Persistent glutamate increase in TANGO2 deficiency with normalization after vitamin supplementation: first documentation by MR spectroscopy

TANGO2 deficiency is a rare inherited metabolic disorder characterized by recurrent metabolic crises, rhabdomyolysis, arrhythmias, and encephalopathy. Recent studies suggest that TANGO2 functions as a mitochondrial lipid-acyl-CoA handling protein. Nonetheless, the cerebral metabolic abnormalities underlying neurological deterioration remain elusive. In this study, we present the first longitudinal evaluation of brain metabolism using proton magnetic resonance spectroscopy (MRS) before and after vitamin therapy, during the acute, subacute, and post-treatment phases, highlighting improved clinical manifestations following treatment. We longitudinally evaluated cerebral metabolites using MRS during the acute, subacute, and post-treatment phases. A 2-year-old boy with genetically confirmed TANGO2 deficiency presented with a metabolic crisis, status epilepticus, and rhabdomyolysis (CK peak, 282,695 U/L). Despite the absence of structural abnormalities on the magnetic resonance imaging conducted on day 2, MRS revealed markedly increased glutamate (Glu; 11.51 mM; reference: 6.70 ± 0.59) with normal glutamine (Gln). On day 50, despite clinical stabilization, Glu levels remained abnormally high (9.29 mM), indicating a persistent dysfunction of the cerebral Glu–Gln cycle. Upon initiation of vitamin supplementation, including that of all eight B vitamins (i.e. B₁, B₂, B₃, B₅, B₆, B₇, B₉, and B₁₂) at the age of 3, no further crises occurred. Follow-up MRS at the age of 4 demonstrated Glu normalization (7.20 mM; reference: 6.50 ± 0.70). This case provides pioneering in vivo evidence of sustained cerebral Glu accumulation in a patient with TANGO2 deficiency along with improvement after metabolic therapy. Our results suggest that the impairment of energy-dependent Glu–Gln cycling and astrocytic Glu clearance might constitute a potential mechanism underlying neurological vulnerability in TANGO2 deficiency. Longitudinal MRS may allow metabolic instability and treatment responsiveness monitoring in this disorder.