Objective: To describe a novel association between parkinsonism and a pathogenic variant in the KMT5B gene, expanding the clinical spectrum of KMT5B-related disorders.

Background: Neuropsychiatric disorders can present with parkinsonism, often linked to neuroleptic treatment [1]. However, heredodegenerative disorders can also manifest with both psychiatric and movement disorders, complicating diagnosis. KMT5B encodes a histone methyltransferase essential for neurodevelopment, and pathogenic variants in this gene have been associated with developmental delay, intellectual disability, autism spectrum disorder and dysmorphic features [2]. The motor delay and hypotonia also observed in KMT5B patients are attributed to defects in skeletal muscle maturation [3]. Other histone methyltransferases, such as KMT2B, have been associated to movement disorders, particularly dystonia [4]. To date, no movement disorder has been reported in KMT5B-related conditions.

Method: Case report.

Results: We report the case of a 38-year-old woman with lifelong psychomotor delay, autistic features, intellectual disability and dysmorphic traits. She developed progressive parkinsonism at age 27 while receiving neuroleptic treatment. Clinical evaluation included neurological examination, SPECT imaging with ioflupane (123I), and genetic analysis, including next generation sequencing. Neurological findings revealed hypomimia, hypometric saccades, bradykinesia, rigidity, mild postural tremor, and pyramidal signs. Imaging [figure1] showed bilateral, asymmetrical dopaminergic deficit, suggesting a neurodegenerative component beyond the drug-induced parkinsonism. Whole-exome sequencing identified the heterozygous de novo c.581G>T (p.Gly194Val) variant in the KMT5B gene (NM_017635.4). The variant was absent from population databases, predicted to be deleterious, and classified as pathogenic per ACMG guidelines [5]. The patient’s parkinsonism remained stable despite neuroleptic reduction, and levodopa treatment was not initiated due to patient and family preference.

Conclusion: This case expands the phenotypic spectrum of KMT5B-related disorders, suggesting that parkinsonism may contribute to the motor features. While neuroleptic treatment could have contributed, imaging findings indicate a primary nigrostriatal dysfunction. Further studies are needed to determine the role of KMT5B in movement disorders.

Figure1

References: 1. Conn H, Jankovic J. Drug-induced parkinsonism: diagnosis and treatment. Expert Opin Drug Saf. 2024 Dec;23(12):1503-1513. doi: 10.1080/14740338.2024.2418950.

2. Eliyahu A, Barel O, Greenbaum L, et al. Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay. Front Pediatr. 2022 Mar 30;10:844845. doi: 10.3389/fped.2022.844845.

3. Hulen J, Kenny D, Black R, et al. KMT5B is required for early motor development. Front Genet. 2022 Aug 12;13:901228. doi: 10.3389/fgene.2022.901228.

4. Cif L, Demailly D, Lin JP, et al. KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation. Brain. 2020 Dec 5;143(11):3242-3261. doi: 10.1093/brain/awaa304.

5. Richards S, Aziz N, Bale S, et al; ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/parkinsonism-in-kmt5b-related-disorders-expanding-the-spectrum/