Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus.

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.

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.

Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis.

AIM: To describe the phenotype and genotype of pyruvate dehydrogenase complex (PDHc) deficiency. METHOD: Twenty-two participants with enzymologically and genetically confirmed PDHc deficiency were analysed for clinical and imaging features over a 15-year period. RESULTS: Four groups were identified: (1) those with neonatal encephalopathy with lactic acidosis (one male, four females; diagnosis at birth); (2) those with non-progressive infantile encephalopathy (three males, three females; age at diagnosis 2-9mo); (3) those with Leigh syndrome (eight males; age at diagnosis 1-13mo); and (4) those with relapsing ataxia (three males; 18-30mo). Seventeen mutations involved PDHA1 (a hotspot was identified in exons 6, 7, and 8 in seven males with Leigh syndrome or recurrent ataxia). Mutations in the PDHX gene (five cases) were correlated with non-progressive encephalopathy and long-term survival in four cases. INTERPRETATION: Two types of neurological involvement were identified. Abnormal prenatal brain development resulted in severe non-progressive encephalopathy with callosal agenesis, gyration anomalies, microcephaly with intrauterine growth retardation, or dysmorphia in both males and females (12 cases). Acute energy failure in infant life produced basal ganglia lesions with paroxysmal dystonia, neuropathic ataxia due to axonal transport dysfunction, or epilepsy only in males (11 cases). The ketogenic diet improved only paroxysmal dysfunction, providing an additional argument in favour of paroxysmal energy failure.

MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood.

The prognostic factors for relapse of the initial MRI findings after a first episode of acute CNS inflammatory demyelination are unclear in children. In this study we aimed to identify initial MRI factors that are predictive of a second attack and disability after a first episode of acute CNS inflammatory demyelination in childhood. A cohort of 116 children who had a first episode of acute CNS inflammatory demyelination between 1990 and 2002 was studied using survival analysis methods. The initial MRI data were reviewed in a systematic, standardized, double-blind manner. The average follow-up was 4.9 +/- 3 years. Multivariate analysis showed that the rate of second attack was higher in patients with corpus callosum long axis perpendicular lesions (34 out of 116 patients, 30%) on the initial MRI [hazard ratio (HR) 2.89; 95% confidence interval (CI) 1.65-5.06] and/or with the sole presence of well-defined lesions (46 out of 116 patients, 40%) (HR 1.71; 95% CI 1.29-2.27). Both criteria were more specific predictors (100%) of relapse, demonstrating conversion to multiple sclerosis, than the three Barkhof criteria (63%), but were less sensitive (21% compared with 52%). None of the MRI criteria was predictive of severe disability. Using initial MRI and survival analysis methods, we identified two specific predictors of relapse and conversion to multiple sclerosis after a first episode of acute CNS inflammatory demyelination in childhood. Their low sensitivity, however, shows that this prediction remains difficult.

Limits of early diagnosis of herpes simplex encephalitis in children: a retrospective study of 38 cases.

The prognosis of herpes simplex encephalitis (HSE) depends on the early and appropriate administration of specific antiviral therapy. We retrospectively reviewed 38 cases of children with proven HSE, to evaluate the reliability of polymerase chain reaction results, according to the time of cerebrospinal fluid (CSF) sampling. Initial negative results were observed in 8 of 33 CSF samples drawn before day 3 of the disease and were significantly associated with a low level of protein and <10 leukocytes/mm3 in the CSF.

Herpes simplex encephalitis: diagnostic problems and late relapse.

A 5-year-old female presented with prolonged afebrile right-sided focal seizures, right brachio-facial paralysis, and dysarthria; consciousness was not altered. Fever appeared 20 hours after onset of neurological symptoms. At admission (day 1) cerebral computerized tomography and cerebrospinal fluid (CSF) analyses were normal including undetectable alpha-interferon (alpha-IFN) and negative herpes simplex virus (HSV) polymerase chain reaction (PCR). Acyclovir was started at a dosage of 60mg/kg/day for 21 days and neurological symptoms improved. Cerebral magnetic resonance imaging (MRI) showed lesions in the left thalamus and left parietal lobe. On day 8, CSF contained an elevated leukocyte count with a predominance of lymphocytes, but alpha-IFN and HSV DNA were still undetectable. Delayed intrathecal synthesis of specific anti-HSV antibodies was found on day 26 and confirmed herpes simplex encephalitis (HSE) diagnosis. Twenty months after this episode, the patient presented with a febrile meningeal syndrome. PCR detected HSV DNA in CSF and cerebral imaging showed a new left temporal lesion. At relapse onset, intrathecal synthesis of specific anti-HSV antibodies had disappeared. Acyclovir was started at a dosage of 60mg/kg/day for 21 days and neurological status improved. At discharge, neurological examination showed right hemiparesis and bucco-facial dyspraxia. Diagnostic problems of HSE diagnosis in children are highlighted. It is suggested that the premature disappearance of intrathecal synthesis of a specific anti-HSV antibody might play a permissive role in the resurgence of cerebral viral replication.

Unexplained mental retardation: is brain MRI useful?

BACKGROUND: Mental retardation (MR), defined as an IQ below 70, is a frequent cause of consultation in paediatrics. OBJECTIVE: To evaluate the yield of brain MRI in the diagnostic work-up of unexplained MR in children. PATIENTS AND METHODS: The MRI features and clinical data of 100 patients (age 1-18 years) affected with non-progressive MR of unknown origin were compared to an age-matched control group (n=100). Two radiologists conducted an independent review of the MRI scans. RESULTS: Univariate and multivariate analyses showed a higher incidence of brain anomalies in the MR group than in the control group (53 vs 17, OR=5.7 [2.9-11.1]), for signal abnormalities within the periventricular white matter (OR=20.3 [2.6-155.3]), lateral ventricular dilatation (OR=15.6 [2.0-124]), mild corpus callosum abnormalities (shortness, atrophy) (OR=6.8 [1.8-25.6]) and subtle cerebellar abnormalities, including fissure enlargement (OR=5.2 [1.1-26.2]). The diagnostic value of MRI abnormalities was considered good in 5% of patients (Alexander disease n=1, diffuse cortical malformation n=1, leukomalacia n=1, vermian agenesis n=1, commissural agenesis n=1), and weak in 48% of patients, in whom non-specific abnormalities did not lead to a diagnosis. Some clinical features resulted in a significantly higher percentage of abnormal MRI scans: abnormal neurological examination (82% vs 47%, P=0.008), abnormal skull circumference (66% vs 49%, P=0.04). Motor delay was associated with cerebellar abnormalities (P=0.01). CONCLUSIONS: This study confirms the weak diagnostic yield of MRI in mentally retarded children. The use of a control group has enabled us to identify the neuroimaging markers frequently associated with MR. Subgrouping patients according to neuroimaging markers and clinical signs should help identify those who would benefit from molecular studies.

First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability.

OBJECTIVES: To evaluate prognostic factors for second attack and for disability in children presenting with an initial episode of central nervous system (CNS) demyelination. STUDY DESIGN: A cohort of 296 children having a first episode of acute CNS inflammatory demyelination was studied by survival analysis. RESULTS: The average follow-up was 2.9+/-3 years. At the end of the follow-up, 57% of patients had a diagnosis of multiple sclerosis (MS), 29% had a monophasic acute disseminated encephalomyelitis, and 14% had a single focal episode. The rate of a second attack was (1). higher in patients with age at onset >or=10 years (hazard ratio, 1.67; 95% CI, 1.04-2.67), MS-suggestive initial MRI (1.54; 1.02-2.33), or optic nerve lesion (2.59; 1.27-5.29); and (2). lower in patients with myelitis (0.23; 0.10-0.56) or mental status change (0.59; 0.33-1.07). Of patients with a second attack, 29% had an initial diagnosis of acute disseminated encephalomyelitis. At the end of the follow-up period, 90% of patients had no or minor disability. Occurrence of severe disability was associated with a polysymptomatic onset (3.25; 1.16-11.01), sequelae after the first attack (26.65; 9.42-75.35), further relapses (1.49; 1.16-1.92), and progressive MS (3.57; 1.21-8.72). CONCLUSIONS: Risk of second attack of CNS demyelination is higher in older patients and lower in patients with mental status change. Risk of disability is higher in polysymptomatic and relapsing patients.

Prenatal diagnosis of cerebral malformation with an uncertain prognosis: a study concerning couple's information and consequences on pregnancy.

UNLABELLED: Fetal ultrasound (FU) is used during almost all pregnancies and makes a large contribution to the identification of fetal malformation. It is particularly difficult to announce a malformation, particularly those affecting the brain, because there are often doubts concerning both the diagnosis and the prognosis. AIM: The aim of this study was to analyze how imaging for prenatal screening is organized and how couples are managed and supported. We concentrated on the procedures used to inform couples: content, method of delivery and consequences. METHOD: Study amongst large multidisciplinary centers in Paris and the Paris region, by semi-directed interviews using a questionnaire. RESULTS: We showed that it is difficult to standardize the way in which information is supplied before and after the examination, and that doctors tend to recommend abortion when the prognosis is uncertain. DISCUSSION: These results provide information that will help decision-making concerning a standardized procedure allowing couples to benefit from all the capacities of prenatal screening, particularly when the diagnosis and prognosis are uncertain. There is a need for multidisciplinary teams to support and to accompany the decision concerning whether to have an abortion or to continue the pregnancy.

Agenesis of corpus callosum: prenatal diagnosis and prognosis.

INTRODUCTION: Agenesis of corpus callosum (ACC) is commonly diagnosed prenatally. When isolated, it appears to carry a good prognosis but studies are often retrospective and follow-up short. We report a prospective study of 17 children (11 boys, 6 girls) with prenatally diagnosed isolated ACC. METHODS: Neuropsychological evaluation was performed each year and results at the ages of 2, 4, and 6 years were compared. RESULTS: Febrile seizures occurred in 3 patients. Median intellectual quotient (IQ) was within the normal range (80-109) and nonrelated to partial or complete ACC, sex, or febrile seizures. Lower median IQ was significantly related to low cultural status. With age, the number of children with IQ in the lower range (80-89) increased and slowness, attentional troubles, and instability appeared. CONCLUSION: This study demonstrates that if outcome of isolated ACC is favorable, a long follow-up is necessary: with age, IQ in the lower range and behavioral troubles are linked to difficulties in school.