Pierre Castelnau

Pallidal stimulation improves pantothenate kinase–associated neurodegeneration

Pantothenate kinase–associated neurodegeneration (PKAN) causes a progressive generalized dystonia which remains pharmacologically intractable. We performed bilateral internal globus pallidus stimulation in six patients with genetically confirmed PKAN who obtained a major and long‐lasting improvement of their painful spasms, dystonia, and functional autonomy. This study shows the benefits of pallidal DBS for the dystonia of PKAN patients. Ann Neurol 2005;57:738–741

Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of L-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after L-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of L-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with L-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.

Novel Human Reovirus Isolated from Children with Acute Necrotizing Encephalopathy

TOC summary line: This new virus may be another cause of encephalitis.

Lamotrigine Is Neuroprotective in the Energy Deficiency Model of MPTP Intoxicated Mice

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibits the mitochondrial complex I of the respiratory chain. This results in ATP and ion homeostasis disturbances, which lead to selective death of the substantia nigra dopaminergic neurons. Well known as a Parkinsons disease model, the MPTP animal model also provides a potential paradigm of the energy deficiencies found in childhood. In these conditions, anticonvulsants may provide neuroprotection by limiting cellular energy consumption. We tested valproate, topiramate and lamotrigine in the MPTP mouse model. Dopamine transporter (DAT) density was assessed by quantitative autoradiography, tyrosine hydroxylase (TH) was evaluated by immunohistochemistry and dopamine (DA) levels by HPLC-ED whereas neuronal apoptosis was monitored through active caspase-3. Expectedly, the DAT density, TH immunoreactive neurons and DA content in the MPTP group were respectively reduced to 51%, 40% and 26% versus control animals. Unlike valproate and topiramate, lamotrigine provided a significant neuroprotection against MPTP in maintaining these levels at 99%, 74% and 58% respectively and reducing the induced apoptosis. Altogether, the data indicate that lamotrigine limits dopaminergic neuronal death in the substantia nigra and promotes striatal dendrites sprouting. Lamotrigine, a widely used and well-tolerated molecule in young patients, could represent a valuable adjuvant therapy in various energy deficiency conditions during childhood.

Regional characterization of energy metabolism in the brain of normal and MPTP-intoxicated mice using new markers of glucose and phosphate transport

The gibbon ape leukemia virus (GALV), the amphotropic murine leukemia virus (AMLV) and the human T-cell leukemia virus (HTLV) are retroviruses that specifically bind nutrient transporters with their envelope glycoproteins (Env) when entering host cells. Here, we used tagged ligands derived from GALV, AMLV, and HTLV Env to monitor the distribution of their cognate receptors, the inorganic phosphate transporters PiT1 and PiT2, and the glucose transporter GLUT1, respectively, in basal conditions and after acute energy deficiency. For this purpose, we monitored changes in the distribution of PiT1, PiT2 and GLUT1 in the cerebellum, the frontal cortex, the corpus callosum, the striatum and the substantia nigra (SN) of C57/BL6 mice after administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridinium (MPTP), a mitochondrial complex I inhibitor which induces neuronal degeneration in the striato-nigral network.The PiT1 ligand stained oligodendrocytes in the corpus callosum and showed a reticular pattern in the SN. The PiT2 ligand stained particularly the cerebellar Purkinje cells, while GLUT1 labelling was mainly observed throughout the cortex, basal ganglia and cerebellar gray matter. Interestingly, unlike GLUT1 and PiT2 distributions which did not appear to be modified by MPTP intoxication, PiT1 immunostaining seemed to be more extended in the SN. The plausible reasons for this change following acute energy stress are discussed.These new ligands therefore constitute new metabolic markers which should help to unravel cellular adaptations to a wide variety of normal and pathologic conditions and to determine the role of specific nutrient transporters in tissue homeostasis.

Psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorders

We conducted a comprehensive review of studies assessing the efficacy and tolerability of psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorder (encompassing autism disorder, Asperger’s syndrome and pervasive developmental disorders not otherwise specified). PubMed, Ovid, EMBASE, Web of Science, ERIC and CINHAL were searched through 3 January 2012. From a pool of 348 potentially relevant references, 12 citations (11 studies) were retained as pertinent. Four of the included studies had a randomized controlled design. Most of the studies assessed methylphenidate immediate release. Despite inter-study heterogeneity, taken together, the results of the selected reports suggest that psychostimulants may be effective for ADHD-like symptoms in autism spectrum disorder individuals. The most common adverse events reported in the included trials were appetite reduction, sleep-onset difficulties, irritability and emotional outbursts. We discuss future directions in the field, including the need for trials assessing more ecological outcomes and combined treatment strategies tailored to the specific individual features.

Thalamo-Striatal T2-Weighted Hyperintensities (Unidentified Bright Objects) Correlate With Cognitive Impairments in Neurofibromatosis Type 1 During Childhood

Learning disabilities represent the main childhood complication in neurofibromatosis type 1 (NF1). Patients frequently exhibit T2-weighted hyperintensities called unidentified bright objects (UBOs) on brain magnetic resonance imaging (MRI), with unclear relationship to such cognitive disabilities. This study aimed to determine whether thalamo-striatal UBOs correlate with cognitive disturbances. Thirty-seven NF1 children were studied: 24 with UBOs (18 of which were thalamo-striatal UBOs), and 13 without UBOs. NF1 subjects carrying thalamo-striatal UBOs had significantly lower IQs and visuospatial performances than those without UBOs in this location. These results suggest that UBOs may contribute to NF1 cognitive impairments through thalamo-cortical dysfunction.

Atypical language impairment in two siblings: Relationship with electrical status epilepticus during slow wave sleep

We report the case of a young girl who presented severe learning disabilities in oral and written language related to a continuous spike-waves during slow sleep (CSWS) syndrome. A sleep EEG recording obtained in her younger brother, who presented a clinical pattern suggesting developmental dysphasia, also showed a CSWS syndrome. These two clinical cases underscore the need to look for this syndrome in the siblings of an affected child when learning difficulties appear in a child who previously had normal psychomotor development.

Proton MR spectroscopic imaging of basal ganglia and thalamus in neurofibromatosis type 1: correlation with T2 hyperintensities

IntroductionNeurofibromatosis type 1 (NF1) is frequently associated with hyperintense lesions on T2-weighted images called “unidentified bright objects” (UBO). To better characterize the functional significance of UBO, we investigate the basal ganglia and thalamus using spectroscopic imaging in children with NF1 and compare the results to anomalies observed on T2-weighted images.MethodsMagnetic resonance (MR) data of 25 children with NF1 were analyzed. On the basis of T2-weighted images analysis, two groups were identified: one with normal MR imaging (UBO− group; n = 10) and one with UBO (UBO+ group; n = 15). Within the UBO+ group, a subpopulation of patients (n = 5) only had lesions of the basal ganglia. We analyzed herein seven regions of interest (ROIs) for each side: caudate nucleus, capsulo-lenticular region, lateral and posterior thalamus, thalamus (lateral and posterior voxels combined), putamen, and striatum. For each ROI, a spectrum of the metabolites and their ratio was obtained.ResultsPatients with abnormalities on T2-weighted images had significantly lower NAA/Cr, NAA/Cho, and NAA/mI ratios in the lateral right thalamus compared with patients with normal T2. These abnormal spectroscopic findings were not observed in capsulo-lenticular regions that had UBO but in the thalamus region that was devoid of UBO.ConclusionMultivoxel spectroscopic imaging using short-time echo showed spectroscopic abnormalities in the right thalamus of NF1 patients harboring UBO, which were mainly located in the basal ganglia. This finding could reflect the anatomical and functional interactions of these regions.

Prenatal Exposure to Methylphenidate Affects the Dopamine System and the Reactivity to Natural Reward in Adulthood in Rats

Background: Methylphenidate (MPH) is a commonly-used medication for the treatment of children with Attention-Deficit/Hyperactivity Disorders (ADHD). However, its prescription to adults with ADHD and narcolepsy raises the question of how the brain is impacted by MPH exposure during pregnancy. The goal of this study was to elucidate the long-term neurobiological consequences of prenatal exposure to MPH using a rat model. Methods: We focused on the effects of such treatment on the adult dopamine (DA) system and on the reactivity of animals to natural rewards. Results: This study shows that adult male rats prenatally exposed to MPH display elevated expression of presynaptic DA markers in the DA cell bodies and the striatum. Our results also suggest that MPH-treated animals could exhibit increased tonic DA activity in the mesolimbic pathway, altered signal-to-noise ratio after a pharmacological stimulation, and decreased reactivity to the locomotor effects of cocaine. Finally, we demonstrated that MPH rats display a decreased preference and motivation for sucrose. Conclusions: This is the first preclinical study reporting long-lasting neurobiological alterations of DA networks as well as alterations in motivational behaviors for natural rewards after a prenatal exposure to MPH. These results raise concerns about the possible neurobiological consequences of MPH treatment during pregnancy.