Two groups of researchers independently described KMT2B gene mutations causing childhood‐onset dystonia in 2016. 1 , 2 KMT2B‐dystonia usually presents in the first decade of life with lower limb symptoms that progressively generalize. Patients have varying intellectual disability, dysphonia, and facial dysmorphism.
Our proband is a 41‐year‐old male who presented with a decade of hand tremors, 2 years of head bobbing, and normal childhood gross motor development. Examination revealed head rotation and tilt to the right, severe hypertrophy in sternocleidomastoid and trapezii muscles, but no dysphonia or abnormal facial features. Severe neck retro‐flexion and arching of the back made ambulation difficult (Video S1).
Burke‐Fahn‐Marsden Movement and Disability Subscales (BFMMS, BFMDS) were 35 and 4, respectively. Intellectual function was at the 1st percentile (score 63, Wechsler Adult Intelligence Scale, 4th edition). Magnetic Resonance Imaging (MRI) of the brain was unremarkable. Anticholinergics, benzodiazepines, muscle‐relaxants, and botulinum toxin were only partially effective. The patient's mother had right hand dystonia and postural tremor (Video S1). Next‐generation sequencing and copy number analysis revealed missense mutation (NM_014727.2: c.4960T>C (p.Cys1654Arg) in KMT2B in both the proband and mother. Other monogenic causes of dystonia were excluded (Supporting information in Appendix S1).
The patient underwent bilateral GPi directional electrode implantation with robotic assistance (ROSA®). Surgery was performed awake with a CRW frame and co‐registration of pre‐operative 3.0 Tesla MRI and intraoperative CT scan. There were no untoward stimulation effects with microelectrodes from 15 mm above target, and final electrodes were implanted in the bilateral ventral posterolateral GPi, then confirmed by post‐operative CT. His clinical effect was rapid (several days, see Video S1), with initial stimulation parameters of 2.5 milliamp, 120 microsecond pulse width at 130 Hertz (right lead contacts E10‐11‐12, left lead contacts E2‐3‐4). One month after initial programming, BFMMS and BFMDS scores were 4 and 1, respectively. Preoperative medications were ceased.
Our proband's dystonia started in his upper extremity in his late 20's and worsened to involve the neck and trunk. KMT2B‐ related dystonia typically starts in childhood with lower limb involvement, then generalizes. Involvement of the larynx and oromandibular region is nearly universal. Almost 80% of KMT2B‐related dystonia patients have generalized dystonia. 3 Dystonic hand tremor as the only manifestation of KMT2B‐related dystonia in his mother is extremely rare. Almost 30%–50% of cases can have non‐motor abnormalities such as dysmorphism, intellectual or developmental disability, short stature, microcephaly, dysphonia, or deafness. Our index case had intellectual disability, but no other non‐motor manifestations.
Only one other family has been described with KMT2B‐related dystonia due to this exact mutation. 4 PolyPhen and SIFT analysis predict this variant's pathogenicity. This allele is not found in the gnomAD database. Generally, older age at surgery is associated with worse outcomes in dystonia, as in Torsin‐1 related dystonia (DYT‐TOR1A). With a handful of cases reported, KMT2B‐related disease seems to respond well to surgery despite older age. Improvement in the BFMMS score in our patient post‐DBS was comparable to that of DYT‐TOR1A. GPi DBS in DYT‐SGCE, DYT‐ACTB, DYT‐TAF1, and DYT‐GNAO1 have yielded results comparable to that of DYT‐TOR1A, whereas outcomes were worse in DYT‐THAP1, DYT‐PANK2, and DYT‐ADCY‐5. 5
Author Roles
Research project: A. Conception, B. Organization, C. Execution;
Statistical Analysis: A. Design, B. Execution, C. Review and Critique;
Manuscript Preparation: A. Writing of the first draft, B. Review and Critique
N.W.: 1B 1C, 2C, 3A 3B
A.M.: 1A, 2C, 3B
D.L.: 1A 1B 1C, 2A 2B, 3A 3B
L.Z‐R.: 1A, 2A, 3B
Disclosures
Funding Sources/Conflict of Interest
No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the previous 12 months
The authors declare that there are no additional disclosures to report.
Ethical Compliance Statement
The local institutional review board deemed no formal was necessary to complete this case report. The ethical principles outlined by the European Association for Chemical and Molecular Sciences were followed in the composition of this manuscript. Written consent for collection and publication of patient data was obtained prior to manuscript preparation or video sample recording. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Supporting information
Appendix S1. Supplementary material: List of genes included in comprehensive dystonia genetics panel used for clinical work‐up of proband.
Video S1. Severe retrocollis with some lateral neck tilt, mild scoliosis, and posturing of the hands.
Video S2. Symptom improvement with walking.
Video S3. Mild retrocollis and laterocollis to the right still remain 1 month after stimulation began.
Video S4. Kinetic tremor of the right hand in the patient's mother.
Video S5. Posturing of the right hand while outstretched.
Acknowledgment
The authors would like to thank the staff of the Illinois Neurological Institute for helping coordinate patient care and visits.
References
- 1. Zech M, Boesch S, Maier EM, et al. Haploinsufficiency of KMT2B, encoding the lysine‐specific histone methyltransferase 2B, results in early‐onset generalized dystonia. Am J Hum Genet 2016;99(6):1377–1387. 10.1016/j.ajhg.2016.10.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Meyer E, Carss KJ, Rankin J, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early‐onset dystonia. Nat Genet 2017;49(2):223–237. 10.1038/ng.3740. [DOI] [PubMed] [Google Scholar]
- 3. Zech M, Lam DD, Winkelmann J. Update on KMT2B‐related dystonia. Curr Neurol Neurosci Rep 2019;19(11):92 10.1007/s11910-019-1007-y. [DOI] [PubMed] [Google Scholar]
- 4. Ng A, Galosi S, Salz L, et al. Failure to thrive – an overlooked manifestation of KMT2B‐related dystonia: a case presentation. BMC Neurol 2020;20(1):246 10.1186/s12883-020-01798-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Artusi CA, Dwivedi A, Romagnolo A, et al. Differential response to pallidal deep brain stimulation among monogenic dystonias: systematic review and meta‐analysis. J Neurol Neurosurg Psychiatry 2020;91(4):426–433. 10.1136/jnnp-2019-322169. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1. Supplementary material: List of genes included in comprehensive dystonia genetics panel used for clinical work‐up of proband.
Video S1. Severe retrocollis with some lateral neck tilt, mild scoliosis, and posturing of the hands.
Video S2. Symptom improvement with walking.
Video S3. Mild retrocollis and laterocollis to the right still remain 1 month after stimulation began.
Video S4. Kinetic tremor of the right hand in the patient's mother.
Video S5. Posturing of the right hand while outstretched.