Abstracts

Rationale: SSADH (Succinic Semialdehyde Dehydrogenase) deficiency is a rare autosomal recessive neurological disorder. A mutation in the ALDH5A1 gene causes an enzyme defect in the GABA degradation pathway. Clinical symptoms include developmental delay, hypotonia, mental retardation, ataxia, seizures, hyperkinetic behavior, aggression, and sleep disturbances. The role of elevated gammahydroxybutyric acid (GHB) and GABA in the pathophysiology of SSADH deficiency is unclear. As GHB is known to activate GABA-B receptors in higher concentrations, accumulation of endogenous GHB may lead to increased inhibition of GABA-ergic interneurons, subsequently causing disinhibition of glutamatergic neurons. There may also be down-regulation of pre- and post-synaptic GABA receptor expression by accumulated GHB/GABA. Here, we investigate cortical excitability in children with SSADH deficiency, parents of these patients (obligate heterozygotes), age-matched healthy children and adults using single and paired pulse transcranial magnetic stimulation over the motor cortex to improve our understanding of the underlying neurotransmitter imbalance based on characteristic TMS measures. Methods: In eight families (parents plus patient) with at least one child suffering from SSADH deficiency we investigated resting motor threshold (RMT), MEP recruitment curves, short and long interval intracortical inhibition (SICI, LICI), cortical silent period (CSP), intracortical facilitation (ICF), and M-waves. The results were compared within the families but also with values obtained in healthy volunteers. Results: SSADH deficiency patients showed a significantly shortened cortical silent period (p<0.01) and a complete loss of long interval intracortical inhibition (p<0.0001) compared to heterozygotes (parents) and healthy volunteers. Both parameters are thought to reflect GABA-B-ergic neurotransmission. A slight increase in RMT and a slightly depressed recruitment curve with lower max. M-wave was detected in patients, which corresponds well to the typical mild muscle weakness in these patients. No changes in SICI and ICF were seen. There were no differences between heterozygotes and healthy volunteers.Conclusions: The results of our study confirm an imbalance of intracortical inhibitory mechanisms as reflected by a specific change of TMS parameters that are presumably GABA-B-ergic in SSADH deficiency patients. Excessive hyperexcitability, as for example expressed by higher MEP recruitment, loss of SICI or increase of ICF was not seen in the motor cortex, but might be present in other cortical areas. Cortical excitability of heterozygotes did not differ from healthy volunteers, supporting the assumption of unaltered neurotransmission.