Williams Syndrome

With a prevalence of 1 in 20,000, Williams syndrome (WS) is a rare clinical diagnosis. Nevertheless, it is of considerable interest to clinicians and researchers because of its unique phenotype and the genetic mechanisms that produce it. The pheno-type of WS is almost a mirror image of the phenotype of autism. These children are often outgoing, social, and communicative, and many have a special propensity for music, dance, and simple but highly embellished forms of storytelling. Children with WS are typically small, and they often have pixyish facial features, including a broad forehead, prominent ears, full lips, an upturned nose, and a small chin. IQ averages about 50, but the range is considerable and in some children IQ can be within the normal range. The cognitive profile in WS children is distinctive and includes prominent deficits in visuospatial skills. Relative strengths are seen in more verbal domains, including vocabulary, the social use of language, auditory memory, as well as recognizing and remembering faces (Bellugi et al., 1999). They have a variety of cardiovascular problems.

Genetics. Most children with WS have a large deletion of a segment on the long arm of chromosome 7 (1 to 2 Mb in the 7q11.23 region). The deletion typically occurs as a spontaneous new mutation, a consequence of an unequal crossover event during meiosis in the gametes of one of the parents (Urban et al., 1996). Historically, the cardiovascular problems associated with WS were noted to co-segregate with a gene in the deleted region that produces elastin, an important component of blood vessels, skin, and lung tissues. The absence of elastin is thought to cause the various cardiovascular and kidney problems of WS, as well as diminished joint flexibility. Deficient elastin production probably also causes the characteristic faces of these children. Because elastin is not present in fetal or adult brain tissue, however, deficient elastin production is unlikely to cause the cognitive impairments associated with WS.

A second gene was soon reported in this same deleted region, and its sequence was observed to be nearly identical to a previously identified gene, LIM kinase 1. This second gene is expressed in the brain in high concentrations, and many believe that disturbances in its protein product will prove to be responsible for the cognitive deficits associated with WS. At least 16 contiguous genes, however, are now known to reside in the deleted region. They include CLIP-115, replication factor C subunit, syntaxin 1A, Frizzled 9, and transcription factor 21. Although the role of these genes in WS is unknown, it seems likely that the specific deletion present in any one child will produce a particular constellation of symptoms and a specific clinical phenotype.

Neurobiological Substrate. The regions of the brain where expression of the protein product encoded by the WS gene are altered are thus far unknown, although it is an area of intense investigation. The relative specificity of the cognitive abnormalities in WS suggests, however, that the regions of altered expression will also be relatively specific. A number of imaging studies have suggested that the visuospatial deficits in these children are mediated by anatomical abnormalities in posterior brain systems.

The largest neuroanatomical imaging study of WS has come from a single cohort of young adults studied in a single laboratory. This investigation demonstrated a reduction in overall brain volume in the WS group. Volumes of the cerebellum and superior temporal gyrus are relatively preserved, whereas those of the brainstem are disproportionately reduced; also an increased ratio of volumes of frontal to posterior tissues was noted, and volumes of white matter were reduced to a greater degree than gray matter in the WS group, with the greatest reduction in gray matter observed in the right occipital lobe (Reiss et al., 2000b). Posterior portions of the corpus callosum were disproportionately small, consistent with the overall white matter findings, and the size of the posterior cerebellar vermis was larger in the WS subjects, but only when corrected for the reduction in overall brain size (Schmitt et al., 2001a, b). Subjects with WS also exhibited significantly increased gyrification of the cerebral cortex globally, especially in the right parietal, right occipital, and left frontal cortices (Schmitt et al., 2002). Taken together, this series of imaging studies suggests the presence of anatomical disturbances in dorsal and posterior brain regions of individuals with WS that may account for their relatively specific deficits in visuospatial processing.

The first anatomical MRI study of young children with WS (mean age 21 months) (Jones et al., 2002) reported enlarged cerebellums in the WS group, consistent with the findings in older children and adults. Finally, a magnetic resonance spectroscopy (MRS) study of children and adults with WS detected reduced phosphomonoesters in a frontoparietal region of interest (ROI) and reduced NAA (a marker for the number of viable neurons) in the cerebellum (Rae et al., 1998). Cerebellar NAA levels correlated with measures of verbal and performance IQ. Whether these findings would be detected in other regions of the brain, or whether they are specific to the cerebellum, is unknown.

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