Treatment of ARS deficiencies with specific amino acids.

PURPOSE: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities. METHODS: In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments. RESULTS: Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (PLARS and PFARSB), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2-2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency. CONCLUSION: For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation.

Neuropsychological Profile of Children with Early and Continuously Treated Phenylketonuria: Systematic Review and Future Approaches.

OBJECTIVE: To provide a comprehensive systematic review of the literature by examining studies published on all cognitive aspects of children with early and continuously treated phenylketonuria (ECT-PKU) included in the databases Medline, PsycINFO, and PsycARTICLE. METHOD: In addition to a classical approach, we summarized methodology and results of each study in order to discuss current theoretical and methodological issues. We also examined recent advances in biochemical markers and treatments of PKU, with implications for future research on metabolic control and its role as a determinant of neuropsychological outcome. RESULTS: Consistent with previous reviews, the hypothesis of a specific and central executive impairment in children with ECT-PKU was suggested. However, findings are inconclusive regarding the nature of executive impairments as well as their specificity, impact on everyday life, persistence over time, and etiology. CONCLUSION: Given the current state of the science, we suggest future directions for research that utilizes a developmental and integrative approach to examine the effects of recent advances in biochemical markers and treatment of PKU. (JINS, 2019, 25, 624-643).

Cognitive Abilities of Children With Neurological and Liver Forms of Wilson Disease.

Cognitive impairment in adult patients experiencing Wilson disease is now more clearly described, even in liver forms of the disease. Although this condition can appear during childhood, the cognitive abilities of children have not yet been reported in a substantial case series. This retrospective study included 21 children with Wilson disease who had undergone general cognitive assessment. The results argue in favor of a poor working memory capacity in the liver form of the disease, and more extensive cognitive impairments in its neurological form. Extensive neuropsychological investigations on all children experiencing Wilson disease are thus required.

Blood phenylalanine fluctuation in phenylketonuric children treated by BH4 or low-phenylalanine diet from birth.

The prognosis of phenylketonuria (PKU) is related to the quality of metabolic control all life-long. PKU treatment is based on a low-Phe diet, 6R-tetrahydrobiopterin (BH4) treatment for the BH4-responsive PKU patients or enzyme replacement therapy. Fluctuations in blood phenylalanine (Phe) concentrations may be an important determinant of intellectual outcome in patients with early and continuously treated phenylketonuria (PKU). The aim of this work is to study the fluctuation of Blood Phe in patients treated by BH4 from birth in comparison with patients treated by low-Phe diet. We conducted a retrospective study in a national reference center for PKU management. We compared mean phenylalanine blood concentration and its fluctuation in 10 BH4-responder patients (BH4R) and in 10 BH4 non-responder patients (BH4NR) treated from birth. The mean blood Phe concentration is similar between the two groups before 10 years of age (290 ± 135 (BH4R) vs. 329 ± 187 µmol/L, p = 0.066 (BH4NR)) while it is lower in the BH4R group after 10 years of age. (209 ± 69 vs. 579 ± 136 µmol/L, p = 0.0008). Blood Phe fluctuation is significantly lower in the BH4R group compared to the BH4NR group (70.2 ± 75.6 vs. 104.4 ± 111.6 µmol/L, p < 0.01) before 6 years of age. There are no significant differences observed on nutritional status, growth, and neuropsychological tests between the two groups. BH4 introduced in the neonatal period is associated with less blood Phe fluctuation before 6 years. Additional time and patients are required to determine if the decrease in Phe fluctuation would positively impact the long-term outcome of PKU patients.

Episodic Autobiographical Memory in Adults With Autism Spectrum Disorder: An Exploration With the Autobiographical Interview.

Introduction: The literature has provided contradictory results regarding the status of episodic memory in autism spectrum disorder (ASD). This might be explained by methodological differences across studies. In the present one, the well-recommended Autobiographical Interview was used in which important aspects of episodic memory were assessed, namely, the number and richness of phenomenological memory details, before and after a retrieval support. Method: Twenty-five well-documented adults with ASD without Intellectual Disability (nine women) and 25 control participants were included and asked to recall six specific autobiographical events. The number and richness of details were assessed globally and for five categories of details (perceptual/sensory, temporal, contextual, emotional, and cognitive), firstly before and then after a specific cueing phase consisting in a series of specific questions to elicit more precise memory details. Results: Cumulatively, from the spontaneous recall to the cueing phase, the number of internal details was lower in ASD individuals compared to controls, but this difference was relevant only after the specific cueing procedure and observed only for contextual details. In contrast, no relevant group difference was observed during spontaneous recall. The detail richness was not impaired in ASD throughout the Autobiographical Interview procedure. Conclusion: Our results speak against a clear impairment of episodicity of autobiographical memory in ASD individuals. They thus challenge previous ones showing both a reduced specificity and episodicity of autobiographical memory in this population and call for further studies to get a better understanding on the status of episodic autobiographical memory in ASD.