Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti-N-methyl-d-aspartate receptor encephalitis.

Aim We report four cases of acquired severe encephalopathy with massive hyperkinesia, marked neurological and cognitive regression, sleep disturbance, prolonged mutism, and a remarkably delayed recovery (time to full recovery between 5 and 18mo) with an overall good outcome, and its association with anti-N-methyl-d-aspartate (anti-NMDA) receptor antibodies. Method We reviewed the four cases retrospectively and we also reviewed the literature. Results Anti-NMDA receptor antibodies (without ovarian teratoma detected so far) were found in the two children tested in this study. Interpretation The clinical features are similar to those first reported in 1992 by Sebire et al.,(1) and rarely recognized since. Sleep disturbance was not emphasized as part of the disorder, but appears to be an important feature, whereas coma is less certain and difficult to evaluate in this setting. The combination of symptoms, evolution (mainly seizures at onset), severity, paucity of abnormal laboratory findings, very slow recovery, and difficult management justify its recognition as a specific entity. The neuropathological substrate may be anatomically close to that involved in encephalitis lethargica, in which the same target functions (sleep and movement) are affected but in reverse, with hypersomnolence and bradykinesia. This syndrome closely resembles anti-NMDA receptor encephalitis, which has been reported in adults and is often paraneoplastic.

Hypertension portale et prise en charge de l'ascite [Management of ascites due to portal hypertension].

Portal hypertension is regularly encountered by the general practitioner. It is defined by an elevation of the porto-systemic pressure gradient, with complications such as ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, variceal bleeding, hypersplenism, hepatopulmonary syndrome or hepatic encephalopathy occuring when a significant elevation of this gradient is reached. Cirrhosis is the primary cause of portal hypertension in industrialized countries. Symptomatic portal hypertension carries a poor prognosis. Management should be initiated rapidly, including the identification and correction of any reversible underlying condition. Liver transplantation should be considered in advanced cases.

Fissures du labrum glénoïdal postérieur et lésions associées de l'épaule: une étude en arthroscanner [Fissures of the posterior labrum and associated lesions: CT arthrogram evaluation]

PURPOSE: To describe osseous, chondral and tendinous lesions associated with fissures of the posterior labrum. To better understand the pathological processes leading to fissure of the posterior labrum. Materials and methods. Retrospective study of 43 CT arthrograms performed in 43 patients that showed a fissure of the posterior labrum. The following associated lesions were noted: osseous and chondral remodeling of the humeral head and/or glenoid and articular surface fissures of the rotator cuff. Based on type of associated lesions, patients were separated into one of four pathological subgroups: posterior instability, posterosuperior or internal impingement, anterior instability and isolated fissure of the posterior labrum. RESULTS: Sixteen patients (37.2%) of patients showed posterior instability, 12 (27.9%) showed lesions of internal impingement, and 11 (25.6%) showed lesions of anterior instability. Only 4 patients (9.3%) had an isolated fissure of the posterior labrum. CONCLUSION: Posterior instability, internal impingement and anterior instability are the main pathologies leading to fissure of the posterior labrum, which seldom occurs in isolation. Evaluation of these associated lesions allows understanding of the underlying pathological processes leading to fissure of the posterior labrum.

Early neurological impairment and severe anemia in a newborn with Pearson syndrome

BACKGROUND: Pearson marrow-pancreas syndrome (PS) is usually a fatal mitochondrial disease, mostly diagnosed during infancy or postmortem. PS is caused by the deletions or duplications of mitochondrial DNA (mtDNA). The tissue distribution and relative proportions of expressed abnormal mtDNA determine the phenotype and the clinical course. MATERIALS AND METHODS: We describe the case of a term baby boy who was diagnosed with PS early in the neonatal period due to severe aregenerative anemia and persistent lactic acidosis. RESULTS: His neurological examination was abnormal since birth. Brain magnetic resonance imaging (MRI) at term was abnormal, indicating that mitochondrial encephalopathy in PS can be already manifested in the neonatal period. To our knowledge, neonatal encephalopathy in PS has not been previously described. CONCLUSION: PS is a rare condition diagnosed in the newborn. It should be suspected in the presence of severe anemia and persistent lactic acidosis, and may manifest with early encephalopathy.

Retinal Dystrophy In The Oculo-auricular Syndrome Due to HMX1 Mutation.

Purpose: To report on the clinical and electrophysiological findings in a patient with oculo-auricular syndrome due to HMX1 mutation, with a follow-up of 12 years. Background: Oculo-auricular syndrome (MIM: 612109) is a rare developmental recessive condition affecting the eye and external ear that results from a mutation in the HMX1 gene. Previously described ocular abnormalities include bilateral microcornea, posterior synechiae, cataract, chorioretinal colobomas and rod-cone dystrophy. Methods: Retrospective chart review of an affected boy followed over a period of 12 years who had serial complete ophthalmologic examinations, fundus photographs, Goldmann perimetry and full-field electroretinograms (ERG). Results: Initial ERG tracings revealed generalized rod more than cone dysfunction. Thereafter, a rapid deterioration in rod and cone function was detected on follow up ERGs. Conclusion: The retinal degeneration in the recessively inherited oculo-auricular syndrome is a progressive rod-cone dystrophy. Visual prognosis is guarded considering the progressive nature of the retinal dystrophy in early infancy.

Central Horner's syndrome with contralateral ataxic hemiparesis: a diencephalic alternate syndrome.

OBJECTIVE: To assess whether thalamic strokes presenting with a central Horner's syndrome (HS) show specific clinicoanatomic patterns. METHODS: From the Lausanne Stroke Registry (period 1993 to spring 2002), the authors selected all patients with thalamic stroke presenting with ipsilateral HS. Patients with complete infarction of the posterior cerebral artery territory, with involvement of middle cerebral artery territory or bilateral lesions, were excluded. Lesions on brain MRI were correlated with standard neuroanatomic templates. RESULTS: Nine patients with thalamic infarction presenting with central HS were found; all showed contralateral ataxic hemiparesis (AH). Lesions involved the anterior or paramedian thalamus and extended to the hypothalamic or rostral paramedian mesencephalic area in all but one subject. Associated clinical signs included dysphasia (two patients), somnolence (six), vertical gaze paresis (two), asterixis (two), and hemihypesthesia (three). CONCLUSION: The alternate clinical pattern of central HS with contralateral AH is a stroke syndrome of the diencephalic-mesencephalic junction, resulting from the involvement of the common arterial supply to the paramedian/anterior thalamus, the posterior hypothalamus and the rostral paramedian midbrain.

High prevalence of the metabolic syndrome in HIV-infected patients: impact of different definitions of the metabolic syndrome.

INTRODUCTION: This study describes the characteristics of the metabolic syndrome in HIV-positive patients in the Data Collection on Adverse Events of Anti-HIV Drugs study and discusses the impact of different methodological approaches on estimates of the prevalence of metabolic syndrome over time. METHODS: We described the prevalence of the metabolic syndrome in patients under follow-up at the end of six calendar periods from 2000 to 2007. The definition that was used for the metabolic syndrome was modified to take account of the use of lipid-lowering and antihypertensive medication, measurement variability and missing values, and assessed the impact of these modifications on the estimated prevalence. RESULTS: For all definitions considered, there was an increasing prevalence of the metabolic syndrome over time, although the prevalence estimates themselves varied widely. Using our primary definition, we found an increase in prevalence from 19.4% in 2000/2001 to 41.6% in 2006/2007. Modification of the definition to incorporate antihypertensive and lipid-lowering medication had relatively little impact on the prevalence estimates, as did modification to allow for missing data. In contrast, modification to allow the metabolic syndrome to be reversible and to allow for measurement variability lowered prevalence estimates substantially. DISCUSSION: The prevalence of the metabolic syndrome in cohort studies is largely based on the use of nonstandardized measurements as they are captured in daily clinical care. As a result, bias is easily introduced, particularly when measurements are both highly variable and may be missing. We suggest that the prevalence of the metabolic syndrome in cohort studies should be based on two consecutive measurements of the laboratory components in the syndrome definition.

Molecular Analysis of the PTEN Gene in a Choroidal Schwannoma in the Context of a Hamartomatous Syndrome

Purpose: To investigate the molecular involvement of PTEN, a tumor suppressor gene, in a case of cellular pigmented choroidal Schwannoma in a patient with hamartomatous syndrome due to heterozygous PTEN germline mutation. Methods: Histopathological, immunohistochemical, and electron microscopy analyses were performed by standard procedures. Paraffin-embedded samples of normal and tumor eye tissues were collected and DNA was extracted. A 145 bp region flanking the heterozygous c.406T>C mutation in exon 5 of PTEN was amplified by PCR and sequenced. To evaluate the allelic status of PTEN in the tumor sample, we cloned different PCR products in E. coli using a TA cloning procedure. Results: Histopathology demonstrated a posterior choroidal mass measuring 1.3 x 1.6 x 1.4 cm. The tumor was composed by fascicles of spindle cells with wavy cytoplasm. No Verrocay bodies could be identified. Scattered histiocytes with clear cytoplasm were present. By immunohistochemistry, the cells were expressing S100 and focally Melan A proteins. Pericellular type IV collagen could be demonstrated. Interlacing cytoplasmic processes covered by thick basement membrane could be found by electron microscopy as well as few premelanosomes. Moderate PTEN expression by immunohistochemistry was identified in some cells. As expected, the germline mutation could be detected by DNA sequencing in both the paraffin-embedded normal and tumor eye tissues. Analysis of 33 E. coli colonies bearing clones from the tumor eye tissue DNA surprisingly revealed that most of them contained the PTEN wild-type allele (29 vs. 4, Fisher's test p-value = 0.002). Conclusions: This is the first reported case of choroidal cellular Schwannoma arising in the context of a PTEN hamartomatous syndrome. Allelic analysis of PTEN in the tumor suggests a statistically-significant partial loss of heterozygozity in favor of the wild-type allele. Our findings are in clear contrast with what is usually observed in cancer tissues, for which mutated alleles of tumor suppressor genes are usually brought to homozygosity. Similar results were previously reported in human non-Hodgkin's lymphomas, displaying an overexpression of the wild-type form of the tumor suppressor gene p53. We are in the process of investigating additional DNA derived from other fresh and paraffin-embedded tissues from the patient, in order to gain insights on the molecular bases of PTEN involvement in this rare choroidal Schwannoma.

Traitement des plagiocéphalies postérieures d'origine positionnelle [Treatment of posterior positional plagiocephaly]

In 1992, the American academy of paediatrics has recommended that infants be placed on their backs to sleep, because prone sleeping has been correlated with sudden infant death syndrome. Following this article, medical paediatric community has documented an exponential increase in the diagnosis of posterior cranial deformities, which were considered as the consequence of unrelieved pressure onto the occiput during infant sleep. These last 15 years, management of posterior positional plagiocephaly has evolved but is still not standardized; it varies according to local specificities, and medical or parental preferences. Treatment of deformational plagiocephaly includes preventive counseling, repositioning adjustments and exercises, physiotherapy, osteopathy, treatment by dynamic cranial orthosis. On extremely rare occasions, corrective surgery is proposed. This article aims at reviewing the epidemiologic, diagnostic, and various therapeutic options of posterior positional plagiocephaly.

Left temporal lobe epilepsy revealing left posterior cortical atrophy due to Alzheimer's disease.

Seizures can be an early symptom of Alzheimer's disease (AD) and can precede cognitive decline. Early epilepsy in AD can mimic transient epileptic amnesic syndrome (TEAS) or epileptic amnesic syndrome. We report the case of a patient who started a cerebrospinal fluid (CSF)-proven AD with partial seizures and TEAS that secondarily became a cortical posterior atrophy syndrome. CSF biomarkers showed a high amyloid production, amyloidopathy, and high level of total tau and p-Tau. This observation adds data to the complex AD-early epilepsy interactions and illustrates that atypical AD can cause a TEAS. Possible red flags for an underlying neurodegenerative process in TEAS are discussed.

An atypical 7q11.23 deletion in a normal IQ Williams-Beuren syndrome patient.

Williams-Beuren syndrome (WBS; OMIM no. 194050) is a multisystemic neurodevelopmental disorder caused by a hemizygous deletion of 1.55 Mb on chromosome 7q11.23 spanning 28 genes. Haploinsufficiency of the ELN gene was shown to be responsible for supravalvular aortic stenosis and generalized arteriopathy, whereas LIMK1, CLIP2, GTF2IRD1 and GTF2I genes were suggested to be linked to the specific cognitive profile and craniofacial features. These insights for genotype-phenotype correlations came from the molecular and clinical analysis of patients with atypical deletions and mice models. Here we report a patient showing mild WBS physical phenotype and normal IQ, who carries a shorter 1 Mb atypical deletion. This rearrangement does not include the GTF2IRD1 and GTF2I genes and only partially the BAZ1B gene. Our results are consistent with the hypothesis that hemizygosity of the GTF2IRD1 and GTF2I genes might be involved in the facial dysmorphisms and in the specific motor and cognitive deficits observed in WBS patients.

NR2E3 mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP).

NR2E3, also called photoreceptor-specific nuclear receptor (PNR), is a transcription factor of the nuclear hormone receptor superfamily whose expression is uniquely restricted to photoreceptors. There, its physiological activity is essential for proper rod and cone photoreceptor development and maintenance. Thirty-two different mutations in NR2E3 have been identified in either homozygous or compound heterozygous state in the recessively inherited enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), and clumped pigmentary retinal degeneration (CPRD). The clinical phenotype common to all these patients is night blindness, rudimental or absent rod function, and hyperfunction of the "blue" S-cones. A single p.G56R mutation is inherited in a dominant manner and causes retinitis pigmentosa (RP). We have established a new locus-specific database for NR2E3 (www.LOVD.nl/eye), containing all reported mutations, polymorphisms, and unclassified sequence variants, including novel ones. A high proportion of mutations are located in the evolutionarily-conserved DNA-binding domains (DBDs) and ligand-binding domains (LBDs) of NR2E3. Based on homology modeling of these NR2E3 domains, we propose a structural localization of mutated residues. The high variability of clinical phenotypes observed in patients affected by NR2E3-linked retinal degenerations may be caused by different disease mechanisms, including absence of DNA-binding, altered interactions with transcriptional coregulators, and differential activity of modifier genes.

Phenotypic consequences of copy number variation: insights from Smith-Magenis and Potocki-Lupski syndrome mouse models.

A large fraction of genome variation between individuals is comprised of submicroscopic copy number variation of genomic DNA segments. We assessed the relative contribution of structural changes and gene dosage alterations on phenotypic outcomes with mouse models of Smith-Magenis and Potocki-Lupski syndromes. We phenotyped mice with 1n (Deletion/+), 2n (+/+), 3n (Duplication/+), and balanced 2n compound heterozygous (Deletion/Duplication) copies of the same region. Parallel to the observations made in humans, such variation in gene copy number was sufficient to generate phenotypic consequences: in a number of cases diametrically opposing phenotypes were associated with gain versus loss of gene content. Surprisingly, some neurobehavioral traits were not rescued by restoration of the normal gene copy number. Transcriptome profiling showed that a highly significant propensity of transcriptional changes map to the engineered interval in the five assessed tissues. A statistically significant overrepresentation of the genes mapping to the entire length of the engineered chromosome was also found in the top-ranked differentially expressed genes in the mice containing rearranged chromosomes, regardless of the nature of the rearrangement, an observation robust across different cell lineages of the central nervous system. Our data indicate that a structural change at a given position of the human genome may affect not only locus and adjacent gene expression but also "genome regulation." Furthermore, structural change can cause the same perturbation in particular pathways regardless of gene dosage. Thus, the presence of a genomic structural change, as well as gene dosage imbalance, contributes to the ultimate phenotype.