Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co‐activator complex activity, similarly to what was observed in Menke‐Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5‐binding region. Recently, TTC5‐related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5‐related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre‐ and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Objective: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies.Methods: KETASER01 is a multicenter, randomized, controlled, open‐label, sequentially designed, non‐profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children.Results: During the 5‐year recruitment phase, a total of 76 RCSEs treated with third‐line therapy were observed in five of the 10 participating Centers; only 10 individuals (five for each study arm; five females, mean age 6.5 ± 6.3 years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s).Significance: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here, we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials.

Involuntary movements can appear before and after initiation of vitamin B12 treatment. The pathogenesis of involuntary movements in vitamin B12 deficiency and their relationship with cobalamin injection remain unclear due to a lack of video‐EEG documentation making the electroclinical correlation difficult to ascertain. Here, we report video‐EEG and neuroimaging findings of an 11‐month‐old girl with vitamin B12 deficiency, who acutely developed involuntary movements a few days after initiation of vitamin B12 treatment with normal vitamin plasmatic levels. Abnormal movements were a combination of tremor and myoclonus involving the face, mouth, and left arm, which disappeared after discontinuation of therapy. [Published with video sequences]

Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype–phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.