Genetic ablation of the Rho GTPase Rnd3 triggers developmental defects in internal capsule and the globus pallidus formation.

The forebrain includes the cerebral cortex, the thalamus, and the striatum and globus pallidus (GP) in the subpallium. The formation of these structures and their interconnections by specific axonal tracts take place in a precise and orchestrated time and spatial-dependent manner during development. However, the knowledge of the molecular and cellular mechanisms that are involved is rather limited. Moreover, while many extracellular cues and specific receptors have been shown to play a role in different aspects of nervous system development, including neuron migration and axon guidance, examples of intracellular signaling effectors involved in these processes are sparse. In the present work, we have shown that the atypical RhoGTPase, Rnd3, is expressed very early during brain development and keeps a dynamic expression in several brain regions including the cortex, the thalamus, and the subpallium. By using a gene-trap allele (Rnd3gt ) and immunological techniques, we have shown that Rnd3gt/gt embryos display severe defects in striatal and thalamocortical axonal projections (SAs and TCAs, respectively) and defects in GP formation already at early stages. Surprisingly, the corridor, an important intermediate target for TCAs is still present in these mutants. Mechanistically, a conditional genetic deletion approach revealed that Rnd3 is primarily required for the normal development of Medial Ganglionic Eminence-derived structures, such as the GP, and therefore acts non-cell autonomously in SAs and TCAs. In conclusion, we have demonstrated the important role of Rnd3 as an early regulator of subpallium development in vivo and revealed new insights about SAs and TCAs development.

Síndrome de Leigh causado por la mutación G14459A del ADN mitocondrial en una familia mexicana / Leigh syndrome caused by the mitochondrial DNA G14459A mutation in a mexican family

Introducción. El síndrome de Leigh es una enfermedad neurodegenerativa y progresiva, de aparición en la infancia, que está causada por defectos tanto en el genoma nuclear como en el mitocondrial. La mutación G14459A del ADN mitocondrial se ha asociado con anterioridad a la neuropatía óptica hereditaria de Leber y recientemente al síndrome de Leigh. Caso clínico. Niña mexicana de 10 meses de edad diagnosticada, después de un seguimiento clínico, neurológico y radiológico, de síndrome de Leigh. Se le realizó el análisis de mutaciones puntuales en el ADN mitocondrial asociadas a este síndrome, y se encontró la mutación G14459A en un porcentaje próximo a la homoplasmia y en heteroplasmia en la madre. El resto de familiares relacionados por vía materna carecen de la mutación. Conclusión. La mutación G14459A, aunque poco frecuente en la patología, debe de estudiarse en pacientes con síndrome de Leigh que no presentan las mutaciones puntuales más comunes (AU)

Introduction. Leigh syndrome is a neurodegenerative and progressive disease that appears usually in childhood due to defects in nuclear or mitochondrial genome. The mutation G14459A in mitochondrial DNA has been associated previously to Leber hereditary optic neuropathy and recently to Leigh syndrome. Case report. A 10 months-old Mexican girl diagnosed of Leigh syndrome. Molecular-genetic studies detected the mutation G14459A in a percentage close to homoplasmy and in low heteroplasmy in her mother. The rest of the maternally related family members analyzed were negative. Conclusion. The G14459A mutation, although not very frequently associated to Leigh syndrome, should be analyzed in patients that do not present the most common point mutations (AU)

Basal ganglia shape abnormalities in the unaffected siblings of schizophrenia patients.

BACKGROUND: Abnormalities of basal ganglia structure in schizophrenia have been attributed to the effects of antipsychotic drugs. Our aim was to test the hypothesis that abnormalities of basal ganglia structure are intrinsic features of schizophrenia by assessing basal ganglia volume and shape in the unaffected siblings of schizophrenia subjects. METHOD: The study involved 25 pairs of schizophrenia subjects and their unaffected siblings and 40 pairs of healthy control subjects and their siblings. Large-deformation, high-dimensional brain mapping was used to obtain surface representations of the caudate, putamen, and globus pallidus. Surfaces were derived from transformations of anatomic templates, and shapes were analyzed using reduced-dimensional measures of surface variability (i.e., principal components and canonical analysis). Canonical functions were derived using schizophrenia and control groups and were then used to compare shapes in the sibling groups. To visualize shape differences, maps of the estimated surface displacement between groups were created. RESULTS: In the caudate, putamen, and globus pallidus, the degree of shape abnormality observed in the siblings of the schizophrenia subjects was intermediate between the schizophrenia and control subjects. In the schizophrenia subjects, significant correlations were observed between measures of caudate, putamen, and globus pallidus structure and the selected measures of lifetime psychopathology. CONCLUSIONS: Attenuated abnormalities of basal ganglia structure are present in the unaffected siblings of schizophrenia subjects. This finding implies that basal ganglia structural abnormalities observed in subjects with schizophrenia are at least in part an intrinsic feature of the illness.

Shape deformity of the corpus striatum in obsessive-compulsive disorder.

Volumetric changes of striatal structures based on magnetic resonance imaging (MRI) have been inconsistent in patients with obsessive-compulsive disorder (OCD) due to methodological limitations. The purpose of this study was to investigate shape deformities of the corpus striatum in patients with OCD. We performed 3-D shape deformation analysis of the caudate nucleus, the putamen, and the globus pallidus in 36 patients with OCD and 36 healthy normal subjects. Shape analysis showed deformity of the striatal structures, especially the caudate nucleus. Outward deformities in the superior, anterior portion of the bilateral caudate were observed in patients with OCD. In addition, an outward deformity in the inferior, lateral portion of the left putamen was also detected. These results suggest that patients with OCD have shape deformities of the corpus striatum, especially the caudate nucleus, compared with healthy normal subjects, and that shape analysis may provide an important complement to volumetric MRI studies in investigating the pathophysiology of OCD.

Inactivation of Arx, the murine ortholog of the X-linked lissencephaly with ambiguous genitalia gene, leads to severe disorganization of the ventral telencephalon with impaired neuronal migration and differentiation.

ARX loss-of-function mutations cause X-linked lissencephaly with ambiguous genitalia (XLAG), a severe neurological condition that results in profound brain malformations, including microcephaly, absence of corpus callosum, and impairment of the basal ganglia. Despite such dramatic defects, their nature and origin remain largely unknown. Here, we used Arx mutant mice as a model to characterize the cellular and molecular mechanisms underlying the basal ganglia alterations. In these animals, the early differentiation of this tissue appeared normal, whereas subsequent differentiation was impaired, leading to the periventricular accumulation of immature neurons in both the lateral ganglionic eminence and medial ganglionic eminence (MGE). Both tangential migration toward the cortex and striatum and radial migration to the globus pallidus and striatum were greatly reduced in the mutants, causing a periventricular accumulation of NPY+ or calretinin+ neurons in the MGE. Arx mutant neurons retained their differentiation potential in vitro but exhibited deficits in morphology and migration ability. These findings imply that cell-autonomous defects in migration underlie the neuronal localization defects. Furthermore, Arx mutants lacked a large fraction of cholinergic neurons and displayed a strong impairment of thalamocortical projections, in which major axon fiber tracts failed to traverse the basal ganglia. Altogether, these results highlight the critical functions of Arx in promoting neural migration and regulating basal ganglia differentiation in mice, consistent with the phenotype of XLAG patients.

Basal ganglia volumes in drug-naive first-episode schizophrenia patients before and after short-term treatment with either a typical or an atypical antipsychotic drug.

The present study examined basal ganglia volumes in drug-naive first-episode schizophrenic patients before and after treatment with either a specific typical or atypical antipsychotic compound. Sixteen antipsychotic drug-naive and three minimally medicated first-episode schizophrenic patients and 19 matched controls participated. Patients were randomly assigned to treatment with either low doses of the typical antipsychotic drug, zuclopenthixol, or the atypical compound, risperidone. High-resolution magnetic resonance imaging (MRI) scans were obtained in patients before and after 12 weeks of exposure to medication and in controls at baseline. Caudate nucleus, nucleus accumbens, and putamen volumes were measured. Compared with controls, absolute volumes of interest (VOIs) were smaller in patients at baseline and increased after treatment. However, with controls for age, gender and whole brain or intracranial volume, the only significant difference between patients and controls was a Hemisphere x Group interaction for the caudate nucleus at baseline, with controls having larger left than right caudate nuclei and patients having marginally larger right than left caudate volumes. Within patients, the two medication groups did not differ significantly with respect to volume changes after 3 months of low dose treatment in any of the VOIs. Nevertheless, when medication groups were examined separately, a significant volume increase in the putamen was evidenced in the risperidone group. The altered asymmetry in caudate volume in patients suggests intrinsic basal ganglia pathology in schizophrenia, most likely of neurodevelopmental origin.

Validity of large-deformation high dimensional brain mapping of the basal ganglia in adults with Tourette syndrome.

The basal ganglia and thalamus may play a critical role for behavioral inhibition mediated by prefrontal, parietal, temporal, and cingulate cortices. The cortico-basal ganglia-thalamo-cortical loop with projections from frontal cortex to striatum, then to globus pallidus or to substantia nigra pars reticulata, to thalamus and back to cortex, provides the anatomical substrate for this function. In-vivo neuroimaging studies have reported reduced volumes in the thalamus and basal ganglia in individuals with Tourette Syndrome (TS) when compared with healthy controls. However, patterns of neuroanatomical shape that may be associated with these volume differences have not yet been consistently characterized. Tools are being developed at a rapid pace within the emerging field of computational anatomy that allow for the precise analysis of neuroanatomical shape derived from magnetic resonance (MR) images, and give us the ability to characterize subtle abnormalities of brain structures that were previously undetectable. In this study, T1-weighted MR scans were collected in 15 neuroleptic-naïve adults with TS or chronic motor tics and 15 healthy, tic-free adult subjects matched for age, gender and handedness. We demonstrated the validity and reliability of large-deformation high dimensional brain mapping (HDBM-LD) as a tool to characterize the basal ganglia (caudate, globus pallidus and putamen) and thalamus. We found no significant volume or shape differences in any of the structures in this small sample of subjects.

Globus pallidus volume is related to symptom severity in neuroleptic naive patients with schizophrenia.

This study compares globus pallidus (GP) volume between neuroleptic naive patients with schizophrenia and healthy controls using structural MRI. The volume of the external segment of the GP (GPe) was positively correlated with the severity of global symptoms, as measured by the Scale for the Assessment of Negative Symptoms and Scale for the Assessment of Positive Symptoms (SANS/SAPS, Andreasen and Olsen, 1982). The volume for the GP, GPe, and internal segment (GPi) did not differ between groups.

Congenital bilateral perisylvian syndrome with partial epilepsy. Case report with long-term follow-up.

Congenital bilateral perisylvian syndrome (CBPS) is a rare neurological disorder characterised by pseudobulbar palsy, cognitive deficits and epilepsy associated with bilateral perisylvian cortical dysplasia on neuroimaging studies. We report a long-term follow-up of a 18-years girl diagnosed with CBPS according to the typical clinical and magnetic resonance imaging (MRI) features. The patient showed faciopharyngoglossomasticatory diplegia, severe dysarthria, ataxia, spastic quadriparesis and severe mental retardation. Brain MRI evidenced bilateral perisylvian cortical dysplasia. Since early life she suffered from complex febrile seizures and epilepsy consisting of complex partial attacks with affective manifestations associated with centro-temporal EEG abnormalities. During 18 years of follow-up she was treated with phenobarbital, carbamazepine, lamotrigine, gabapentin but did not show any significant clinical improvement. Subsequently, monotherapy with phenytoin (PHT) was followed by a significant clinical improvement. At age 17, because of adverse effects, PHT was gradually substituted by topiramate (TPM). Full control of seizures was obtained at the age of 17 years with TPM. EEG abnormalities throughout the years have been reduced according to the clinical course. These findings emphasised the importance of long-term follow-up, suggesting that the prognosis for epilepsy may not be predicted based on the early response to treatment or on the presence of structural encephalic abnormalities, as reported in the literature.

Unilateral absence of the basal ganglia plus epilepsy without motor symptoms.

A patient with absence of the basal ganglia and refractory epilepsy without impairment of pyramidal or extrapyramidal motor function is reported. Imaging findings suggest a vascular insult as etiology. Preserved motor function could be explained by neuronal plasticity involving contralateral corticostriatal and pallidothalamic connections and points to a lesion received in early pregnancy.

Enfermedad de hallervorden-spatz: manifestaciones clínico-radiológicas

Se presenta el caso de una paciente de 18 años con diagnóstico de enfermedad de Hallervorden-Spatz cuya sintomatología neurológica progrsiva con movimientos anormales en miembros inferiores y superiores, disartria y deterioro mental se inicio desde la edad de 4 años. El examen de resonancia magnética que demuestra depósitos de hiero anormales en los globos pálidos y en la sustancia nigra confirma la impresión clínica de la enfermedad

Basal ganglia volumes in children with attention-deficit hyperactivity disorder.

Previous research has demonstrated volume reduction of the left globus pallidus in children with the codiagnoses of Tourette syndrome and attention-deficit hyperactivity disorder (ADHD), in comparison with children who have Tourette syndrome alone and with normal controls. The purpose of this study was to determine whether children with ADHD alone also had volume reduction of the globus pallidus or other basal ganglia structures. Subjects were 10 boys with ADHD, 16 boys with Tourette syndrome and ADHD, and 11 normal control boys. Groups were matched for age. Boys with ADHD were individually matched for age, handedness, and IQ to 10 of the 16 boys with Tourette syndrome and ADHD. Volumes of caudate, putamen, and globus pallidus were measured and corrected for brain volume. The boys with ADHD had significantly smaller left globus pallidus volume and total globus pallidus volume (corrected for brain volume) than the normal controls. The Tourette syndrome plus ADHD group did not differ from the ADHD group on any of the measures. We conclude that small globus pallidus volume, particularly on the left side, is associated with ADHD.

Electroencephalographic findings of hereditary dentatorubral-pallidoluysian atrophy (DRPLA).

The electroencephalograms (EEGs) of 22 patients suffering from hereditary DRPLA were studied. Epileptoform patterns were observed in 14 patients (63.6%) with epileptic seizures. The epileptoform patterns most frequently observed were those atypical spike-wave complexes. Slow wave bursts were seen in 18 patients (81.8%). Photosensitivity was revealed in six (27.3%) patients, all of whom presented progressive myoclonus epilepsy (PME) syndrome. Abnormal background activity was evident in 17 (77.3%) patients. These abnormalities in EEG were more severe in patients in the PME type than those of the A (ataxia) and AE (ataxia and epilepsy) types.

Left globus pallidus abnormality in never-medicated patients with schizophrenia.

Schizophrenia is a severe psychiatric disorder characterized by onset in young adulthood, the occurrence of hallucinations and delusions, and the development of enduring psychosocial disability. The pathophysiology of this disorder remains unknown. Studies of cerebral blood flow and metabolism designed to identify brain abnormalities in schizophrenia have been limited by inadequate methods of anatomical localization and the possibility of persistent medication effects. We have now used positron emission tomography and a validated method of anatomical localization in an attempt to identify abnormalities of regional cerebral blood flow in newly diagnosed never-medicated patients with schizophrenia. An exploratory study of 5 patients and 10 normal control subjects identified abnormally high blood flow in the left globus pallidus of patients with schizophrenia. A replication study of 5 additional patients and 10 additional control subjects confirmed this finding. No other abnormalities were found.

Familial lissencephaly with extreme neopallial hypoplasia.

Two siblings, male and female, with identical lethal brain malformation are described. Their anomaly is characterized by very low brain weight, lissencephaly, wide ventricles and thin neopallium (colpocephaly) varying in thickness between 0.2 and 3 mm. The neocortex is four layered as in classic lissencephaly. Brainstem and cerebellar anomalies are more extensive than in cases hitherto described in detail. No extracranial malformation is found. The parental karyotypes are normal. The relationship to previously reported familial cases of lissencephaly and several inherited syndromes featuring lissencephaly is discussed. The present family may represent a severe expression of previously described autosomal recessive lissencephaly without extracranial anomaly or may represent a new genetic lissencephaly syndrome.