The burden of inherited leukodystrophies in children.

OBJECTIVES: Leukodystrophies are diseases of the white matter for which data concerning clinical characteristics, incidence, disease burden, and description of outcomes are sparse. The purpose of our study was to determine the incidence and most common types of inherited leukodystrophies in a population, the mortality and time course of deaths, common neurologic features in patients, and health care costs associated with leukodystrophies. METHODS: We conducted a retrospective, hospital- and clinic-based surveillance of inherited leukodystrophies among children younger than 18 years presenting to a regional children's hospital. We enrolled children evaluated from January 1, 1999, through December 31, 2007; clinical information was obtained from medical records. We calculated incidence based on state birth rates. RESULTS: A total of 122 children with an inherited leukodystrophy were identified; 542 patients were excluded. A total of 49% had epilepsy, 43% required a gastrostomy tube, and 32% had a history of developmental regression. Mortality was 34%; average age at death was 8.2 years. No final diagnosis was reported in 51% of patients. The most common diagnoses were metachromatic leukodystrophy (8.2%), Pelizaeus-Merzbacher disease (7.4%), mitochondrial diseases (4.9%), and adrenoleukodystrophy (4.1%). Endocrine abnormalities and hypoplastic cerebellum were noted in significant portions of patients (15% and 14%). Average yearly per-patient medical costs were $22,579. Population incidence was 1 in 7,663 live births. CONCLUSIONS: Inherited leukodystrophies are associated with substantial morbidity and mortality in children. Overall population incidence is higher than generally appreciated (1 in 7,663 live births). Most leukodystrophies remain undiagnosed, but a logical algorithm based on prevalence could aid testing.

Infant botulism in the age of botulism immune globulin.

Infant botulism causes acute bulbar dysfunction, weakness, and respiratory failure in infants living in endemic regions of the United States. Until Food and Drug Administration approval of botulism immune globulin (BIG) in October 2003, management of infant botulism had changed little since the 1970s. Currently, IV therapy with BIG is advised to shorten the duration and diminish the potential complications of the disorder. This review describes two decades of experience with infant botulism and provides a contemporary perspective on the role and benefit of BIG.

Neuropathophysiology of movement disorders in cerebral palsy.

Recent developments in understanding the pathophysiology of disordered motor control in cerebral palsy are reviewed. In spastic cerebral palsy, evidence for abnormal segmental as well as supraspinal control of motor neuron output exists. Impaired Ia inhibition of antagonist muscles has been suggested but recently contested. Evidence also supports the role of decreased presynaptic inhibition of Ia afferents and decreased nonreciprocal Ib inhibition. Furthermore, early cerebral injury results in reorganization of supraspinal (corticospinal) inputs to motor neuron pools. In extrapyramidal cerebral palsy, injury of basal ganglia or thalamus has been demonstrated. A scheme for understanding the neurochemical circuitry of the extrapyramidal system is discussed. Animal models and certain specific human diseases provide examples of how this circuitry may be disturbed, thereby resulting in an imbalance between the direct and indirect striatal output systems and in impaired motor control. Future studies employing postmortem neurochemical analysis, functional magnetic resonance imaging, and positron emission tomographic scanning may foster progress in this area.

The temporal evolution of striatal dopamine receptor binding and mRNA expression following hypoxia-ischemia in the neonatal rat.

Neonatal hypoxic-ischemic (HI) brain injury in the rat alters dopamine receptors. To determine whether such changes are permanent, dopamine receptors and corresponding mRNA were examined at various time points after neonatal HI using receptor autoradiography and in situ hybridization. Rat pups underwent ligation of the left common carotid artery followed by hypoxic exposure (8.5% O2 for 3 h). Controls underwent sham surgery alone. Animals surviving for 2-80 days following HI were studied. Striatal D1 receptors (labeled by [3H]SCH23390) were reduced as early as 2 days following HI, remained depressed for 21 days, but recovered to control levels by young adulthood (3 months of age). D2 receptors (labeled by [125I] iodosulpride) did not decline until 10 days after HI, and remained uniformly depressed throughout the caudate-putamen thereafter. Changes in D1 receptor mRNA transcripts closely paralleled alterations in receptors: early reductions in D1 mRNA signal recovered by young adulthood. D2 mRNA exhibited a unique temporal profile with an early decrease (2 days following HI), and prompt, persistent recovery. Dopamine receptors and transcripts are differentially affected by HI injury early in development. Whereas D1 receptor expression recovers from neonatal HI injury, D2 receptors remain permanently affected despite the presence of normal levels of D2 receptor transcripts. A persistent, post-transcriptional effect of HI on D2 receptor expression is suggested.

The dihydropyridine nitrendipine inhibits [3H]MK 801 binding to mouse brain sections.

The L-type Ca2+ channel antagonist nitrendipine inhibits N-methyl-D-aspartate (NMDA)-activated Ca2+ flux into cerebellar granule cells, and [3H]dibenzocyclohepteneimine ([3H]MK 801) binding to mouse cerebral cortical and hippocampal membranes. To further study this interaction between nitrendipine and NMDA-activated channels, the effects of several L-channel active agents on [3H]MK 801 binding to mouse brain were investigated in an autoradiographic assay. Serial slide-mounted sagittal sections of mouse brain were labeled with [3H]MK 801 in the presence of varying concentrations of the L-channel active agents nitrendipine, nimodipine, nifedipine, Bay K 8644, and verapami. Nitrendipine potently displaced 2 nM [3H]MK 801 binding to mouse brain sections (IC50 = 89.8 nM). Dose-dependent inhibition of [3H]MK 801 binding by nitrendipine was demonstrated in most brain regions examined. 10(-5) M and 10(-8) M concentrations of the other dihydropyridines studied, and of verapamil, were without effect. The data supports a unique, direct interaction between nitrendipine and the NMDA-activated ion channel.

Effects of chronic haloperidol and clozapine treatment on neurotensin and c-fos mRNA in rat neostriatal subregions.

Previous studies have shown elevation of neurotensin neuromedin N (NT/N) and c-fos mRNA in the dorsolateral region of the rat neostriatum (DLSt) by acute administration of only typical antipsychotic drugs. However, NT/N mRNA in the nucleus accumbens-shell is enhanced acutely by several clinically efficacious antipsychotic drugs, regardless of their motor side effect liability. In the present study, induction of NT/N mRNA in the DLSt was observed again after 28 days of continuous administration (via osmotic minipumps) of haloperidol, but not clozapine. However, this response was only about 50% of that caused by acute haloperidol and c-fos mRNA levels in the DLSt were not elevated after the chronic treatment. An acute challenge of haloperidol 24 hr after chronic haloperidol treatment did not affect the tolerant response of NT neurons but caused a small increase in c-fos mRNA in the DLSt. Similar to the DLSt, chronic haloperidol (but not clozapine) significantly enhanced NT/N gene expression in the ventrolateral striatum, a region thought to be involved in abnormal oral movements, perhaps related to tardive dyskinesia. Interestingly, dopamine D2 receptor binding using [125I]iodosulpride nearly doubled in all regions of the striatum after chronic haloperidol but not clozapine. In contrast to the lateral neostriatum, NT/N mRNA expression in the nucleus accumbens-shell was elevated similarly by chronic treatment with haloperidol and clozapine to a level observed after acute haloperidol treatment. These results demonstrate further that region-specificity of NT/N mRNA regulation discriminate between typical and atypical antipsychotic drugs.

Comparison of the distribution of D-1 and D-2 dopamine receptors in the rat brain.

The distribution of dopamine type 1 (D-1) and dopamine type 2 (D-2) receptors in the brain have been compared as assessed by the technique of autoradiography after labelling with highly selective ligands. D-1 receptors, as evidenced by the specific binding of [3H]R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-IH-3-benzazepine -7- ol (SCH 23390), were found in high concentrations in the caudate-putamen, nucleus accumbens, islands of Calleja, olfactory tubercle and the zona reticulata of the substantia nigra. A similar but distinct distribution was seen for [3H]sulpiride, a ligand which is highly selective for D-2 receptors. Like [3H]SCH 23390, this ligand also labelled the caudate-putamen, nucleus accumbens, islands of Calleja and the olfactory tubercle; however, only a very low density of D-2 receptors could be found in the zona reticulata of the substantia nigra, while a greater degree of binding was present in the zona compacta. Additional brain areas which contained D-1 but not D-2 receptors included the cerebral cortex, accessory olfactory nucleus, amygdala, thalamus, suprachiasmatic nucleus, choroid plexus, claustrum, endopiriform nucleus, zona incerta, dorsal lateral geniculate nucleus and the dentate gyrus. D-2 receptors were also found in areas which appeared to contain only low amounts of D-1 receptors such as the glomerular layer of the olfactory bulb, bed nucleus of the stria terminalis, hypothalamus, habenula, stratum lacunosum moleculare of the hippocampus, intermediate lobe of the pituitary, lateral mammillary nucleus, periaqueductal gray, inferior colliculus, nodulus of the cerebellum and the dorsal horn of the spinal cord. The results show the precise localization of dopamine receptors throughout the brain and provide a means of direct comparison between the distribution of dopamine receptor subtypes. These subtypes are pharmacologically and anatomically distinct entities and their comparison indicates areas where additional biochemical and neuroanatomical studies may be performed to elucidate the roles for these receptor subtypes in the central nervous system.

Evidence for dopamine D-2 receptors on cholinergic interneurons in the rat caudate-putamen.

The aziridinium ion of ethylcholine (AF64A) is a neurotoxin that has demonstrated selectivity for cholinergic neurons. Unilateral stereotaxic injection of AF64A into the caudate-putamen of rats, resulted in a decrease in dopamine D-2 receptors as evidenced by a decrease in [3H]-sulpiride binding. Dopamine D-1 receptors, labeled with [3H]-SCH 23390, were unchanged. The efficacy of the lesion was demonstrated by the reduction of Na+-dependent high affinity choline uptake sites labeled with [3H]-hemicholinium-3. These data indicate that a population of D-2 receptors are postsynaptic on cholinergic interneurons within the striatum of rat brain.

Dopamine D-2 auto- and postsynaptic receptors in the nigrostriatal system of the rat brain: localization by quantitative autoradiography with [3H]sulpiride.

In vitro receptor autoradiography with [3H]sulpiride (a selective D-2 antagonist) was used to assess the effect of 6-hydroxydopamine and ibotenic acid lesions of the caudate-putamen and substantia nigra pars compacta on D-2 dopamine receptors in rat brain. A marked reduction in [3H]sulpiride binding within the pars compacta of the substantia nigra resulted from lesions of the substantia nigra compacta with either toxin, while substantial reduction in binding within the caudate-putamen followed only ibotenate lesions of that structure. Since (-)sulpiride is a selective D-2 antagonist, these data confirm that autoreceptors on nigral DA neurons are of the D-2 type, while a portion of D-2 receptors in the caudate-putamen are postsynaptic on striatal neurons.

Presynaptic and postsynaptic D1 dopamine receptors in the nigrostriatal system of the rat brain: a quantitative autoradiographic study using the selective D1 antagonist [3H]SCH 23390.

Ibotenic acid lesions of the caudate-putamen in rat brain resulted in dramatic reductions in [3H]SCH 23390 binding in both the ipsilateral caudate-putamen and substantia nigra reticulata as assessed by quantitative autoradiography. Nigral ibotenic acid and 6-hydroxydopamine lesions did not significantly alter the binding in either structure. This indicates that D1 receptors in the caudate-putamen are postsynaptic on striatal neurons, while those in the substantia nigra reticulata are presynaptic on nerve terminals originating in the caudate-putamen.

Evidence that [3H]forskolin binding in the substantia nigra is intrinsic to a striatal-nigral projection: an autoradiographic study of rat brain.

The neuronal localization of binding sites for the diterpene activator of adenylate cyclase, forskolin, has been determined. Kainic or ibotenic acid lesions were administered into the caudate-putamen or substantia nigra of Sprague-Dawley rats. The binding of 20 nM [3H]forskolin was examined autoradiographically and quantitated using computerized densitometry with tritium standards. Neurochemical lesions placed in the caudate-putamen markedly reduced [3H]forskolin binding in this structure and distal to the site of injection in the substantia nigra. Ibotenic acid lesions placed in the substantia nigra did not appreciably alter binding in the substantia nigra, caudate-putamen, nucleus accumbens or olfactory tubercle. These results indicate that 'forskolin-identified' adenylate cyclase in the substantia nigra is located in nerve terminals from the caudate-putamen. In addition, these sites are presumably located on cell bodies or interneurons in the caudate-putamen.