LAUSR

Although several genes have been implicated in the pathogenesis of generalized dystonia, most cases remain without an identifiable cause. The incomplete knowledge of the pathophysiology of dystonia is a major obstacle to developing treatments targeting underlying disease mechanisms. Two major new papers have recently identified mutations in a new gene, Lysine-Specific Methyltransferase 2B (KMT2B), as a cause of early-onset generalized dystonia. Zech and colleagues performed whole-exome sequencing (WES) on a proband-parent trio involving an Austrian index subject with early-onset generalized dystonia. A KMT2B single nucleotide deletion was the only identified de novo change which was predicted to severely affect protein function. WES of a 30 German-Austrian cohort with unsolved disease revealed 3 further loss-of-function KMT2B mutations. For the total 4 KMT2B mutations found, 3 mutations were de novo in families with only 1 affected individual, and 1 mutation showed complete cosegregation with dystonia in a family with 3 affected members across 3 generations. The phenotype included lower-limb onset generalized dystonia or focal dystonia involving the hand and forearm. Additional presenting symptoms included microcephaly and impairment of speech and cognition. mRNA expression studies demonstrated nonsense-mediated decay, supporting KMT2B haploinsufficiency. Similarly, Meyer and colleagues report heterozygous variants in KMT2B in 27 unrelated individuals with a complex, progressive, early-onset dystonia. Most patients had heterozygous interstitial microdeletions or protein-truncating variants. They reported additional associated features such as a typical facial appearance (elongated face and bulbous nasal tip) and characteristic brain magnetic resonance imaging findings (subtle, symmetrical hypointensity of the globus pallidi). Over time, most affected individuals developed prominent cervical, cranial, and laryngeal dystonia. They also found that patients who received deep brain stimulation showed marked clinical improvement. These papers provide strong evidence that mutations in KMT2B are a cause of autosomal dominant, complex, combined dystonia typically of infantile or childhood onset. The KMT2B gene encodes an epigenetic regulator that catalyzes methylation of the fourth lysine residue of histone H3, which is implicated in neurodevelopment and neurodegenerative states. The identification of KMT2B mutations in dystonia suggests a role for haploinsufficiency causing faulty epigenetic mechanisms in the disease pathogenesis. Investigation of the role of the KMT2B mutations in disrupting the sensorimotor circuit, thought to be the underlying cause of dystonia, may reveal a genetic target for the future treatment of this disorder. We await further studies into KMT2B that may prove to be an important new gene for dystonia research.