Thirty-five patients, exclusively girls, from three countries had a uniform and striking progressive encephalopathy. After normal general and psychomotor development up to the age of 7 to 18 months, developmental stagnation occurred, followed by rapid deterioration of higher brain functions. Within one-and-a-half years this deterioration led to severe dementia, autism, loss of purposeful use of the hands, jerky truncal ataxia, and acquired microcephaly. The destructive stage was followed by apparent stability lasting through decades. Additional insidious neurological abnormalities supervened, mainly spastic parapareses, vasomotor disturbances of the lower limbs, and epilepsy. Prior extensive laboratory investigations have not revealed the cause. The condition is similar to a virtually overlooked syndrome described by Rett in the German literature. The exclusive involvement of females, correlated with findings in family data analyses, suggests a dominant mutation on one X chromosome that results in affected girls and nonviable male hemizygous conceptuses.

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.

Eight infants developed a progressive disorder of the central nervous system with bilateral spasticity and dystonia, acquired microcephaly, and a rapid course toward profound deterioration and death. All the patients had abnormal cerebrospinal fluid with mild but persistent lymphocytosis. Computed tomography showed various combinations of bilateral symmetrical calcifications in the basal ganglia, progressive brain atrophy, and deep white matter hypodensities, the first two being present in all families but not in every individual patient. The disorder is familial and probably genetic in origin, although some features, especially the pleocytosis, may erroneously suggest an inflammatory condition.

We recently reported on three young patients with severe impairments of episodic memory resulting from brain injury sustained early in life. These findings have led us to hypothesize that such impairments might be a previously unrecognized consequence of perinatal hypoxic-ischaemic injury. Neuropsychological and quantitative magnetic resonance investigations were carried out on five young patients, all of whom had suffered hypoxic-ischaemic episodes at or shortly after birth. All five patients showed severe impairments of episodic memory (memory for events), with relative preservation of semantic memory (memory for facts). However, none had any of the major neurological deficits that are typically associated with hypoxic-ischaemic injury, and all attended mainstream schools. Quantitative magnetic resonance investigations revealed severe bilateral hippocampal atrophy in all cases. As a group, the patients also showed bilateral reductions in grey matter in the regions of the putamen and the ventral part of the thalamus. On the basis of their clinical histories and the pattern of magnetic resonance findings, we attribute the patients' pathology and associated memory impairments primarily to hypoxic-ischaemic episodes sustained very early in life. We suggest that the degree of hypoxia-ischaemia was sufficient to produce selective damage to particularly vulnerable regions of the brain, notably the hippocampi, but was not sufficient to result in the more severe neurological and cognitive deficits that can follow hypoxic-ischaemic injury. The impairments in episodic memory may be difficult to recognize, particularly in early childhood, but this developmental amnesia can have debilitating consequences, both at home and at school, and may preclude independent life in adulthood.

SUMMARY Two hundred and thirty‐nine cases of status epilepticus in children 0–15 years old have been studied. Generalized tonic‐clonic and unilateral clonic convulsions constituted the bulk of cases. Status is mostly observed in young infants since 37% of all cases occurred in the first year, 73% in the first 3 years and 85% before 5 years of age. In only 23% of the patients did brief convulsions precede the episode of status epilepticus. Conversely seizures were noticed after status in almost three quarters of patients followed for one year or more. One half of our cases were apparently due to organic brain damage, either acute or chronic, the remaining half had no recognized etiological factors. More than half of these cryptogenic cases were related to non‐specific febrile episodes. The prognosis of children's status epilepticus is grave, mental or neurological residua or both being present in at least 57% of our patients. Approximately one half of these children had had normal development prior to their bout of convulsions. Gross brain damage was the main cause of status below 6 months of age, whereas cryptogenic convulsions predominated during the second year. Most of these cases were associated with fever. It is suggested that status epilepticus is capable of causing brain damage whatever its cause and that many cryptogenic episodes of febrile status are but the most severe cases in the spectrum of febrile convulsions. RÉSUMÉ Deux cents trente‐neuf cas d'état de mal épileptique chez l'enfant de 0–15 ans ont étéétudiées. Les crises généralisées tonico‐cloniques et les crises cloniques unilatérales sont la majorité. L'état de mal est surtout fréquent chez l'enfant jeune, 37% des cas survenant dans la premiére année, 73% avant trois ans et 85% avant cinq ans. L'état de mal n'a été précédé de convulsions courtes que dans 23% des cas. A l'inverse des crises aprés l'état de mal ont ete notées chez prés de trois quarts des malades suivis un an ou plus. La moitié de nos cas semble due à une atteinte cérebrale organique, aigüe ou chronique, l'autre moitié de ces états n'ayant pas de cause reconnue. Plus de la moitié de ces états de mal cryptogenétiqués étaient en relation avec des infections banales n'intéressant pas primitivement le cerveau. Le pronostic de l'état de mal épileptique de l'enfant est grave, puisque des séquelles mentales ou neurologiques étaient présentes chez 57% de nos enfants. Chez à peu prés la moitié de ceux‐ci le développement neuro‐psychique avait été normal jusqu'à l'état de mal. Avant l'âge de 6 mois les lésions organiques sont la cause commune des états de mal alors que les formes idiopathiques sont prédominates dans la seconde anneé, le plus souvent en association avec de la fiévre. l'état de mal épileptique semble capable á lui seul de créer des lésions cérébrates définitives quelle que soit sa cause. Nombre d'états de mal fébriles ne seraient que la forme extrême des convulsions fébriles.

Aicardi syndrome (AS) is characterized by a triad of callosal agenesis, infantile spasms and chorioretinal 'lacunae'. It occurs only in individuals with two X chromosomes and is not familial. The outcome of AS is severe, with a high early mortality, considerable morbidity and a generally poor developmental outcome. However, the spectrum of AS seems broader than previously defined with a small proportion of the affected girls only moderately or mildly retarded. Several novel and important features should be added to the classic triad. The brain malformation is complex with cortical migration abnormalities, often cystic formations and sometimes choroid plexus papillomas; the eye anomalies, often feature a coloboma in addition to the lacunae, and focal seizures rather than spasms, are common. AS has been reported in 2 boys, both with an XXY complement, supporting the hypothesis of an X-linked gene lethal early in pregnancy for male conceptuses. A locus at Xp22.3 has been suggested but has not been confirmed. Treatment is only symptomatic.

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