Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency

Summary Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ‐aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale ( p < 0.001), basal ganglia ( p = 0.01), and midbrain ( p = 0.001), as well as a higher MRS‐derived GABA/NAA peak ( p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS‐derived GABA/NAA ( p = 0.04) and lower plasma GABA ( p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ‐estimated sleep disturbances scores ( R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep‐related disorders and neurodegenerative conditions associated with glymphatic dysfunction.