Details

Autor(en) / Beteiligte

• Tokatly Latzer, Itay
• Hanson, Ellen
• Bertoldi, Mariarita
• García‐Cazorla, Àngeles
• Tsuboyama, Melissa
• MacMullin, Paul
• Rotenberg, Alexander
• Roullet, Jean‐Baptiste
• Pearl, Phillip L.
• Gibson, K Michael
• Arning, Erland
• DiBacco, Melissa L
• Aygun, Deniz
• Sachee, Daniyal
• Lee, Henry H C
• Papadelis, Christos
• Opladen, Thomas
• Jeltsch, Kathrin
• Warfield, Simon
• Hoffman, Carolyn

Titel

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency

Ist Teil von

• Developmental medicine and child neurology, 2023-12, Vol.65 (12), p.1596-1606

Ort / Verlag

England

Erscheinungsjahr

2023

Quelle

Wiley Blackwell Single Titles

Beschreibungen/Notizen

• Aim To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ‐aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. Method In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. Results Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months–18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = −0.67, p < 0.001) and γ‐hydroxybutyrate levels (r = −0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = −0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 μM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. Interpretation ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA‐related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD. Succinic semialdehyde dehydrogenase (SSADH) deficiency is an inherited disorder of GABA catabolism, resulting in hyper‐physiologic concentrations of GABA. Altered GABA homeostasis, including user‐dependent downregulation of GABAA receptors and increase in the excitation:inhibition ratio, contribute to the pathomechanisms of autism spectrum disorders (ASDs) in this condition. ASDs are more likely to onset in people with SSADH deficiency beyond a relatively late age of 7 years 2 months and as plasma GABA levels drop below ~2.5µM. Knowledge of these cutoff values may be applicable for earlier diagnosis and management of ASDs in this population. SSADH deficiency needs to be considered in the diagnostic evaluation of ASDs, especially if autistic symptoms appear at an older age than that of non‐syndromic ASDs. Video Podcast: https://youtu.be/y‐PnJodEr2g This original article is commented on by Frye on pages 1544–1545 of this issue. Plain language summary: https://onlinelibrary.wiley.com/doi/10.1111/dmcn.16032