Treatment of Mitochondrial Phenylalanyl-tRNa-Synthetase Deficiency (FARS2) with Oral Phenylalanine

Abstract

Objective By loading transfer RNAs with their cognate amino acids, aminoacyl-tRNA synthetases (ARS) are essential for protein translation. Both cytosolic ARS1-deficiencies and mitochondrial ARS2 deficiencies can cause severe diseases. Amino acid supplementation has shown to positively influence the clinical course of four individuals with cytosolic ARS1 deficiencies. We hypothesize that this intervention could also benefit individuals with mitochondrial ARS2 deficiencies.

Methods This study was designed as a N-of-1 trial. Daily oral L-phenylalanine supplementation was used in a 3-year-old girl with FARS2 deficiency. A period without supplementation was implemented to discriminate the effects of treatment from age-related developments and continuing physiotherapy. Treatment effects were measured through a physiotherapeutic testing battery, including movement assessment battery for children, dynamic gait index, gross motor function measure 66, and quality of life questionnaires.

Results The individual showed clear improvement in all areas tested, especially in gross motor skills, movement abilities, and postural stability. In the period without supplementation, she lost newly acquired motor skills but regained these upon restarting supplementation. No adverse effects and good tolerance of treatment were observed.

Interpretation and Conclusion Our positive results encourage further studies both on L-phenylalanine for other individuals with FARS2 deficiency and the exploration of this treatment rationale for other ARS2 deficiencies. Additionally, treatment costs were relatively low at 1.10 €/day.

Keywords

aminoacyl-tRNA-synthetase - individual treatment - ataxia - mitochondrial disorder - mitochondrial diseases

Authors' Contributions

S.L.O., K.S., M.T.A., E.G., R.E.B., W.M.S., E.T., E.H., A.E., D.M., and J.A.M. made substantial contributions to acquisition, analysis, or interpretation of data for the work and drafted the work. SBW conceptualized and designed the study and contributed substantially to acquisition and analysis of data, drafting a significant portion of the manuscript or figures.

All authors revising it critically for important intellectual content and approved the final version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

^* These authors contributed equally.

Publikationsverlauf

Eingereicht: 01. Dezember 2022

Angenommen: 04. Januar 2023

Accepted Manuscript online:
05. Januar 2023

Artikel online veröffentlicht:
20. Februar 2023

• References

• 1 Gorman GS, Chinnery PF, DiMauro S. et al. Mitochondrial diseases. Nat Rev Dis Primers 2016; 2: 16080
• 2 Hoytema van Konijnenburg EMM, Wortmann SB, Koelewijn MJ. et al. Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app. Orphanet J Rare Dis 2021; 16 (01) 170
• 3 Repp BM, Mastantuono E, Alston CL. et al. Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: is riboflavin supplementation effective?. Orphanet J Rare Dis 2018; 13 (01) 120
• 4 Zweers H, van Wegberg AMJ, Janssen MCH, Wortmann SB. Ketogenic diet for mitochondrial disease: a systematic review on efficacy and safety. Orphanet J Rare Dis 2021; 16 (01) 295
• 5 Konovalova S, Tyynismaa H. Mitochondrial aminoacyl-tRNA synthetases in human disease. Mol Genet Metab 2013; 108 (04) 206-211
• 6 Almannai M, Faqeih E, El-Hattab AW. et al. FARS2 deficiency. In: Adam MP, Everman DB, Mirzaa GM. et al., eds. GeneReviews((R)). Seattle (WA, USA): 1993
• 7 Kok G, Tseng L, Schene IF. et al. Treatment of ARS deficiencies with specific amino acids. Genet Med 2021; 23 (11) 2202-2207
• 8 Elo JM, Yadavalli SS, Euro L. et al. Mitochondrial phenylalanyl-tRNA synthetase mutations underlie fatal infantile Alpers encephalopathy. Hum Mol Genet 2012; 21 (20) 4521-4529
• 9 Vantroys E, Larson A, Friederich M. et al. New insights into the phenotype of FARS2 deficiency. Mol Genet Metab 2017; 122 (04) 172-181
• 10 [Anonymous] . World Medical Association declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects. JAMA 1997; 277 (11) 925-926
• 11 van Wegberg AMJ, MacDonald A, Ahring K. et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis 2017; 12 (01) 162
• 12 Psotta R, Abdollahipour R. Factorial validity of the movement assessment battery for children-2nd Edition (MABC-2) in 7-16-year-olds. Percept Mot Skills 2017; 124 (06) 1051-1068
• 13 Lubetzky-Vilnai A, Jirikowic TL, McCoy SW. Investigation of the dynamic gait index in children: a pilot study. Pediatr Phys Ther 2011; 23 (03) 268-273
• 14 Beckers LW, Bastiaenen CH. Application of the gross motor function measure-66 (GMFM-66) in Dutch clinical practice: a survey study. BMC Pediatr 2015; 15: 146
• 15 Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med Care 1999; 37 (02) 126-139