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.
We have studied 23 children from 13 families with a clinical diagnosis of Aicardi-Goutières syndrome. Affected individuals had developed an early-onset progressive encephalopathy that was characterized by a normal head circumference at birth, basal ganglia calcification, negative viral studies, and abnormalities of cerebrospinal fluid comprising either raised white cell counts and/or raised levels of interferon-alpha. By means of genomewide linkage analysis, a maximum-heterogeneity LOD score of 5.28 was reached at marker D3S3563, with alpha=.48, where alpha is the proportion of families showing linkage. Our data suggest the existence of locus heterogeneity in Aicardi-Goutières syndrome and highlight potential difficulties in the differentiation of this condition from pseudo-TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus types 1 and 2) syndrome.
SUMMARY The compliance and maturation of visual acuity of 1245 ½‐ to nine year olds was investigated. Testing was undertaken as part of routine surveillance. Ability to letter match, to achieve a binocular measure and to achieve monocular measures for children under three years was 89, 78 and 37 per cent, for children aged three to four years 97, 91 and 66 per cent, and for children over four years 99.9. 99.9 and 99. respectively A statistical model was developed to give acuity norms by age for use by surveillance and diagnostic teams. RÉSUMÉ La maturation tie lcar;acuitc linéaire et la participation au systéme de mesuie dcar;acuité de Sonksen ‐Silver che: les jeunes enfanls La participation et la maturation de lcar;acuilc visttelle out été recherchees chez 1245 enfants ages de 27‐ à neuf ans. Le test fut entreprts dans le cadre dcar;une surveillance de routine, l.a capacité dcar;appaner des leures. dcar;elfecture des mesures binoculaires et monoculaires fut respectivement de 89. 78 et 37 pour cent des enfants en dessous de trois ans. respectivement de 97. 9] et 66 pour cent chez les enfants ágés de trois a quatre ans et respectivement de 99.9, 99.9 et 99 pour tent chez les enfants de plus de quartre ans. Un modèle statisque a pu étre effectué. dormant les noniics dcar;acuité par âge en vue de'emploi par les équipes de surveillance et de diagnostic. de tres a cuatro años. y de 99,9, 99,9 y 99 por ciento respectivamente en niños de más de cuatro anos. Se desarrolló un inodelo estadistico para dar unas nornias de agutdeza según la edad. para uso de equipos de vigilancia y diagnóstics. ZUSAMMENFASSUNG Compliance und Reifung der Sehschärfe wurden bci 1245 Kinderen im Alter von 2½‐ bis neun Jahren untersucht. Die Kinder wurden im Rahmen von Routineuntersuchungen getestet. Die fähigkeit Buchstaben zu vergleichen. einen binokulären Befund und monokuläre Befunde zu erlangen. betrug für Kinder unler drei Jahren 89 b/w. 78 b/w. 37 Prozent, für Kinder zwischcn drei und vier Jahren 97, 91 und 66 Prozent und für Kinder über vier Jahren 99.9, 99.9 und 99 Prozent. I‐s wurde em statistisches Modell entwickelt. altersentsprechende Normwerte der Sehschärfe für Vorsorge‐ und diagostische lintersuchungen herauszugeben. RESUMEN Maduración de la axtideza linear y conipliunza usando el sistenia de agudeza Sonksen‐Sitver en nihos pe que lias Se investigó la complianza y la maduración de la agudcza visual de 1245 niños de 27½.‐ a neueve años. La exploraeion se realize formando parte de una vigilancia rutinaria. l.a habilidad de emparejar leirasy hacer mediciones binoculares y monoculares fue de 89. 78 y 37 por ciento respectivamente en niños de tres a cuatro añose de 97, 91 y 66 por ciento respectivamente en niños
The visual acuities of 1140 children between the ages of 2 and 9 years were measured using the Sonksen-Silver Acuity System (SSAS) from a distance of 3 metres. Ordered logistic regression was used to construct smoothly changing age-related reference ranges for the proportions of children at different ages expected to have acuities in each of three ordinal categories. Exponential functions of age fitted the data better than polynomials. The resulting reference ranges can be used to derive the ages at which a given percentage of children achieve each of the acuity cut-offs. However, since it is unlikely that all children will be available for testing at the exact appropriate age, two possible alternatives are introduced and discussed. First, a new ordinal category that would result in a chosen outcome at a pre-selected age is calculated. Secondly, because it may be more feasible to use the current SSAS system whilst varying the distance of measurement, age-related standards showing the distances required to give constant pass-rates with the usual letter-sizes are also presented.
tiredness, which disappeared on reducing the dose to 25 ig a day. Two weeks later he suddenly became severely short of breath and had central chest pain. He had recovered by the time he was brought to hospital.On examination the apex beat could not be palpated, the heart sounds were very quiet, but there was no pericardial rub. A chest x ray film showed a large globular heart suggesting a pericardial effusion (Fig. 1) and the electrocardiogram showed low voltage in every lead with electrical alternans. The pericardiothoracic ,ratio was 0-7 1. An echocardiogram confirmed the presence of a large pericardial effusion (Fig. 2). The patient appeared remarkably well despite such a massive effusion, and since there was no evidence of tamponade medical treatment was continued. The
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