Study On Clinical Diagnosis And Cognitive Function Of Williams Syndrome

Williams syndrome (WS) is a microdeletion syndrome caused by haploinsufficiency of genes at 7q11.23. The majority of the deletions span a genomic region of 1.5 Mb～1.6 Mb. Williams syndrome is a complex developmental disorder characterized by a distinctive set of facial features, cardiovascular anomalies, a unique personality, mild to moderate mental retardation and a characteristic cognitive profile. The WS uneven cognitive profile is a striking one, characterized by strengths in certain complex faculties (language, music, face processing, and sociability) alongside weaknesses in visuospatial construction, conceptual reasoning, problem solving and arithmetic. Many studies on cognition of WS have been reported in the west countries over past years, but its specific cognitive disorders have not been elucidated yet. In China, cognitive dysfunctions of WS have not been reported before. This project is to explore the clinical characteristics of WS patients and investigate the diagnostic criteria of Williams syndrome; the definite WS children were examined for their features of visual attention and executive function through visual search. Specialcognitive handicap of WS children were identified in contrast to the Down syndrome children and healthy chronological age- and mental age-matched children. The project will be helpful to provide evidence for investigating the neurocognition and pathway in brain development of genetic mental retardation, as well as exploring the complicated relation between gene, neurology and cognition.Part one Study on clinical diagnosis of Williams syndromeMethods WS clinical diagnosis score table proposed by American Academy of Pediatrics and WS phenotype measuring scale proposed by Lowery were used for analyzing the clinical data of WS suspects from clinical symptoms. Peripheral blood was collected for chromosome karyotype analysis and fluorescence in situ hybridization (FISH) to make sure the final diagnosis. Growth and development appraisal, blood pressure, echocardiography and laboratory examination such as blood calcium and so on were measured in the definite WS patients, in order to get more information of WS clinical characteristics.Results From July 2004 to December 2006,71 WS suspects were found by clinical screening. Microdeletion of gene including ELN and LIMK1 on the 7th chromosome was found in 40 patients through FISH detection, the positive percentage was 56.3%. There are 36 cases whose scores exceeded 4 by Lowery phenotype measuring scale and 35 cases whose scores exceeded 5 by WS clinical diagnosis score table proposed by American Academy of Pediatrics. In all of the 40 patients (100%), special facial features including long philtrum, thick lip, broad mouth, swelling fossa orbitalis andcolplanate dorsum nasi were detected. At least one phenotype of cardiovascular system diseases was found in 33 patients (82.5%), including 18 cases of supravalvular aortic stenosis (54.5%) in which 4 cases were complicated with peripheral pulmonary artery stenosis, 3 cases with patent ductus arteriosus (9.1%) (1 was associated with other malformations), 1 with isolated pulmonary stenosis (3.0%), 4 with hypertention (12.1%) in which 2 were associated with aortic coarctation, 2 with mild aortic valve regurgitation (6.1%) and 6 with mild to moderate mitral valve regurgitation (18.2%). All of the patients have growth retardation. 31 children showed mental retardation through Wechsler intelligence scale for children or Peabody picture vocabulary test (PPVT), the other 9 patients didn't undertake intellectual test because of small age below 2 years and 1 month. 33 children showed overfriendliness (89%). 18 cases complicated with inguinal hernia (45%).Conclusions The suspects whose score exceeded 4 by Lowery phenotype measuring scale or exceeded 5 by WS clinical diagnosis score table proposed by American Academy of Pediatrics can be diagnosed as Williams sysdrome. FISH which is direct-viewing and easy to be understood is a credible method for clinical differential diagnosis. WS children always have special facial features, and usually complicated with cardiovascular disease and growth retardation. Most of them have mental retardation, and there is also a high incidence of patients complicated by inguinal hernia.Part two Study on cognitive function of WSMethods Components of visual attention were examined through visual search. The part of selective attention included three single-task visual search tests. In the first one, subjects were told to find out the special black upright ellipses around many non-targets with different colors or shapes or directions; the second and the third tasks were also to find out the red horizontal ellipses; but in the third task, equal number of red horizontal ellipses flatter than the targets were added. When they found out the 20th target or click 50 times the task ended. And the correct hits, total clicks, mean time per hit, mean distance per hit and four-type errors were recorded by program. The mean measure of task one and task two were serviced as the measure of selective attention. The part of switching attention held one test. Subjects were told to find out the special black upright ellipses and the red horizontal ellipses sequentially, with many non-targets similar to selective tasks. When they found out the 20th target or click 50 times the task ended. And the correct hits, total clicks, mean time per hit, mean distance per hit and five-type errors were recorded by program. Sustained attention held one test. Subjects were told that just those shapes with a yellow light ring were the targets, but they didn't know when the ring would arrive, they should keep their attention and waiting for it. The task had 16 targets, any click in non-targets and click in targets while the ring absent recorded as false alarm. And the correct hits, false alarms, mean time per hit, mean distance per hit and some type errors were recorded by program. Using Wilding monster sorting test, which is similar to the Wisconsin card sorting test, we observed the ability to form concept, sustain set andthe ability to shift attention from one set to another when they are solving a problem. First, showed them four monster kings with different numbers, colors, and shapes. Then asked them to sort 64 monsters one by one to the king based on either of the characteristics. And the king will smile if they did correctly. After 10 correct sortings, the rule to sort was changed and we didn't let it known to the subjects. There were 6 categories. The correct number, the categories they solved, the number of repeat errors, repeat corrects and errors after the set switching were recorded.Results 1. Results of selective attention: we got the data of 21 WS patients, 45 healthy chronological age-matched children, 25 DS patients and 41 healthy mental age-matched children. When the task was simple (with few similar distractors), compared with healthy chronological age-matched children, the correct reaction rate of WS patients was lower (P<0.01), the reaction time was slower (P<0.01) and search distance was longer (P<0.01). Compared with DS patients, only the reaction time was slower (P<0.05). Compared with healthy mental age-matched children, there isn't any statistical difference in correct reaction rate, reaction time and search distance (P>0.05). When the non-targets which were very similar to the targets were added, the correct reaction rates of all these four groups of children were cut down (P＜0.01), the reaction time was slower (P<0.01), and the reaction distance was longer (the group of healthy mental age-matched children didn't have statistical difference in the reaction distance). All of these index were significantly different between WS patients and healthy mental age-matched children and chronological age-matched children (P＜0.01). The result showed that correct reaction rate was lower, reaction time was slower and reaction distance was longer in the WS children; however, Children withWS and DS did not differ significantly in the above indexes (P>0.05). Analysis on error types of selective attention: when there was few similar distractors, the error types of shape were significantly higher in WS group compared with healthy chronological age-matched children (P＜0.01); and also higher when compared with DS group and healthy mental age-matched children, but it didn't have statistical difference (P>0.05). WS children made fewer other errors than healthy mental age-matched children (P<0.01). When the added non-target was very similar to the target, the error rate of the shape was higher in WS group than in both of children at chronological age- and metal age-matched (P<0.01), but there was no difference in DS group. 2. The results of switching attention: we got the data of 21 WS patients, 30 healthy mental age-matched children, 24 DS patients and 45 healthy chronological age-matched children. Compared with healthy chronological age-matched children, the error rates of type of shape, colour, and switching were all significantly higher in WS group (P<0.01). Compared with healthy mental age-matched children, switching error rate was higher (P＜0.01). But there was no significant difference between WS group and DS group. 3. The results of sustained attention: we got the data of 22 WS patients, 40 healthy mental age-matched children, 24 DS patients and 45 healthy chronological age-matched children. Compared with chronological age-matched children, correct rate was lower and error hits were higher in WS group (P＜0.01), but there wasn't any difference between DS group and mental age-matched children (P>0.05). Compared with healthy chronological age- and mental age-matched children, search time was longer in WS group (P＜0.01) whose speed was slower, but there was no difference in DS group. 4. The results of WMST: we got the data of 20WS patients, 35 healthy mental age-matched children, 25 DS patients and 45 healthy chronological age-matched children. Compared with healthy chronological age-matched children, the correct reaction number and categories were fewer, level of conceptualization was lower (P＜0.01), and repeat errors rate was higher (P<0.01). Compared with DS group, repeat errors rate was aslo higher (P＜0.01). Compared with mental age-matched children, the correct categories were fewer, level of conceptualization was lower (P＜0.01), and repeat errors rate was higher (P<0.01). Conclusions The development of selective attention, switching attention and sustained attention in WS children was overall delayed. There were special deficits that didn't match with mental age in visual perceptual and discrimination skills, attention shifting and frontal executive function in children with WS. These probably result from different pathway in brain development compared to healthy children. Compared with DS children, the ability of cognitive diversion is weak in WS children.