Objective: To investigate the genetic defect in patients with early-onset dystonia and myoclonus accompanying various neurological features.

Background: Unlike other Mendelian disorders, dystonia genetics has been progressing at a very slow pace due to difficulty assuming the genetic model. Moreover, there have been few pathological hallmarks in dystonia except DYT3, therefore, identification of dystonia gene contributes to diagnosis and understanding pathophysiology in dystonia.

Methods: A cohort of patients with seemingly sporadic early-onset generalized combined dystonia recruited in Japan was investigated clinically and genetically. After exclusion of the genes currently known to be associated with generalized dystonia, we conducted the whole-exome trio analysis including proband and parents. Biological effects by nucleotide variation were predicted using bioinformatic tools and confirmed by reverse transcription polymerase chain reaction (RT-PCR) experiment. Measurement of KMT2B transcripts were conducted in cultured T cells treated with nonsense pre-mRNA mediated decay (NMD) inhibitor.

Results: Two patients had de novo heterozygous frameshift mutations in KMT2B, c.3325_3326insC (p.Arg1109Profs*4) and c.5631delG (p.Gly1879Valfs*16). Measurement of KMT2B transcripts showed haploinsufficiency as the underlying pathogenic mechanism. Clinical features of the two cases included myoclonus-dystonia, psychomotor impairment, microcephaly, as well as short stature.

Conclusions: Mutations in KMT2B are associated with myoclonus-dystonia with impaired psychomotor ability.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/haploinsufficiency-of-kmt2b-causes-myoclonus-dystonia-with-impaired-psychomotor-ability/