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Williams syndrome

Dr. Simon Moss

Overview

Williams syndrome, sometimes called Williams-Beuren syndrome (Pober & Morris, 2007), is a rare genetic disorder. Individuals with Williams syndrome tend to be friendly and cheerful as well as enjoy music. However, they will usually demonstrate particular intellectual deficits and learning disabilities as well as difficulties with language and various tasks that demand visual, spatial, and motor skills (Hocking, Rinehart & Bradshaw, 2008). They may, for example, experience problems walking down stairs or negotiating uneven surfaces (van der Geest et al., 2005& Withers et al., 1996). The likelihood of cardiovascular problems is also elevated (for a review, see Pober & Morris, 2007). They also do not process intonation effectively.

Walking and talking tend to be delayed. Individuals do not tend to walk until they are approximately 21 months of age. They do not tend to express any words until 1.5 to 2 years of age.

Stromme, Bjornstad, and Ramstad (2002) examined the prevalence of this genetic disorder. They estimated that Williams syndrome is observed once in every 7500 to 20000 births.

Cause

Williams syndrome can be ascribed to a mutation on a particular chromosome, 7q11.23. This mutation is not inherited from parents, and is thus called de novo. Furthermore, the mutation is a microdeletion--that is, the loss of a minute section of the chromosome, too small to be identified by regular light microscopes, but only detectable by molecular chromosome analysis, DNA analysis, or high-resolution chromosome banding (see Tassabehji, 2003).

This deleted section of chromosome includes almost 30 genes. One of these genes, called ELN codes elastin, a protein that is vital to the formation of connective tissue and the cardiovascular system. Other genes, such as CLIP2, may underpin some of the cognitive difficulties.

Several tests can be administered to diagnose Williams syndrome. For example, the fluorescent in situ hydridisation test for the gene elastin represents one possible source of diagnosis, particularly if coupled with clinical observations from a relevant medical practitioner.

Signs of Williams syndrome

Appearance

Several facial features are common in individuals with individuals with Williams syndrome. Their nasal bridge is relatively low on their face. Furthermore, their face seems somewhat elfin.

Social and emotional characteristics

In general, individuals with Williams syndrome tend to be friendly. They feel very comfortable approaching strangers and interact cheerfully and excitedly. During social interactions, people with Williams syndrome will often focus appreciably on the eyes of other people (Riby & Hancock, 2008).

Despite their ease in social settings, individuals with Williams syndrome may experience elevated levels of anxiety in other contexts. For example, Dodd and Porter (2011) examined the distribution of attention in Williams syndrome and people with no diagnosis of the same age. The attention of people with Williams syndrome was especially biased towards threatening scenes, arguably underpinned by elevated levels of amygdala activation. Hence, their attention seems to be directed to nonsocial threats but not to social threats, like angry faces.

Furthermore, although they enjoy social interactions, people with Williams syndrome do not always process the intonations and inflections of other individuals very well. In addition, their own intonations and inflections are not always typical and informative.

To investigate the mechanisms that underpin this tendency, Pinheiro, Galdo-Alvarez, Rauber, Sampaio, Niznikiewicz, and Goncalves (2011) examined electrophysiological responses to neutral, happy, and angry utterances in people with Williams syndrome as well as in people without a diagnosed disorder, matched on age, gender, and laterality. Some of the utterances were intelligible& other utterances were unintelligible. The task of participants was to decipher the emotion that underpinned each utterance.

Event-related potentials did differ between the two groups. The N100 was reduced in people with Williams syndrome for emotional utterances with intelligible content. The P200 was more positive for angry or happy utterances with intelligible content. The N300 was reduced for both intelligible and unintelligible speech. These findings indicate that some difficulties in processing the intonations and inflections in speech can be ascribed to early auditory processes. Furthermore, because differences between the two groups on the N100 and P200 were observed only when the speech was intelligible, top-down processes may also be impaired.

Motor skills

As Tsai, Wu, Liou, and Shu (2008) demonstrated, motor skills tend to be delayed or impaired in people with Williams syndrome. These authors administered tests of psychomotor development, such as the Bayley Scales of Infant Development and the Bruininks-Oseretsky Test of Motor Proficiency. The sample comprised young children, aged between 8 and 29 months, as well as older children and adolescents, aged between 82 and 210 months. Both samples showed some impairments in motor performance, approximating the lowest 10% of the population. For example, these children and adolescents exhibited difficulties with dexterity and speed of their arms and hands. They also manifested difficulties with responding effectively to visual information.

Similarly, in a study conducted by Atkinson et al. (1997), children were asked to post a card into slots of various shapes. Relative to their peers, these children could not as readily orient the card suitably to complete this task successfully.

Furthermore, Hocking, Rinehart, McGinley, Moss, and Bradshaw (2011) reported a study in which adults with Williams syndrome, Down syndrome, or no diagnosed disorder completed the Fitt's aiming task. That is, two circles were presented on a touch screen. The size of these circles and the distance between these circles was varied. Participants needed to shift a stylus between these circles.

Relative to the other groups, as the task became more difficult, adults with Williams syndrome decelerated to the targets more slowly. Movement planning time was also prolonged in Williams syndrome and Down's syndrome. Arguably, the individuals cannot as readily compare the expected and anticipated sensory consequences of movement to optimize adjustments.

Gait

The gait or walking style of individuals with Williams syndrome has also been investigated (see Hocking, McGinley, Moss, Bradshaw, & Rinehart, 2010& Hocking, Rinehart, McGinley, & Bradshaw, 2009). In these studies, people with Williams syndrome, Down's syndrome, or no diagnosed disorder walked across a specific walkway several times. The kinematics of each walk were measured.

Specifically, in one study, participants were encouraged to walk with a stride length that exceeds their preferred stride length by 20%. They either received tangible cues--lights--to facilitate this task. Alternatively, they were asked to maintain this stride length without these cues (Hocking, McGinley, Moss, Bradshaw, & Rinehart, 2010). With the cues, individuals with Williams syndrome reduced the speed of their walking relative to people with no diagnosed disorder, perhaps reflecting dysfunction in the cerebellum or basal ganglia. Without the cues, individuals with Williams syndrome also reduced speed as well as varied their speed significantly across trials, possibly reflecting dysfunction in executive functioning and thus fronta-parietal regions.

Sleep quality

Annaz, Hill, Ashworth, Holley, and Karmiloff-Smith (2011) examined the sleep quality of children with Williams syndrome. Specifically, parents completed surveys that gauged the sleep habits of their children, 64 of whom had been diagnosed with Williams syndrome and 92 of whom had not been diagnosed with any disorder, matched on age. Parents reported elevated levels of sleep anxiety, resistance to bed, night walking, and daytime sleepiness in children with Williams syndrome& indeed, 97% of these parents reported some of these difficulties. These sleep difficulties could magnify the learning impairments in these children. Some of the cognitive difficulties in this population could be, at least partly, ascribed to sleep impairment.

Perceptual characteristics

Some sensory and perceptual characteristics have also been observed in people with Williams syndrome. These individuals are especially sensitive to particular sounds, called hyperacusis, and even exhibit an aversion to loud sounds in general, called phonophobia. A malfunctioning auditory nerve may underpin some of these tendencies (Gothelf, Farber, Raveh, Apter, & Attias, 2006).

Mechanisms that underpin deficits

Dysfunction in the dorsal visual pathway

Some dysfunction has been observed in the dorsal visual stream but not in the ventral visual stream. The dorsal stream is represented in the occipital-parietal regions of the cortex. The ventral stream is represented in the temporal-parietal regions. The dorsal stream underpins unconscious spatial awareness, such as avoiding obstacles on the ground. This stream integrates spatial information. The ventral stream represents conscious identification and analysis of objects, such as the recognition of faces or objects.

For example, if individuals need to reach between two objects, they will not avoid obstacles effectively if this dorsal stream is damaged. However, they can readily indicate the midpoint of a line (see Rice, Edwards, Schindler, et al., 2008& Schindler, Rice, McIntosh, et al., 2004). In contrast, if the visual stream is damaged, the reverse pattern is observed: Individuals cannot indicate the midpoint of a line but will nevertheless avoid obstacles while reaching between two objects. Similarly, if the ventral stream is impaired, individuals can avoid obstacles while walking, although their perceptual judgments of the height or size of this obstacle are impaired (Patla & Goodale, 1997).

Evidence indicates that only the dorsal visual stream is impaired in Williams syndrome. Imaging studies indicate structural abnormalities in these regions: the volume of gray matter and sulcal depth is limited. Furthermore, functional MRI studies indicate limited activation of these regions during visuospatial tasks (Meyer-Lindenberg et al., 2004).

Dysfunction in the cerebellum

Abnormalities in the cerebellum might also be likely in people with Williams syndrome (e.g., Rae et al., 1998). The neocerebellar lobules are enlarged (Reiss et al., 2000)& N-acetylaspartate is elevated during visuomotor tasks (Rae et al., 1998). These abnormalities could also compromise locomotion that is guided by visual cues.

References

Annaz, D., Hill, C. M., Ashworth, A., Holley, S., & Karmiloff-Smith, A. (2011). Characterisation of sleep problems in children with Williams syndrome. Research in Developmental Disabilities, 32, 164-169.

Atkinson, J., King, J., Braddick, O., et al. (1997). A specific deficit of dorsal stream function in Williams syndrome. Neuroreport, 8, 1919-1922.

Atkinson, J., Braddick, O., Anker, S., Curran, W., Andrew, R., Wattam-Bell, J., & Braddick, F. (2003) Neurobiological models of visuo-spatial cognition in young Williams syndrome children: Measures of dorsal-stream and frontal function. Developmental Neuropsychology, 23, 139-172.

Bellugi, U., Lichtenberger, L., Mills, D., Galaburda, A., Korenberg, J. R. (1999). Bridging cognition, the brain and molecular genetics: evidence from Williams syndrome. Trends in Neuroscience, 22, 197-207. doi:10.1016/S0166-2236(99)01397-1

Boddaert, N., Mochel, F., Meresse, I., et al. (2006). Parieto-occipital gray matter abnormalities in children with Williams syndrome. Neuroimage, 30,721-725.

Chapman, C. A., du Plessis, A., & Pober, B. R. (1995). Neurologic findings in children and adults with Williams syndrome. Neurology, 10, 63-65.

Chiang, M. C., Reiss, A. L., Lee, A. D., Bellugi, U., Galaburda, A.M., Korenberg, J. R., Mills, D. L., Toga, A. W., & Thompson, P. M. (2007). 3-D pattern of brain abnormalities in Williams syndrome visualized using tensor-based morphometry. Neuroimage 36, 1096-1109.

Dodd, H. F., & Porter, M. A. (2011). There's that scary picture: Attention bias to threatening scenes in Williams syndrome. Neuropsychologia, 49, 247-253.

Eckert, M. A., Hu, D., Eliez, S., Bellugi, U., Galaburda, A., Korenberg, J., Mills, D., & Reiss, A. L. (2005). Evidence for superior parietal impairment in Williams syndrome. Neurology, 64,152-153.

Elliott, D., Welsh, T. N., Lyons, J., Hansen, S., & Wu, M. (2006). The visual regulation of goal- directed reaching movements in adults with Williams syndrome, Down syndrome, and other developmental delays. Motor Control, 10,34-54.

Gothelf, D., Farber, N., Raveh, E., Apter, A., & Attias, J. (2006). Hyperacusis in Williams syndrome: Characteristics and associated neuroaudiologic abnormalities. Neurology, 66, 390-395. doi:10.1212/01.wnl.0000196643.35395.5f

Hocking, D. R., Bradshaw, J. L., & Rinehart, N. J. (2008) Fronto-parietal and cerebellar contributions to motor dysfunction in Williams syndrome: A review and future directions. Neuroscience and Biobehavioral Reviews, 32, 497-507.

Hocking, D. R., Rinehart, N. J., McGinley, J. L., & Bradshaw, J. L. (2009). Gait function in adults with Williams syndrome. Experimental Brain Research, 192, 695-702.

Hocking, D. H., McGinley, J. L., Moss, S. A., Bradshaw, J. L., & Rinehart, N. J. (2010). Effects of external and internal cues on gait function in Williams syndrome. Journal of the Neurological Sciences, 291, 57-63.

Hocking, D. H., Rinehart, N. J., McGinley, J. L., Moss, S. A., & Bradshaw, J. L. (2011). A kinematic analysis of visually-guided movement in Williams syndrome. Journal of the Neurological Sciences, 301, 51-58.

Jernigan, J. L., Bellugi, U., Sowell, E., Doherty, S., & Hesselink, J. R. (1993). Cerebral morphologic distinctions between Williams and Down syndromes. Archives of Neurology, 50, 186-191.

Lenhoff, H. M., Wang, P. P., Greenberg, F., & Bellugi, U. (1997). Williams syndrome and the brain. Scientific American, 277, 68-73.

Martens, M. A., Wilson, S. J., & Reutens, D. C. (2008). Research review: Williams syndrome: a critical review of the cognitive, behavioral, and neuroanatomical phenotype. Journal of Child Psychology and Psychiatry, 49, 576-608. doi:10.1111/j.1469-7610.2008.01887.x

Meyer-Lindenberg, A., Kohn, P., Mervis, C. B., Kippenhan, J. S., Olsen, R. K., Morris, C. A., Berman, K. F. (2004). Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron, 43, 623-631.

Mervis, C. B., & Klein-Tasman, B. P. (2000). Williams syndrome: Cognition, personality, and adaptive behaviour. Mental Retardation and Developmental Disability Research Reviews, 6, 148-158.

Patla, A. E., & Goodale, M. A. (1996). Obstacle avoidance during locomotion is unaffected in a patient with visual form agnosia. Neuroreport, 8, 165-168.

Pinheiro, A. P., Galdo-Alvarez, S., Rauber, A., Sampaio, A., Niznikiewicz, M., & Goncalves, O. F. (2011). Abnormal processing of emotional prosody in Williams syndrome: An event-related potentials study. Research in Developmental Disabilities, 32, 133-147.

Pober, B. R., & Morris, C. A. (2007). Diagnosis and management of medical problems in adults with Williams-Beuren syndrome. American Journal of Medical Genetics Part C: Seminars in Medical Genetics,145, 280-290.

Riby, D. M., & Hancock, P. J. (2008). Viewing it differently: Social scene perception in Williams syndrome and Autism. Neuropsychologia, 46, 2855-2860. doi:10.1016/j.neuropsychologia.2008.05.003.

Rice, N. J., Edwards, M. G., Schindler, I., et al. (2008). Delay abolishes the obstacle avoidance deficit in unilateral optic ataxia. Neuropsychologia, 46,1549-1557.

Schindler, I., Rice, N. J., McIntosh, R. D., et al. (2004) Automatic avoidance of obstacles is a dorsal stream function: Evidence from optic ataxia. Nature Neuroscience, 7, 779-784.

Stromme, P., Bjornstad, P. G., & Ramstad, K. (2002). Prevalence estimation of Williams syndrome. Journal of Child Neurology, 17, 269-271.

Tassabehji, M. (2003). Williams-Beuren syndrome: A challenge for genotype-phenotype correlations. Human Molecular Genetics, 12, R229-R237.

Trauner, D. A., Bellugi, U., & Chase, C. (1989). Neurologic features of Williams and Down syndromes. Pediatric Neurology, 5, 166-168.

Tsai, S., Wu, S., Liou, Y., & Shu, S. (2008). Early development in Williams syndrome. Pediatrics International, 50, 221-224.

Van der Geest, J. N., Lagers-van Haselen, G. C., van Hagan, J. M., Brenner, E., Govaerts, L.C. P, de Coo, I. F. M., & Frens, M. A. (2005). Visual depth processing in Williams-Beuren syndrome. Experimental Brain Research, 166, 200-209.

Withers, S. (1996). A new clinical sign in Williams syndrome. Archives of Disease in Children, 75, 89.






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Last Update: 7/18/2016