A case of myopathy due to ADSS1 mutations leading to defect in muscle purine synthesis



Poster Number: 198


Elizabeth Varughese, MD, University of California Los Angeles, Perry Shieh, MD, PhD, University of California, Los Angeles

Objective: We describe a patient with a homozygous c.910G>A (p.Asp304Asn) variant in ADSS leading to a mild myopathy
Background: Adenylosuccinate Synthetase 1(ADSS1) is a rare genetic myopathy first described in adolescent Korean population. Since then there have been two other cases reported in patients of Indian and Turkish origins respectively. ADSSL1 encodes a key enzyme for the de novo purine synthesis pathway that converts inosine monophosphate to adenosine monophosphate. This is the second case of ADSS1 myopathy in a patient of Indian origin. There is limited data on phenotypic presentation of ADSS1 myopathy outside of the Korean and Japanese population.
Case: A 16 year old Indian boy with no known medical history was in his usual state of health until early childhood when his parents noted weakness with running and jumping as well as climbing stairs. It was not until the age of 14 that he began to have weakness while walking with and exhibited significant easy fatigability. There was no bulbar or respiratory muscle weakness. His examination was notable for mild proximal and distal lower extremity weakness. He was on oral pyridostigmine for several years for presumed diagnosis of congenital myasthenic syndrome without significant benefit. After the onset of weakness with walking, a comprehensive neuromuscular gene panel was sent which returned negative did not reveal any pathogenic genetic mutations. Whole exome sequencing was then performed which revealed a homozygous pathogenic variant c.910G>A (p.Asp304Asn) in the ADSS1 gene. His sister who is also symptomatic was found to be homozygous for the same variant.
Discussion:ADSS1 encodes a muscle specific isoform of the enzyme responsible for de novo purine synthesis. A review of previously reported cases of ADSS1 myopathy suggests considerable phenotypic variability in presentation, from mild slowly progressive muscle weakness to severe ambulatory dysfunction with bulbar and respiratory muscle weakness. Specific targets within the purine synthesis pathway may provide some possible treatment options for this myopathy.