LAUSR

In their letter, von Hardenberg et al. (2020) describe a female infant with mild malformations and neonatal onset seizures with a burst-suppression pattern on EEG, in whom they identified a novel homozygous splice-site variant in the glutamate decarboxylase 1 gene GAD1. After genetic diagnosis and in the second month of life, they began a precision therapy with a combination of vigabatrin and ketogenic diet. This combination treatment not only resulted in clinical cessation of seizures within 2 days, but at 7 months of age, growth and psychomotor development were unremarkable. The authors provide further support to our recent publication (Chatron et al., 2020), in which we reported 11 patients with a syndrome caused by bi-allelic loss-of-function mutations in GAD1. All individuals reported in our study had an early onset developmental and epileptic encephalopathy with frequent malformations such as cleft palate and joint contractures. We welcome the identification of additional cases, which contribute to a better understanding of the phenotypic spectrum associated with GAD1 variants. The seizure onset age and type, and the malformations of the patient reported in the study of von Hardenberg et al. (2020), nicely reproduce our findings. Their study also provides independent support for our suggestion of a therapeutic benefit from vigabatrin. In our report, five of seven patients who tried vigabatrin showed a remarkably good seizure response. We nevertheless cautioned that the effect of vigabatrin might be driven by seizure type, given that a response was seen particularly in patients with epileptic spasms. The patient in von Hardenberg et al. (2020) indeed also had predominant infantile spasms. What is more remarkable than the seizure response though, is the normal developmental trajectory of the patient. The presence of a neonatal burst-suppression pattern on EEG generally has a dire prognosis, and all families reported in our study indeed had a profound developmental delay. The authors claim that this good clinical outcome relates to the early start of the combination of ketogenic diet and vigabatrin, which was not simultaneously tried in any of the patients in our study. Both treatment strategies are thought to increase the available pool of GABA, and combined they might compensate for the severely impaired GABA synthesis. While this is certainly a reasonable hypothesis, one should be cautious drawing conclusions from one single observation. In this regard, it is interesting to read the recent published paper by Neuray et al. (2020), which describes an additional six cases with bi-allelic GAD1 variants. One patient (Patient C) also appears to take a combination of ketogenic diet and vigabatrin at the age of 28 months, and still has refractory seizures and severe delay. Unfortunately, the paper does not provide a full description of seizure history and drug response, so that it is not clear at what age these respective treatments were started. Whereas we do not agree with von Hardenberg et al. (2020) that there is large phenotypic variability within our families (one sibling of Family E died shortly after a