duration-of-exposure related. When compared to previously reported neuronal cell culture studies utilizing 3H-FLU specific binding, Ro5-4864-displaceable 3H-FLU binding, and protein determinations, glial cells appear to be significantly more resistant to chelated iron exposure.

Effect of ferric nitrilotriacetate on predominantly cortical neuronal cell cultures.

Predominately neuronal cell cultures were produced as described in previous communications. Neuronal cells were exposed to ferric nitrilotriacetate (Fe-NTA) at varying concentrations. Studies of the neuronal cells were performed at 13 and 20 days in culture. In addition to morphologic studies, biochemical assays including choline acetyltransferase (ChAT) activity, specific [3H]flunitrazepam (FLU) binding, clonazepam (CLO)-displaceable [3H]FLU binding, Ro5-4864-displaceable [3H]FLU binding, high-affinity [3H]GABA uptake, and protein determinations were performed. The data demonstrate that chelated ferric iron has an adverse effect on predominately neuronal cultures after 7 days of exposure as measured by choline acetyltransferase activity, while other measures remained unaffected; however, after 14 days of exposure all measures were significantly decreased. The effects of Fe-NTA exposure appear to be both concentration and duration-of-exposure related.

Cockayne syndrome: MRI correlates of hypomyelination.

Two siblings with Cockayne syndrome are reported who had most of the stigmata characteristic of the syndrome as it was initially described in 1936. Unusual findings are emphasized, such as the early onset of cataracts and the early detection of peripheral neuropathy. The previously reported autopsy abnormalities in this condition are correlated with the present magnetic resonance imaging findings of mild ventricular enlargement and delay in myelination of the cerebrum and cerebellum. Properly myelinated structures included the basal ganglia, thalamus, internal capsule, splenium, and genu of the corpus callosum.

Brain tumors in children with neurofibromatosis: computed tomography and magnetic resonance imaging.

Comparisons were made between the results of computed tomography and magnetic resonance imaging (MRI) evaluations in 13 patients with neurofibromatosis. In 8 of 9 patients with intracranial tumors and in 2 of 4 patients without intracranial tumors additional findings were demonstrated by MRI.

Peroxisomal disorders. A review of a recently recognized group of clinical entities.

The peroxisome is a small organelle present in almost all cells. The peroxisomal disorders are a newly recognized group of disease entities that share structural and/or functional abnormalities of the peroxisomes, are inherited, and may have profound neurologic and systemic effects. Some of the disorders lack peroxisomes in cells, while others have single or multiple peroxisomal enzymatic deficiencies despite the presence of normally appearing peroxisomes. The prototype of the peroxisomal disorders is Zellweger syndrome. X-linked adrenoleukodystrophy, neonatal adrenoleukodystrophy, infantile Refsum disease, hyperpipecolic acidemia and Refsum disease are some of the other disease entities presently classified as peroxisomal disorders. Accurate methods of pre- and postnatal diagnosis are available. Treatment strategies are being developed, but at this time prenatal diagnosis and appropriate genetic counseling is the best therapeutic intervention for those peroxisomal disorders characterized by profound neurologic handicap and early death.

Transferrin binding by mammalian cortical cells.

Predominantly neuronal (neuronal) or non-neuronal (glial) cerebral cortical cell cultures were employed to study the kinetics and changes with maturation of 125I-diferric-transferrin uptake. The diferric-transferrin association curve of neuronal cultures at 37 degrees C was nonphasic and indicated equilibrium at 90 minutes. Dissociation was completed by 70 minutes. Diferric-transferrin specific uptake (80% of total) in neuronal cells (evaluated at days 6, 9, 13, 16, and 23 in culture) increased with maturation. Scatchard transformation of the data revealed increasing Bmax from day 6 to day 16 in culture (1626 to 2740 fmoles/mg protein). However, the K uptake was statistically unchanged over time and equaled 48.7 +/- 13.9 nM (mean +/- SD). In contrast, association studies of glial cultures documented equilibrium by 45 minutes and dissociation by 40 minutes. The concentration curves for diferric-transferrin uptake in glial cells, evaluated at days 11, 15, and 18 in culture, revealed virtually identical uptake at the three ages studied, but the percent specific uptake (58%) was less than for neurons (88%). Scatchard transformation of the data revealed no statistical alteration of Bmax or K uptake from days 11 to 18 in culture. Bmax ranged from 595 to 751 fmol/mg protein; overall K uptake was 48.3 +/- 13.2 nM (mean +/- SD).

Chloroquine reduces neuronal and glial iron uptake.

The effect of chloroquine, a lysosomotropic agent, on iron uptake into neuronal and glial cell cultures is reported. Chloroquine significantly inhibited iron uptake in both neuronal and glial cells. These findings suggest that iron transport into both neuronal and glial cells is mediated by the transferrin-iron complex.

Neurotransmitter changes during development of cortical neuronal cultures.

Benzodiazepine (BDZ) ligands clonazepam (CLO) and Ro5-4864 which preferentially bind to neuronal and non-neuronal elements, respectively, have been used to follow neuronal and non-neuronal development in fetal murine cortical cultures. CLO-displaceable BDZ binding, choline acetyltransferase (CAT) activity, high-affinity delta-aminobutyric acid (GABA) uptake, and glutamic acid decarboxylase (GAD) activity reached a maximum value at the end of the second week in culture reflecting maximum neuronal maturation and development. There is a developmental order of these four functions: CAT activity (main enzyme in the synthesis of acetylcholine, a stimulating neurotransmitter) reached maximal levels first, 3H-GABA uptake and CLO-displaceable flunitrazepam receptor binding reached maximal levels 1 day later, and 4 days later GAD activity (primary enzyme in the synthesis of GABA, an inhibitor neurotransmitter) reached maximal levels.

Iron uptake by glial cells.

Dynamic studies of iron metabolism in brain are generally unavailable despite the fact that a number of neurologic conditions are associated with excessive accumulation of iron in central nervous tissue. Cortical non-neuronal (glial) cultures were prepared from fetal mouse brain. After 13 days the cultures were exposed to radiolabeled iron. Brisk and linear total iron uptake and ferritin iron uptake occurred over 4 hours. When methylamine or ammonium chloride was added, (both known inhibitors of transferrin iron release because of their lysosomotropic properties), total iron uptake was diminished. Further studies indicated that methylamine inhibits glial cell ferritin iron incorporation. Glial cell iron transport is similar to previously reported neuronal cell iron transport (1) but glial cell iron uptake proceeds at a faster rate and is more susceptible to the inhibition of certain lysosomotropic agents. The data reinforces the likelihood that iron uptake by nervous tissues is transferrin-mediated.

The effect of iron on mammalian cortical neurons in culture.

We added iron in the ferric form to predominantly neuronal, cortical cell cultures, and determined clonazepam-displaceable [3H]diazepam binding, choline acetyltransferase activity, high-affinity [3H]GABA uptake, and glutamic acid decarboxylase activity. Chronic exposure (14 days) to low concentrations (0.01, 0.04, and 0.1 micrograms/ml) of added ferric iron resulted in a significant decrease in each of the measures studied.

Echocardiographic incidence of cardiac rhabdomyoma in tuberous sclerosis.

Cardiac rhabdomyoma occurs frequently in patients with tuberous sclerosis (TS). Although there have been case reports of detection of cardiac rhabdomyoma by 2-dimensional echocardiography, no study has examined the frequency of cardiac rhabdomyoma detected by cardiac ultrasound in patients with TS. Echocardiography was performed in 16 consecutive patients with TS. Physical examination revealed normal cardiac findings in each. Discrete areas of increased acoustic density were found in 8 of the 16 patients (50%). The maximum diameters ranged from 3 to 20 mm. Multiple areas were found in 3 of 8. The left ventricle was involved in 5 of the 8. Six masses were intracavitary and 8 were intramyocardial. No atrial masses were seen. Left ventricular size and function were normal. Although other tumors cannot be excluded, the diagnosis of cardiac rhabdomyoma is almost certain in these young patients with TS. The male predominance and the high incidence of intracavitary and left ventricular masses are similar to those in reported autopsy series, also supporting the diagnosis of cardiac rhabdomyoma. The prognosis and potential for growth of these masses are not known, but can be determined by longitudinal follow-up. Cardiac ultrasound should be considered for all patients with TS regardless of physical findings.

Early biochemical and EEG correlates of the ketogenic diet in children with atypical absence epilepsy.

Early changes in blood chemistry and the electroencephalogram were monitored during the first three hours after initiating the medium chain triglyceride (MCT) diet in nine children with intractable atypical absence seizures. Serum glucose, insulin, triglycerides, cholesterol, free fatty acids, ketone bodies concentrations, and venous pH were assayed before and at timed intervals after MCT oil was administered orally. The concentration of serum ketones rose progressively over three hours, beta-hydroxybutyrate proportionately higher than acetoacetate. A statistically significant decrease in the group mean number of epileptiform discharges occurred following MCT therapy. Seizure frequency decreased by more than 50 percent in two-thirds of the children during the 10 week treatment period.