Objective: To report the association of lysine-specific histone-methyltransferase 2B gene (KMT2B)-related dystonia (DYT28) and Klippel-Feil Syndrome (KFS).

Background: Dystonia is a hyperkinetic movement disorder characterized by involuntary, sustained or intermittent muscle contractions that cause repetitive and twisting movements or abnormal postures [1]. DYT28 has recently emerged as an important cause of dystonia [2] and represents up to 10% of generalized early-onset dystonias [3]. DYT28 typically presents with foot dystonia, progressing to generalized dystonia over 2-4 years in most cases. Laryngeal dystonia is frequent. About forty-seven variants, (microdeletions, missense, nonsense, frameshift and splice-site) have been described so far [4]. KFS is defined as the congenital fusion of two or more cervical vertebrae and may be associated with other systemic abnormalities [5].

Method: We described a clinical association between KFS and KMT2B-related dystonia emphasizing clinical, laboratorial and radiological data.

Results: A female patient born full-term from non-consanguineous parents presented with congenital scoliosis and was diagnosed with KFS with Sprengel’s anomaly at age 1. Interventricular communication, facial asymmetry, retrognathia, irregularity in dental implantation and 5^th finger clinodactyly bilaterally were noted. At age 6, she presented with focal foot dystonia, which generalized over the following years. There was no family history of dystonia, abnormal neck posture, or skeletal abnormalities. Brain MRI was normal. Spine MRI showed abnormal fusion between cervical and upper thoracic vertebrae, signs of fusion of the right upper ribs associated to bifid rib; and sinister-convex scoliosis in the cervicothoracic transition. Genetic testing showed microdeletion on chromosome 19 between the 19q13.11q13.12 bands, consistent with the cytogenetic location of KMT2B (OMIM 606834). Currently at age 11, she has severe generalized dystonia with partial levodopa response (300 mg/day) and severe spasmodic dysphonia.

Conclusion: Although abnormal neck posture is not infrequent in patients with KFS, generalized dystonia is rarely found [6]. The co-occurrence of typical KMT2B-related dystonia, consisting of focal foot dystonia at onset, with frequent generalization involving laryngeal dystonia, has not been reported in association with KFS to our knowledge. A pathophysiologic and genetic association remains to be investigated.

References: 1. Albanese, A., Bhatia, K., Bressman, S. B., DeLong, M. R., Fahn, S., Fung, V. S., … & Lang, A. E. (2013). Phenomenology and classification of dystonia: a consensus update. Movement Disorders, 28(7), 863-873. 2. Zech, M., Boesch, S., Maier, E. M., Borggraefe, I., Vill, K., Laccone, F., … & Poewe, W. (2016). Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. The American Journal of Human Genetics, 99(6), 1377-1387. 3. Lohmann, K., & Klein, C. (2017). Update on the genetics of dystonia. Current neurology and neuroscience reports, 17(3), 26. 4. Carecchio, M., Invernizzi, F., Gonzàlez‐Latapi, P., Panteghini, C., Zorzi, G., Romito, L., … & Joseph, A. P. (2019). Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single‐center cohort study. Movement Disorders, 34(10), 1516-1527. 5. Jasper, A., Sudhakar, S. V., & Sridhar, G. V. (2015). The multiple associations of Klippel–Feil syndrome. Acta Neurologica Belgica, 115(2), 157-159. 6. Nouri, A., Patel, K., Evans, H., Saleh, M., Kotter, M. R., Heary, R. F., … & Cheng, J. S. (2019). Demographics, presentation and symptoms of patients with Klippel-Feil syndrome: analysis of a global patient-reported registry. European Spine Journal, 28(10), 2257-2265.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/kmt2b-related-dystonia-dyt28-and-klippel-feil-syndrome-a-new-association/