Consistent MRI pattern in ADSS1 myopathy with variable clinical presentations: A Korean cohort study

ADSS1 myopathy (previously referred to as ADSSL1 myopathy) is a rare autosomal recessive muscle disease caused by mutations in the ADSS1 gene, which encodes an enzyme critical for purine nucleotide synthesis. First characterized in Korean patients in 2016, the disease exhibits phenotypic variability in its clinical presentation. We conducted a retrospective cohort study of 30 patients with genetically confirmed ADSS1 myopathy (18 males and 12 females) at Gangnam Severance Hospital from 2002 to 2024. The patients were classified into proximal-onset (n = 9) and distal-onset (n = 20) groups based on the location of initial muscle weakness, with one patient presenting with isolated hyperCKemia. Clinical assessments, genetic analyses, and muscle MRI were performed on 10 patients to evaluate clinical-radiological correlations. The median age at symptom onset was 8.0 years Interquartile range (IQR): 7.0–14.0 with a median disease duration of 24.0 years IQR: 17.0–34.0. The most common initial symptoms were slow running (66.7%), early fatigue (16.7%), and gait disturbances (10.0%). Facial involvement was observed in 80.0% of the patients and oropharyngeal dysfunction in 56.7%. The median serum creatine kinase level was 214.0 IU/L IQR: 125.0–394.0. Genetic analysis revealed five pathogenic ADSS1 variants, with c.781G > A (51.7% of alleles) and c.919del (40.0% of alleles) being the most prevalent. Most patients (73.3%) were compound heterozygous for the two variants. Despite the clinical heterogeneity between the proximal- and distal-onset groups, none of the clinical differences were statistically significant. Muscle MRI revealed a remarkably consistent pattern of preferential involvement of the distal lower limb muscles, particularly the gastrocnemius and soleus muscles, regardless of the initial clinical presentation. This study, which represents the largest Korean ADSS1 myopathy cohort to date, highlights the striking discordance between clinical phenotypes and radiological findings. Although the clinical presentations varied considerably, MRI revealed consistent distal dominant muscle involvement patterns across all patients. This suggests that the underlying pathological process follows a predictable anatomical distribution independent of the initial symptomatic muscle groups. Our findings support the utility of muscle MRI as a valuable diagnostic tool for ADSS1 myopathy and suggest its conceptualization as a unified disease entity with a common pathophysiological mechanism involving selective muscle vulnerability based on metabolic requirements.