PubMed · 2927668
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W C Koller. 1989. Task-specific dystonias.. https://doi.org/10.1212/wnl.39.3.457
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INTRODUCTION: Pathogenic variants in KMT2B cause early-onset dystonia, but a mouse model that has undergone comprehensive, dystonia-oriented phenotyping is lacking. METHODS: We conducted detailed phenotyping on heterozygous Kmt2b constitutive knockout mice and wild-type littermates, assessing growth, neurobehavioural traits, motor coordination, sensorimotor gating, social behaviour and metabolic parameters, combined with striatal RNA sequencing. RESULTS: Kmt2b knockout mice of both sexes were viable but significantly smaller and lighter than littermate controls. Knockouts were hyperlocomotive in the open field and showed approximately two-fold larger acoustic startle responses; unexpectedly, prepulse inhibition was enhanced rather than reduced at all prepulse intensities. On the balance beam, knockouts crossed more slowly and paused more frequently; female knockouts also paused more on the ladder rung task. Frame-by-frame video analysis revealed a claw-like hindpaw posture characterized by abnormal inward flexion of the digits. Knockout mice spent less time investigating a novel conspecific, while social recognition memory remained intact. Striatal RNA sequencing confirmed reduction of Kmt2b transcript to approximately half of control levels and identified 177 differentially expressed genes, including Maob, encoding monoamine oxidase B; gene set enrichment analysis implicated neurodevelopmental, glial and mitochondrial processes. Nociception, vision, body-weight-adjusted grip strength, and clinical chemistry and haematological measures were largely unaffected. CONCLUSION: Heterozygous Kmt2b knockout mice show hyperlocomotion, altered sensorimotor gating, impaired motor coordination with dystonic-like paw posturing and reduced sociability, alongside a striatal transcriptomic signature implicating neurodevelopmental processes. The model mirrors aspects of human KMT2B-related dystonia and provides a platform for mechanistic study; environmental or pharmacological challenge may be needed to unmask overt dystonic features.
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A 48 year old woman complained of mild weakness and paresthesias of the left limbs, followed 15 days later by episodes of paroxysmal dystonia of the left limbs occurring several times daily over 10 day period. Magnetic resonance imaging (MRI) of head and neck revealed a small area of altered signal in the T2-weighted sequences in the left posterolateral quadrant of the cord at the second cervical vertebra. An MRI scan 18 months later showed no lesion. This is the second case of paroxysmal dystonia with a single MRI lesion in the cervical region on record.