Reviewing the Clinical Spectrum Related to Kmt2b Gene Mutations: Unusual Clinical Presentation and a Possible New Pathogenic Mutation

KMT2B related is a generalized its 2016, different phenotypic spectrum have been reported. The aim of the case report is to provide data that may help to understand the spectrum of KMT2B-related disorders. We present two members of a family with a possible non-previously described pathogenic mutation and an unusual KMT2B related dystonia presentation: an adult onset and focal dystonia.


Introduction
KMT2B related dystonia, also known as DYT 28, is a childhood onset movement disorder characterized by lower limb dystonia that progresses to a generalized dystonia with cervical, cranial, and laryngeal involvement that causes dysphagia and/or dysphonia. Intellectual impairment associated with facial dysmorphic signs (elongated face with nasal tip) has been described in more than 50% of reported cases.
Other signs and symptoms are less frequently found: short stature, other movement disorders, eye movement abnormalities and dermatologic features. The aim of the case report is to provide data that may help to understand the spectrum of KMT2B-related disorders. We present two members of a family with a new KMT2B mutation and unusual clinical presentation: adult onset in the index patient and focal dystonia in her family.

Case Presentation
The index patient is a 32 year-old woman with no previous medical history with the exception of anxiety disorder. She presented an insidious walking di culty secondary to a dystonic posture aggravated by ambulation with left hip adduction, clubfoot, and ipsilateral scapular elevation that progressed during the following ve years, affecting ocular movements and causing dysphagia and hypophonic speech. On directed anamnesis she related a maternal uncle (82 year-old) with a childhood-onset static torticollis.
Cognitive function was not affected. Additional tests including an extensive blood test, electromyography and complete column and cranial MRI were normal. Since clinic picture suggested a hereditary generalized dystonia, a genetic panel for DYT was performed after obtaining informed consent. Nextgeneration sequencing revealed a heterozygous missense mutation in KMT2B gene (19q13.12) with a change in the nucleotide c.4219 G > A and therefore in the p.Gly1407Arg aminoacid, described as a variant of uncertain signi cance (VUS). In the light of these ndings the study was also performed to the patient's uncle and asymptomatic mother, con rming the same mutation found in the index patient. The rest of the patient's family -including the mother-was healthy. Treatment with botulinum toxin was successfully initiated in the index patient. Patients's phenotypes were markedly different in spite of presenting the same mutation, adding evidence to the penetrance variability of this mutation. Although characteristic phenotype (83% of patients) of the disease is a childhood onset dystonia (mean age at onset 6.4 ± 5.9 y.o) with a generalized progression, adult onset has been described with only few cases in the late adulthood. (1, 5, 6, 8) Mutation found in these patients was a missense type, (3, 8) same mutation found in our patient and known to be related to a later onset dystonia.(5) Delection mutations are related with a lower age onset of the disease.(8) Also focalized dystonia has been described in two patients of the same family, (2) as our patient's family presented. Asymptomatic mothers can be carriers of the mutation (2) and carrier parents may present sub-clinical disease features and therefore report no symptoms.(8) It has been showed that approximately 9% of inherited mutations are received from an asymptomatic progenitor, (3) suggesting an incomplete penetrance which is further reduced in missense mutations. (8) Despite it is not infrequent de novo mutations, (4) since some patients with healthy progenitors may have been diagnosed with de novo mutations without genetic testing of family members,(4) this rate of inherited KMT2B mutation from asymptomatic carriers could have been underestimated.
Development of next generation sequencing has allowed a better insight to the understanding of genetically determined dystonias, that often present additional neurological and systemic features, being the psychiatric clinic in close relationship with neurological symptomatology. Hyperactivity disorder and anxiety has shown to be frequent in DYT 28,(4) as the index patient presented and hampered the diagnosis. Subtle features of dystonia could have been present in our patient years before referral to specialist, as well as non-motor features such as the anxiety disorder.
The variety in the way this entity develops over the years together with its phenotypic variability add di culty to a disease that is already a diagnostic challenge, even more so for clinicians who are not movement disorder specialists.

Conclusions
KMT2B related dystonia is an emerging and prevalent monogenic dystonia whose incidence, genetic variability and semiology remain unknown. Despite the study of this gene is indicated in childhood onset dystonia, description of cases such as ours shows that its sequencing in patients with an adult-onset dystonia with family history can be useful for the diagnosis and further description of KMT2B-related disorders.

Declarations i. Funding:
This work received no funding.

ii. Con icts of interest/Competing interests:
This research did not receive any speci c grant from funding agencies in the public, commercial, or notfor-pro t sectors.
iii. Ethics approval: Therapeutic clinical decisions were supported by the best available evidence from health care research.
iv. Consent to participate: Consent to participate was obtained from the patient. v. Consent for Publication: Written informed consent was obtained from the patient for publication of this case report.
vi. Availability of data and material: Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
vii. Code availability (software application or custom code): Not applicable.
viii. Authors' contributions: CT.P. wrote the Case Report. J.O.R supervised and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.