We found that patients with SSADH deficiency have reduced benzodiazepine receptor binding measured with 11C-FMZ-PET. Parents, clinically unaffected, showed no binding reduction. This finding parallels results in SSADH null mice and suggests a potential mechanism for neurologic dysfunction in a serious neurodevelopmental disorder.
The subcortical reductions we found could have been related in part to structural abnormalities, because the PVC procedure is less accurate for subcortical structures.14
However, the patients had no cortical abnormalities on MRI, and PVC is reliable in these regions. The cortical binding reductions are unlikely to be due to partial volume effect.
Anesthesia and age were unlikely to have affected our results. Dexmedetomidine has been shown to have no interaction with GABA-benzodiazepine receptors.22
Of the 2 patients who did not receive anesthesia, BPND
values were still below the parent and control range. Moreover, tracer delivery, measured by R1, did not differ across the groups. We were unable to study healthy child volunteers. However, previous studies have shown that [11
C]-FMZ binding is high in young children, decreasing with age, but not reaching adult cortical values until age 20.23
The children studied (aged 2–17 years, mean 9.4 ± SD 4.1 years) had partial epilepsy and used only drugs that do not increase brain GABA. They were compared to adults (29 ± 7 years) with partial epilepsy matched with the children for the same anticonvulsant medications, as well as normal adults (40 ± 9 years) with no history of neurologic or psychiatric disorders. There was no difference between the adult normal and epilepsy groups. Thus, children without metabolic disease would be expected to have higher binding than adults.
Other PET studies have shown that 11
C-FMZ-PET can detect alterations in GABA receptor binding. Prolonged vigabatrin treatment is associated with decreased binding in children with epilepsy.10
Since vigabatrin increases synaptic GABA availability by inhibiting enzymatic degradation, this study supports the concept of receptor downregulation of GABA receptors due to increased GABA levels, potentially exacerbated by elevations of other metabolites (e.g., GHB). Alternatively, reduced binding could be due to altered receptor properties rather than number. In a familial generalized epilepsy syndrome, patients with the GABRG2 (R43Q) mutation had global binding reductions of about 25%, particularly in anterior cortical regions.24
However, significant alterations of GABAA
R β2 subunit levels and functional GABAA
R activity have been demonstrated in murine SSADH-deficient hippocampal preparations.6
Several lines of evidence suggest a relationship between altered GABA receptor binding and the phenotype in SSADH deficiency. Evidence from the murine SSADH knockout suggests that GABA is significantly increased during embryonic development.25
During early development, and most likely in the early postnatal period, GABA is excitatory rather than inhibitory.26,27
The SSADH null animals have markedly smaller brains, with cerebellum particularly affected.28
The murine neurologic phenotype is characterized by ataxia and an epileptic transition from absence seizures to ultimately fatal convulsive status epilepticus by 3 weeks of age.29
GHB also may contribute to downregulation of presynaptic and postsynaptic GABA receptor expression, perhaps leading to the seizures and hyperactive behavior in SSADH deficiency. At the nonphysiologic concentrations (~200–1000 μM) in SSADH deficiency, GHB acts as a weak GABAB
This may lead to inhibition of GABAB
interneurons, disinhibition of glutamatergic neurons, and pathologic hyperexcitability. Other intermediates accumulating in the mouse and human disorders may further heighten GABAergic effects. The GABA-analogues guanidinobutyrate, homocarnosine, succinic semialdehyde, and 4,5-dihydroxyhexanoic acid (DHHA) accumulate both in patient physiologic fluids and knockout mouse CNS.4,25,31–34
These species may exert previously undefined GABA receptor binding effects, and it has been shown that DHHA binds the high-affinity GHB receptor, albeit with low to moderate affinity.
A number of studies have shown reduced FMZ binding in patients with partial seizures, closely correlated with EEG distribution of epileptiform discharges.9,35
In some cases, reduced FMZ binding has been found in patients with normal MRI, as well as after partial volume correction in patients with mesial temporal sclerosis.9,36
The current study lays the groundwork for future clinical interventions in SSADH-deficient patients through identification of an important therapeutic endpoint. Along those lines, the nonphysiologic amino acid taurine has shown benefit in a single SSADH-deficient case.37
Among its many reported roles, taurine may activate GABA receptors.38
Other orally bioactive GABA receptor antagonists, such as SGS-742, can now also be considered in SSADH-deficient patients with monitoring of FMZ binding.39