Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished cases). A Cux1+/− mouse model was used to analyze CUX1 expression in the brain and evaluate susceptibility to epilepsy. We describe 34 patients with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development, and intellectual disability. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was also reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some patients, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. Furthermore, the balance of CUX1 isoform expression in the brain during development appears to be important for this favorable clinical course.

Background Excess weight is a rising concern in patients with phenylketonuria (PKU). It is commonly observed in children and adolescents with PKU; but data on adults are inconsistent. This review aims to summarize available data on excess weight in adult PKU individuals. Methods We conducted a systematic search of literature in English, from inception to October 2021, on PubMed and Embase to identify articles on overweight and obesity in adult PKU patients. Prevalence of overweight and obesity, body mass index (BMI) and gender differences were the outcomes of interest. Results Of 260 articles identified, only 8 fulfilled quality criteria for inclusion after screening of titles, abstracts and full texts. The mean BMI of adult PKU patients in these studies ranged from 26 ± 5.4 to 30.3 ± 1.8 kg/m2. When compared to matched controls, adult PKU patients had higher BMI and higher prevalence of obesity. However, results were inconsistent when PKU adults were compared to the general population. The prevalence of obesity in the included studies varied widely between 4.5% up to 72% in individual studies. Obesity was 2–3 times more frequent in female PKU patients. Conclusions Excess weight is frequent in adult PKU patients, especially in females, even if the difference with the general population is debatable. The heterogeneity of the studies makes it difficult to interpret the results and the factors that contribute to obesity. Content of the diet, psychological status, diet-associated disordered eating, patient’s social environment and lifestyle are listed as potentials contributors to excess weight in PKU adult population. Further studies are needed to better elucidate this question. In the meantime, weight control and healthy eating habits should be considered in the management and follow-up of these patients.

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