What Is Known
- Adult patients experiencing Wilson disease may have more or less severe cognitive impairment.
What Is New
- The intellectual abilities of children with Wilson disease are globally preserved.
- Those with a liver form may have poor working memory capacity.
- Those with a neurological form (motor symptoms and cerebral lesions) experience more extensive cognitive problems.
- Children with Wilson disease may have special educational and rehabilitation needs, such as requiring speech therapy.
Wilson disease (WD) is a rare autosomal recessive disorder affecting copper metabolism that results in an accumulation of copper in organs such as the liver and brain. The signs of hepatic dysfunction that are consistently found in WD may be accompanied by brain lesions—predominantly located in the basal ganglia, brain stem, mid-brain, prefrontal cortex, and cerebellum (1)—and neuropsychiatric symptoms that include motor, cognitive, and behavioral impairments. The cognitive profile of adults experiencing the neurological form of WD is dominated by executive impairment, a slowing of visual motor speeds and a poor learning rate (1–4). Recent reports have indicated that patients with the liver form of WD—that is to say, patients without lesions and motor symptoms typical of cerebral copper accumulation—may also experience executive and attentional impairments, presumably due to mild hepatic encephalopathy (4–6). In other words, cognitive impairment in WD may be due to both copper toxicity affecting the brain and liver failure (7).
Although the initial manifestations of WD may appear during childhood (8), the cognitive abilities of pediatric patients have never yet been described in a case series. In particular, it is not clear whether cognitive impairment is due to the long-term effects of dysfunctional copper metabolism or its presence early in life. The present study was designed precisely to fill this gap by reporting on the general cognitive abilities of children experiencing both liver and neurological forms of WD.
Methods are available online as Supplemental Digital Content (http://links.lww.com/MPG/A748).
In this case series, 21 patients with WD (Table 1) had undergone the Wechsler Intelligence Scale for Children - fourth edition (WISC-IV) (9). Most of the index scores were within the normal range (Fig. 1A). Interestingly, individual analyses revealed that the index scores were highly heterogeneous when compared with the general population. It was in particular noted that the working memory index (WMI) score was abnormally lower than the verbal comprehension index (VCI) score in >45% of patients with the liver form of WD (Table 2).
Group analyses (Fig. 1B) confirmed the heterogeneity of index scores in patients with the liver form (F[3, 48] = 20.96; P < 0.001). More precisely, the WMI score (median ± interquartile range: 94 ± 12) was lower than the VCI (120 ± 20; P < 0.001) and perceptual reasoning index (111 ± 17; P = 0.001) scores among patients in the LIVER group. Other comparisons did not reach the threshold of significance. Age-scaled index scores were also lower in patients with neurological WD than in those with the liver form of WD. The exact probability of the 2 groups differing was 0.001 for VCI (NEUR: 85 ± 4.75 vs LIVER: 120 ± 20), 0.001 for perceptual reasoning index (NEUR: 81.5 ± 8.75 vs LIVER: 111 ± 17), 0.049 for processing speed index (NEUR: 85.5 ± 9.5 vs LIVER: 109 ± 15), and 0.018 for WMI (NEUR: 80.5 ± 11.25 vs LIVER: 94 ± 12).
The present study was designed to generate a picture of the general cognitive abilities of children with WD. In this series, the WISC-IV (9) scores of most children with WD were within the normal range, confirming the global preservation of their intellectual abilities. A finer-grained analysis, however, suggested that slight specific impairments were common.
First of all, children with the neurological form scored less on all indexes than those with the liver form of WD. It is possible that extrapyramidal signs or dystonia might have contributed to the lower scores of written or timed subtests. This, however, could not account for all the difficulties experienced by children with the neurological form because their performance in the verbal comprehension tests were also poorer than those with the liver form, and this index is wholly unaffected by motor abilities or time constraints. These data, therefore, indicate that lesions related to cerebral copper accumulation were responsible for both the motor and cognitive impairment of children experiencing WD.
Secondly, and most striking, was the discrepancy between the 4 WISC-IV indexes in children with the liver form of WD. Without falling into the abnormal range, their verbal working memory capacities were indeed consistently poorer than their verbal and visual-spatial reasoning. It is worth noting that working memory weakness can have a negative effect on numerous cognitive functions. For instance, working memory capacity is strongly linked to attentional and executive functioning, which in turn is responsible for coordinating goal-directed behavior (10). These problems have indeed been reported in adults (4–6) and children with other severe hepatic impairments or portal hypertension (11,12). Another example concerns the development of language abilities. It is well known that children experiencing specific language impairment and dyslexia often experience working memory difficulties (13,14). Language impairment has been described precisely in infants with other chronic hepatic diseases (15). In the present case series, a relatively high proportion of the children had a history of slight or more severe language difficulties (Table 1). Further studies need to confirm this point, but it is tempting to suggest that working memory difficulties may be linked to a certain delay in language development in the context of WD. Clues are therefore accumulating to suggest mild cerebral dysfunction among pediatric patients with just the liver form of WD.
Thirdly, the data reported here throw light on the functional effect of cognitive impairment in children with WD. The frequency of repetition of grades (38% in the present case series, see Table 1) did not differ from that seen in the general French population (16). Normal schooling remains possible in most of the cases, but additional specialized support is sometimes required, especially for children with the neurological form of WD.
The data reported here now need to be confirmed by further extensive neuropsychological studies. Nevertheless, they clearly argue for early mild cerebral dysfunction in the liver form and more general cognitive impairment in the neurological form of WD. In clinical practice, a close examination of cognitive capacities, and particularly working memory, is thus warranted in all children experiencing WD. This psychometric assessment would improve patient care by revealing those children with special educational and rehabilitation needs such as speech therapy.
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