FV 747. Early-Onset Progressive Dystonia in Childhood with New Mutations in KMT2B

Background: Inherited dystonias with manifestation in early childhood comprise a clinically and genetically heterogenous disease entity. There have been recent breakthroughs in the etiological classification through exome sequencing; however, the disease-causing mutations remain unknown in many patients.

Aims: The project was aimed to elucidate the genetic etiology of dystonia in early childhood through exome sequencing and to characterize individual disease progressions as well as responses to interventional therapies.

Here, we focused on KMT2B-associated dystonia.

Methods: Through exome sequencing (Agilent V6, 2x75bp, Varbank pipeline), four patients with mutations in KMT2B were identified. We systematically examined the longitudinal clinical disease progression as well as responses to pharmacotherapy and deep brain stimulation.

Results: We report four patients (three females at the ages of 8, 11, and 18 years as well as one male at the age of 47 years) with inherited dystonia, who showed first dystonic symptoms at preschool age with gait disorder, hyperlordosis, and truncal hyperkinesia with progressive generalization and distinct orofacial involvement over the course of time. The family histories were unremarkable. The etiological classification remained unclear despite extensive diagnostics including neuroimaging. Only through exome sequencing, three new mutations in the KMT2B gene could be identified—two mutations with truncated and probably instable dysfunctional KMT2B (de novo c.3596_3697insC, p.M1202Dfs*22; heterozygote c.4229delA, p.Q1410Rfs*12) as well as one missense mutation (de novo c.7463A>G, p.Y2488C), which in turn leads to an amino acid change (tyrosine) in the poorly characterized C-terminal phenylalanine/tyrosine-rich (FYRC) domain of KMT2B, which is highly conserved in mammals. The FYRC domain is involved in protein–protein interactions and stabilization of KMT2B. A fourth mutation—an in-frame deletion (de novo c.4966_4968TCCdel, p.Ser1656del) has previously been published in a case report (Lange et al, 2017). KMT2B is a histone methyltransferase and regulates the expression of specific genes in the nucleus. The molecular mechanism of KMT2B-associated dystonia remains unclear. A loss of function in trithorax—an ortholog to KMT2B in the fruit fly affects axonal guidance through disruption of glial laminae.

Three patients responded to trihexyphenidyl with restoration of independent ambulation. Further antidystonic medication (levodopa, dopamine agonists, and baclofen) showed no effect. Injections with botulinum toxin showed only mild improvement for cervical dystonia in one patient and for lower extremities in another patient. Bilateral deep brain stimulation in the internal globus pallidus (GPi-DBS) showed sustainable improvement of symptoms in two patients (implantation at the ages of 7 and 10 years).

Conclusion: Through exome sequencing, the probability of a swift etiological classification may rise in childhood-manifested dystonia, and accordingly, therapy options may be utilized. Anticholinergic medication and GPi-DBS present effective therapeutic options for several patients with mutations in KMT2B.