Current insights in ultra-rare adenylosuccinate synthetase 1 myopathy - meeting report on the First Clinical and Scientific Conference. 3 June 2024, National Centre for Advancing Translational Science, Rockville, Maryland, the United States of America

Emma Rybalka^{1

2}, Hyung Jun Park³, Atchayaram Nalini⁴, Dipti Baskar⁴, Kiran Polavarapu⁵, Hacer Durmus⁶, Yang Xia⁷, Linlin Wan⁸, Perry B Shieh⁹, Behzad Moghadaszadeh¹⁰, Alan H Beggs¹⁰, David L Mack¹¹, Alec S T Smith¹¹, Wendy Hanna-Rose¹², Hyder A Jinnah¹³, Cara A Timpani^{14

15}, Min Shen¹⁶, Jaymin Upadhyay^{17

18}, Jeffrey J Brault¹⁹, Matthew D Hall¹⁶, Naveen Baweja²⁰, Priyanka Kakkar²⁰

Affiliations

¹ Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia. emma.rybalka@vu.edu.au.
² Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science, St Albans, VIC, Australia. emma.rybalka@vu.edu.au.
³ Department of Neurology, Gangnam Severance Hospital, Yonshei University College of Medicine, Seoul, Republic of Korea.
⁴ Department of Neurology, National Institute of Mental Health And NeuroSciences (NIMHANS), Bengaluru, India.
⁵ Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1H 5B2, Canada.
⁶ Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁷ Xiangya Hospital, National Medical Metabolomics International Collaborative Research Center, Central South University, Changsha, China.
⁸ Department of Radiology, Xiangya Hospital of Central South University, Changsha, China.
⁹ Departments of Neurology and Pediatrics, University of California Los Angeles, Los Angeles, USA.
¹⁰ Division of Genetics and Genomics, The Manton Centre for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
¹² Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
¹³ Departments of Neurology, Human Genetics and Pediatrics, Emory University, Atlanta, USA.
¹⁴ Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
¹⁵ Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science, St Albans, VIC, Australia.
¹⁶ Division of Preclinical Innovation, National Centre for Advancing Translational Science, National Institutes of Health, Rockville, MD, USA.
¹⁷ Department of Anaesthesia, Critical Care and Pain Management, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁸ Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
¹⁹ Center for Musculoskeletal Health, Department of Anatomy, Cell Biology & Physiology, Indiana School of Medicine, Indianapolis, IN, USA.
²⁰ Cure ADSSL1, Glendale, CA, USA.

PMID: 39593137
PMCID: PMC11590305
DOI: 10.1186/s13023-024-03429-x

Current insights in ultra-rare adenylosuccinate synthetase 1 myopathy - meeting report on the First Clinical and Scientific Conference. 3 June 2024, National Centre for Advancing Translational Science, Rockville, Maryland, the United States of America

Emma Rybalka et al. Orphanet J Rare Dis. 2024.

. 2024 Nov 26;19(1):438.

doi: 10.1186/s13023-024-03429-x.

Authors

Affiliations

¹ Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia. emma.rybalka@vu.edu.au.
² Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science, St Albans, VIC, Australia. emma.rybalka@vu.edu.au.
³ Department of Neurology, Gangnam Severance Hospital, Yonshei University College of Medicine, Seoul, Republic of Korea.
⁴ Department of Neurology, National Institute of Mental Health And NeuroSciences (NIMHANS), Bengaluru, India.
⁵ Children's Hospital of Eastern Ontario Research Institute, Ottawa, K1H 5B2, Canada.
⁶ Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
⁷ Xiangya Hospital, National Medical Metabolomics International Collaborative Research Center, Central South University, Changsha, China.
⁸ Department of Radiology, Xiangya Hospital of Central South University, Changsha, China.
⁹ Departments of Neurology and Pediatrics, University of California Los Angeles, Los Angeles, USA.
¹⁰ Division of Genetics and Genomics, The Manton Centre for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.
¹² Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
¹³ Departments of Neurology, Human Genetics and Pediatrics, Emory University, Atlanta, USA.
¹⁴ Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
¹⁵ Inherited and Acquired Myopathies Program, Australian Institute for Musculoskeletal Science, St Albans, VIC, Australia.
¹⁶ Division of Preclinical Innovation, National Centre for Advancing Translational Science, National Institutes of Health, Rockville, MD, USA.
¹⁷ Department of Anaesthesia, Critical Care and Pain Management, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁸ Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA.
¹⁹ Center for Musculoskeletal Health, Department of Anatomy, Cell Biology & Physiology, Indiana School of Medicine, Indianapolis, IN, USA.
²⁰ Cure ADSSL1, Glendale, CA, USA.

PMID: 39593137
PMCID: PMC11590305
DOI: 10.1186/s13023-024-03429-x

Abstract

The inaugural Clinical and Scientific Conference on Adenylosuccinate Synthetase 1 (ADSS1) myopathy was held on June 3, 2024, at the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS) in Rockville, Maryland, USA.

ADSS1 myopathy is an ultra-rare, inherited neuromuscular disease.

Features of geographical patient clusters in South Korea, Japan, India and the United States of America were characterised and discussed.

Pre-clinical animal and cell-based models were discussed, providing unique insight into disease pathogenesis.

The biochemical pathogenesis was discussed, and potential therapeutic targets identified.

Potential clinical and pre-clinical biomarkers were discussed.

An ADSS1 myopathy consortium was established and a roadmap for therapeutic development created.

Keywords: ADSS1 myopathy; Adenylosuccinate synthetase 1 myopathy; Biomarkers; Cardiac muscle; Clinical presentation; Consortium; Guidelines; Inborn error of metabolism; Pre-clinical models; Purine disorder; Skeletal muscle; Therapeutics; Ultra-rare neuromuscular disease.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: Human and animal studies were approved by the relevant institutional ethics boards and informed consent was given by all human participants. Consent for publication: Not applicable. Competing interests: ER has received consulting income from Santhera Pharmaceutical and Epirium Bio. PBS has received personal compensation from Novartis Gene Therapies Inc., Alexion argenyx, Biogen, Catalyst, Grifols, CSL Behring, Genentech, Pfizer, PTC Therapeutics, and Sarepta Therapeutics; research funding from Astellas Gene Therapies, Biogen, Catalyst, Pfizer, PTC, Sanofi-Genzyme, Sarepta, Solid Biosciences, and Zogenix. DM founded Kinea Bio Inc., is on the scientific advisory board of Curi Bio Inc., Vita Therapeutics Inc., and SoundEats Inc., and receives consulting income from Astellas Gene Therapies. AHB receives consulting income from Kate Therapeutics, Roche Pharmaceuticals, GLG Inc., and Guidepoint Global, and has equity in Kate Therapeutics and Kinea Bio. All other authors declare no competing interests.

Figures

**Fig. 1**
Location and metabolic activity of Adenylosuccinate Synthetase 1 (ADSS1) within purine metabolism. Loss of ADSS1 function compromises the conversion of inosine monophosphate (IMP), generated by *de novo* purine biosynthesis and adenosine monophosphate deaminase (AMPD), to succinyl-AMP/adenylosuccinate (S-AMP) and adenosine monophosphate (AMP). Energy production capacity may be reduced. IMP may be diverted into other reactions and/or degraded and excreted from muscle leading to purine depletion. Potential targets for restoration of metabolic systems are indicated in numbered circles: (1) Overexpression of mitochondrial ADSS2; (2) Inhibition of xanthine oxidoreductase (XOR); (3) Inhibition of AMP deaminase (AMPD); (4) Targeting recycling pathways to increase adenosine concentration; (5) Supplemental adenine combined with XOR inhibition; (6) Supplemental fumarate esters; (7) Supplemental ATP. Schematic was created with Biorender.com

**Fig. 2**
Crystallographic structure of ADSS1. Left panel: Ribbon representation of the mouse ADSS1 co-crystal structure illustrating the dimer formation (PDB code: 1IWE). The monomers are shown in yellow and blue; the substrate/cofactor is shown in green using ball and stick mode. D261 is located at dimer interface which is > 9Å away from the active site. Right panel: Detailed view of the D261 with surrounding residues. Potential hydrogen-bonds are labeled with dotted lines. All molecular depictions were prepared using MOE molecular modeling software (http://www.chemcomp.com/)

See this image and copyright information in PMC

References

1. Park HJ, Hong YB, Choi YC, Lee J, Kim EJ, Lee JS, et al. <ArticleTitle Language=“En”>ADSSL1 mutation relevant to autosomal recessive adolescent onset distal myopathy. Ann Neurol. 2016;79:231–43. - PubMed
1. Park HJ, Shin HY, Kim S, Kim SH, Lee Y, Lee JH, et al. Distal myopathy with ADSSL1 mutations in Korean patients. Neuromuscul Disord. 2017;27:465–72. - PubMed
1. Saito Y, Nishikawa A, Iida A, Mori-Yoshimura M, Oya Y, Ishiyama A, et al. ADSSL1 myopathy is the most common nemaline myopathy in Japan with variable clinical features. Neurology. 2020;95:e1500–11. - PubMed
1. Park HJ, Lee JE, Choi GS, Koo H, Han SJ, Yoo JH, et al. Electron Microscopy Pathology of ADSSL1 Myopathy. J Clin Neurol. 2017;13:105–6. - PMC - PubMed
1. CureADDSL1. www.cure-adssl1.org.

LinkOut - more resources

Full Text Sources
- BioMed Central
- PubMed Central

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Current insights in ultra-rare adenylosuccinate synthetase 1 myopathy - meeting report on the First Clinical and Scientific Conference. 3 June 2024, National Centre for Advancing Translational Science, Rockville, Maryland, the United States of America

Affiliations

Current insights in ultra-rare adenylosuccinate synthetase 1 myopathy - meeting report on the First Clinical and Scientific Conference. 3 June 2024, National Centre for Advancing Translational Science, Rockville, Maryland, the United States of America

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

LinkOut - more resources

Full Text Sources