28 February 2020

How does cognition play a role in rare diseases?

Cambridge Cognition's Jemma Clark shares her insight into how cognitive function can be affected in certain rare diseases and why it is important to include cognitive tests in rare disease trials.

Uncommon in aetiology, rare diseases are thought to impact limited populations. However, across the globe an estimated 400 million people are affected by a rare disease.1 Here we consider how cognitive function can be affected in certain rare diseases and why it is important to include cognitive tests in rare disease trials.

What is a rare disease?

A rare disease is a condition that affects less than 5 in 10,000 of the general population. Each individual disease may only affect a handful of people across the globe, sometimes even just a single individual. However, when looked at collectively, there are currently over 6000 known conditions with 250-280 new diseases being discovered annually, affecting an estimated 6-8% of the population.2 To put that into perspective, the cumulative total of people affected by a rare disease exceeds the population of the United States.3

How does cognition play a role in rare diseases?

An estimated 72% of rare diseases have a genetic origin and therefore exert effects from childhood.4 Such an early onset inevitably influences neurodevelopmental processes such as cognition, resulting in a significant number of rare diseases being associated with some form of cognitive dysfunction. Despite this burden, most rare disease research is focused on the physical rather than cognitive aspects of the disease.

Cognitive domains such as executive function are commonly affected in rare diseases from childhood, into adolescence and throughout adulthood. Executive function includes a diverse set of mental skills such as working memory, planning and attention. These skills develop over time and mature in early adulthood. Therefore, impairment in these skills can lead to difficulties initiating, organising and carrying out activities; problem solving and impulsivity. As these skills are required for many day-to-day tasks, significant impairment in executive function can adversely affect an individual’s ability to function in daily life and thus impact their quality of life.

Rare neurodevelopmental conditions are also often associated with social cognitive deficits, commonly presenting as difficulties in social interaction and increased prevalence of conditions such as Autism Spectrum Disorder (ASD)5. Social cognition is defined as the ability to understand, perceive and interpret information about other people and ourselves in a social setting. The processes underlying social cognition such as emotion recognition and social perception allow us to quickly and flexibly perceive and interpret rapidly changing social information and respond appropriately depending on the social context.5

As cognitive dysfunction is common among those with rare diseases and can adversely affect an individual’s functioning and quality of life, it is important to consider assessing cognition in rare diseases.

Key examples of cognitive impact in rare diseases

Phenylketonuria (PKU)

PKU is a rare autosomal recessive disorder of phenylalanine metabolism, caused by mutations in the phenylalanine hydroxylase (PAH) gene. As a result, individuals with PKU cannot effectively break down the amino acid phenylalanine. When untreated, cerebral accumulation of phenylalanine can disrupt typical brain development and result in significant cognitive impairments.6 Previous work has shown that early dietary management, prior to 3 weeks of age, can have beneficial effects on intellectual function in PKU. The majority of adults that commence dietary treatment shortly after birth, generally fall within the normal range of cognitive ability. However, this restrictive diet has to be maintained throughout life and can therefore be difficult to manage in adolescents and adults. Subsequently, some individuals continue to demonstrate cognitive dysfunction throughout their adult lives. Previous studies using CANTAB (Cambridge Neuropsychological Test Automated Battery) have reported that adults with poor dietary control exhibit deficits in working memory, sustained attention and effective impulse control.7 Recently, there have been advancements in the treatments available; a phase 3 clinical trial has demonstrated that an alternative enzyme substitution therapy treatment ‘Pegavaliase’ was able to sustain blood levels of phenylalanine and increase performance in attention.8

Huntington’s disease (HD)

Cognitive compromise can also be an early indicator of a rare disease. Huntington’s disease (HD) is a progressive disorder which usually presents during 30-50 years of age. It is an autosomal dominant disease caused by mutations in the Huntingtin (HTT) gene which is thought to be play a key role in nerve cell damage. One of the key symptoms of HD is cognitive decline which can be detected up to 10 years before the clinical presentation of motor symptoms.9  These changes in cognition are primarily in relation to executive function, i.e. poor planning, lack of cognitive flexibility and memory impairments.10 This has been demonstrated in previous studies detecting executive and spatial impairments in early HD.11 Furthermore, it has been previously demonstrated that a reduction in Dopamine D2 receptors in the striatum in HD is correlated with impaired executive function.12 Despite this knowledge, current treatments for HD only alleviate the symptoms as they manifest. By identifying the onset of cognitive decline in preventative trials at the early stages of the disease, it may be possible to begin treatment at an earlier stage in the disease progression or alternatively develop new approaches to disease management.

22q11.2 Deletion Syndrome

Impaired social cognition has been demonstrated in rare conditions such as 22q11.2 deletion syndrome, where the individual has a missing piece of chromosome 22 called q11.2. Individuals with 22q11.2 often have difficulties discriminating facial emotions when moderately expressed and difficulties perceiving negative emotions such as sadness and anger.13 Moreover, children with 22q11.2 seem to have difficulties linking contextual and socially relevant cues when the scene is visually complex or based on circumstances.13 This syndrome can therefore result in major deficits in social interaction, especially during childhood and highlights why cognition is important to consider from a social perspective. Understanding how rare diseases affect social cognition can help us to better understand how this shapes our development, educational experience and early relationships.

All of these examples highlight how different aspects of cognition are affected in rare diseases and the importance of assessing cognition. Rare disease management often focuses on the physical manifestations of the condition, however there is a lot that can be done to improve quality of life through alleviating the effects of cognitive dysfunction.

Why should we consider cognition when running a rare disease trial?

Clinical trials in rare diseases face many challenges; study design can be difficult given that very little is known about many rare diseases and validated measures of disease progression are often lacking.14  It can also be hard to achieve recruitment targets to adequately power the sample given the rarity of these diseases.

Cognition should be an important efficacy and safety consideration in rare disease trials. Cognitive dysfunction can contribute to neuropsychological, social and behavioural difficulties throughout life. These challenges impact upon employment, relationships, emotional wellbeing and quality of life. Therefore, it is imperative and logical to consider assessing cognition in rare diseases in order to identify associated cognitive dysfunction. Cognitive assessment can also help to highlight any unwarranted cognitive side effects of new medications and provide suitable management strategies for rare diseases.

It is also important to consider cognitive compromise as early indicators of disease. Assessing executive function in ‘at risk’ HD patient populations could help with diagnosis and disease management of HD up to 10 years prior to presentation of motor symptoms. Deficits in executive function could therefore be a potential reliable biomarker of HD in preventative trials.


Assessing cognition can help towards effective diagnosis and long-term disease management in rare diseases. As correct cognitive functioning is crucial for quality of life, this should be considered equally as important as physical and other medical assessments and treatments. Continued efforts to refine clinical trial design, infrastructure and efforts towards research prioritisation will support the future direction of therapeutic development in rare diseases.14


[1] RARE Facts – Global Genes. Retrieved from

[2] Dawkins, H. J. S., Draghia-akli, R., Lasko, P., Lau, L. P. L., Jonker, A. H., Cutillo, C. M., Irdirc, C. (2018). Progress in Rare Diseases Research 2010 – 2016 : An IRDiRC Perspective. CTS Clinical and Translational Science, 11(October 2017), 11–20.

[3] What is a Rare Disease? Retrieved from

[4] Yau,S. (2018, October 29). Why we need to focus on rare disease – individually rare, collectively common. Retrieved from

[5] Morel, A., Peyroux, E., Leleu, A., Favre, E., Franck, N., & Demily, C. (2018). Overview of Social Cognitive Dysfunctions in Rare Developmental Syndromes with Psychiatric Phenotype. Frontiers in Pediatrics: Pediatric Neurology, 6(102).

[6] Ashe, K., Kelso, W., Farrand, S., Panetta, J., Fazio, T., De Jong, G., & Walterfang, M. (2019). Psychiatric and Cognitive Aspects of Phenylketonuria : The Limitations of Diet and Promise of New Treatments. Frontiers in Psychiatry, 10(561), 1–20.

[7] Bik-multanowski, M., Pietrzyk, J. J., & Mozrzymas, R. (2011). Routine use of CANTAB system for detection of neuropsychological deficits in patients with PKU. Molecular Genetics and Metabolism, 102(2), 210–213.

[8] Harding, Amato et al, presented at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium: September 2016, Rome, Italy

[9] Papoutsi M, Labuschagne I, Tabrizi SJ, Stout JC. The cognitive burden in Huntington’s disease: pathology, phenotype, and mechanisms of compensation. Mov Disord. 2014 Apr 15;29 (5):673-83.

[10] Watkins, L. H. A., Rogers, R. D., Lawrence, A. D., Sahakian, B. J., & Rosser, A. E. (2000). Impaired planning but intact decision making in early Huntington’s disease : implications for specific fronto-striatal pathology. Neuropsychologia, 38, 1112–1125.

[11] Lawrence, A. D., Watkins, L. H. A., Sahakian, B. J., Hodges, J. R., & Robbins, T. W. (2000). Visual object and visuospatial cognition in Huntington ’ s disease : implications for information processing in corticostriatal circuits. Brain, 123, 1349–1364.

[12] Lawrence, A. D., Weeks, R. A., Brooks, D. J., Andrews, T. C., Watkins, L. H. A., Harding, A. E., … Sahakian, B. J. (1998). The relationship between striatal dopamine receptor binding and cognitive performance in Huntington’s disease. Brain, 121, 1343–1355.

[13] Norkett, E. M., Lincoln, S. H., Gonzalez-heydrich, J., & Angelo, E. J. D. (2017). Social cognitive impairment in 22q11 deletion syndrome : A review. Psychiatry Research, 253(November 2016), 99–106.

[14] Augustine, E. F., Adams, H. R., & Mink, J. W. (2013). Clinical Trials in Rare Disease: Challenges and Opportunities. J Child Neurol, 28(9), 1142–1150.

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Jemma Clark

Cambridge Cognition

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