Kmt2b, also known as Lysine-Specific Histone Methyltransferase 2B, is a major H3K4 tri-methyltransferase (H3K4me3). It participates in gene transcription during neurodevelopment, an important process for the normal development and function of the nervous system. Abnormalities in Kmt2b-related transcriptional regulation are associated with the pathophysiology of dystonia [4].

Heterozygous mutations in Kmt2b are linked to an early-onset, progressive and often complex dystonia (DYT28). Since 2016, 66 different KMT2B-affecting variants have been reported in 76 patients. Most mutations are de novo, leading to KMT2B haploinsufficiency and epigenetic dysregulation. DYT-KMT2B is characterized by limb-onset childhood dystonia that spreads progressively to generalized dystonia with cranio-cervical involvement. Co-occurring signs like intellectual disability are common. Deep brain stimulation (DBS) shows a sustained response in 93% of patients [1].

A cohort study of 53 patients with KMT2B mutations further detailed the clinical phenotype and molecular genetic features, including new disease presentations, co-morbidities, and genotype-phenotype correlations. DBS significantly improves motor function and disability, with long-term benefits in some patients [2].

A systematic review and meta-analysis of 42 patients found that KMT2B-associated dystonia responds effectively to pallidal stimulation, with better outcomes in males and those with more severe dystonia at baseline [3].

In conclusion, Kmt2b plays a crucial role in neurodevelopment, and its dysfunction, mainly due to de novo mutations, is strongly associated with DYT-KMT2B. Studies on Kmt2b-related dystonia, including those involving deep brain stimulation, contribute to understanding the disease mechanism and developing potential treatment strategies for this form of dystonia.