Dysregulation of dopamine metabolism in children with spinal muscular atrophy type 1

Abstract Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to affecting motor neuron survival, SMN deficiency impacts multisystem physiology and neurotransmission. Dopaminergic dysfunction has been reported in mouse models of SMA, leading to postural and locomotor impairments that improve following treatment with levodopa and benserazide, which increase central dopamine availability. However, whether altered dopamine metabolism contributes to clinical symptoms in SMA patients remains unclear. To investigate this issue, we conducted a real-world observational study involving pediatric patients with SMA type 1 (SMA1), SMA2, and SMA3, and healthy controls. We quantified the main dopamine-related catabolites – 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) – in cerebrospinal fluid samples collected at baseline and after five intrathecal doses of Nusinersen, an SMN-enhancing therapy. No significant differences were observed in DOPAC and HVA levels across SMA types and controls or following treatment, and no association emerged with SMN2 copy number. In contrast, lower baseline DOPAC levels were detected in SMA1 patients requiring gastrostomy or tracheostomy, and were associated with reduced improvement following Nusinersen, as measured by changes in the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores. Additional high-performance liquid chromatography analyses performed in an independent study cohort revealed significantly lower serum HVA levels in SMA1 patients compared to controls. In conclusion, our exploratory study suggests that altered dopaminergic metabolism is associated with greater disease severity and poorer motor outcomes following treatment, supporting an involvement of dopamine neurotransmission in clinical heterogeneity in SMA.