Previous research had shown that people with galactosemia have a lower well-being and psychosocial development than the control population and people with some other metabolic diseases [9, 10, 15]. Two previous research also showed some deficits in emotion recognition [24, 25] and theory of mind [25]. We wanted to replicate these findings and to deepen the description of possible deficits in these processes. We also investigated whether social cognition processes would be related to psychosocial development and mental well-being.

We hypothesised that our participants with galactosemia would show deficits in social cognition processes compared to control participants. We tested our hypothesis by comparing the scores of 11 patients with galactosemia and 31 control individuals using various neuropsychological assessment tools. We indeed found deficits in four validated social cognition measures: we showed that galactosemia is associated with deficits in cognitive theory of mind, and in affective theory of mind, in basic and complex emotion recognition. Finally, we found for these patients a positive link between emotion recognition and psychosexual development and a positive link between affective theory of mind and social development.

Specific features of theory of mind in our sample with galactosemia

We used a well-validated tool to assess the cognitive theory of Mind [27]. Participants with galactosemia showed deficits in the 2nd order ToM but not in the 1st order ToM. These deficits showed even though we controlled participants correctly understood the stories. Our participants with galactosemia are thus able to build a 1st order theory of mind which is fundamental to basic social relations. A good first-order theory of mind helps adapting to an interlocutor notably when the situation is one-to-one. The 2nd -order theory of mind is more complex, notably because it requires more executive functions (i.e., working memory) and metacognition [39]. Deficits in the second-order theory of mind may hinder interactions when there is a third person involved. Being able to infer what a conversation partner knows/believes about a third party is important because one can predict and explain the behaviour of conversation partners based on what they know/feel. When the social situation exceeds the ability to deal with the different points of views, individuals may feel uneasy and overwhelmed leading to shyness and avoidance [12, 14]. Future research is needed to test whether the social avoidance observed in the galactosemia phenotype could be explained by deficits in second-order theory of mind.

We found that participants with galactosemia globally underperformed on the affective Theory of Mind task compared to controls. When digging deeper, we found they were able to differentiate situations with and without faux-pas, they correctly detected when a ‘faux-pas’ happens, they understood the beliefs of the protagonists (related to their good performance in 1st -order cognitive theory of mind), they were able to explain what was inappropriate and the intentions of the characters: they seem to be aware of social rules and conventions. Future research involving specific tests of social knowledge like the Test of Situations [40] would be interesting to be able to establish the affective theory of mind ability of people with galactosemia, controlling for their social knowledge. However, our participants had significantly more difficulties explaining what the feelings of the characters were. This indicates that they may not be able to show an appropriate reaction to the emotions of the social partner, not being able to empathise with them. This result replicates the deficit in affective empathy found by Hermans et al. [25]. Future replication with other mixed tests of theory of mind, like the combined stories test [40] would be interesting to precisely describe the types of mental states (i.e., epistemic, affective, or volitional mental states) that are difficult to infer for people with galactosemia. This knowledge is fundamental to tailor interventions improving social cognition skills in that population.

We found that, apart from the cognitive and affective ToM performance, participants with galactosemia had deficits in understanding the stories. We believe this is related to the global cognitive deficits found in galactosemia and the large distribution in our sample is congruent with the diversity usually found in cognitive tasks for people with galactosemia. We did not have the means to measure the IQ of our participants and we wonder whether the ability to understand the stories in the ToM15 and Faux-Pas tasks could be a proxy of intellectual level. Although it is reasonable to claim that the intellectual level would predict the understanding of the scenarios, more research is needed to assess how much of a proxy the understanding of scenarios can be to the intellectual level. Future research involving measures of both intellectual functioning and social cognition would help disentangle the respective impact of these domains on the deficits in social functioning. Hermans et al. [25] found little correlations between social cognition and intellectual functioning except with global intelligence. A large sample is required to have enough statistical power to perform multiple regressions.

Specific features of emotion recognition deficits in our sample with galactosemia

We used two different tools to assess emotion recognition. The first measure was a dynamic and timed task with basic facial emotion expressions. Participants with galactosemia showed deficits in that task, with a major impairment in fear, anger and disgust. Korner et al. [24] found specific deficits in anger, disgust, fear and surprise. Hermans et al. [25] found specific deficits in disgust, fear, happiness, and sadness. The recognition of disgust and fear was consistently found to be impaired in the three studies. Recognition of anger was found to be impaired in two studies. All three studies used different tasks and stimuli, with their own strengths and weaknesses, which may explain the differences between emotions. We think it is clear that galactosemia is associated with emotion recognition deficits but the type of emotions impaired is yet to confirm. A large multinational study and a meta-analysis could provide solid knowledge.

However, given the deficit in visual information processing associated with galactosemia [24], one could argue that participants with galactosemia have had issues mostly because the stimuli is very short. It might not be emotion recognition per se that is impaired but more generally rapid visual information processing (including emotions). However, the complex emotion recognition task we used, which was not timed, gives us a hint that emotion recognition is impaired per se. Participants with galactosemia underperformed and their performance was not increased when they spent longer time on the task. It is thus not only a problem of processing speed. We acknowledge that the Reading the Mind in the Eyes Test has another complexity related to language that may have inflated the deficits found in our participants though people with galactosemia do not usually have issues with receptive language and vocabulary. However, we note that some participants found it difficult and future research using the Child RMET (the same task with adapted vocabulary) would be more appropriate to confirm our findings.

Consistent with models of social cognition [19], we found few correlations between the different social cognition measures, among the galactosemia group, indicating that they are distinct dimensions and processes.

Importantly, the ToM and emotion recognition deficits are hurdles to smooth social interactions that require remediations. There are a growing number of evidence-based remediations for social cognition, targeting theory of mind and/or emotion processing (i.e., ToMRemed, RC2S) and could thus be indicated for patients with galactosemia. We contend that early referral to social cognition and mental health specialists should be included in the care and follow-up guidelines for galactosemia.

Well-being and psychosocial development

Previous research showed that patients with galactosemia were delayed in their psychosocial development and had lower mental health than the general population. We tried to replicate these findings using the same psychosocial development measure as Maurice-Stam et al. [15] and a validated mental health tool (the WEMWBS). We also intended to test whether psychosocial and mental health are related to social cognition processes.

Consistent with previous research, we found that participants with galactosemia were significantly delayed compared to control participants in psychosexual development. For participants with galactosemia, their psychosexual development was highly correlated with their (impaired) basic emotion recognition performance and (impaired) understanding of the ToM15 stories. It appears that this social cognition process (emotion recognition) is related to psychosexual development in our sample and future research is needed to replicate and strengthen this finding. Also, another measure of intimate relationship quality (marital status, number of partners, length of relationships, etc.) might be more informative than simply the age of intimacy onset.

We found marginally lower mental health in participants with galactosemia compared to control participants. The average mental health score for participants with galactosemia was 4 points lower than the control score. This result is consistent with the recent paper by Welsink-Karssies et al. [41] where they measured anxiety and depression. People with galactosemia appear to have a lower mental health but the difference with the control population is not significant. Both our study and the one by Welsink-Karssies and colleagues [41] suffer from a small sample and hence a poor statistical power to detect such a small effect. On another note, we did not find correlations between mental well-being and social cognition measures. If there were a relation between mental health and social cognition processes, it might be indirect via intermediate processes we did not address in this study like positive and negative affectivity, social self-esteem and self-efficacy, the feeling of loneliness, the quality of social relations [42,43,44,45,46]. Future research is warranted to investigate a possible contribution of social cognition processes (and deficits) to mental health in galactosemia.

Finally, contrary to what has been found in the literature, our participants with galactosemia were not delayed in their social development. It appears that they reached the milestones just like control participants. Our sample is not representative of the whole galactosemia population. In fact, we recruited them through online messages, so they would have to be quite independent and socially integrated to be aware of our study and decide to participate. However, social development in our galactosemia sample was positively correlated with the (deficient) affective Theory of Mind performance. We think that affective ToM deficit is thus a risk factor to a lower social well-being in galactosemia and additional research is needed. Furthermore, the course of Life questionnaire does not fully address the question of social functioning and well-being. It gives a good picture of the social trajectory with galactosemia. We contend that other tools specifically designed to measure social functioning and well-being would be relevant in future studies. (e.g., social self-esteem and self-efficacy, feeling of loneliness, quality of social relations).

Strengths and Limitations

Our study used social cognition tools that complement previous social cognition studies in a galactosemia sample. We were able to provide new insights into theory of mind and emotion recognition impairments. Obviously, these results need replication, notably with a larger sample, and more knowledge about the characteristics of the participants. Our results should not be generalised and this study does not give a definitive answer to social cognition skills in this condition. However, it participates in cumulative research. Most researchers in the field of rare diseases are faced with the difficulty of accessing patients, and though we all would prefer to lead large-scale studies, small studies help to prune the various avenues to be investigated before investing time, effort and money in large-scale costly research.