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 difficulty secondary to a dystonic posture aggravated by ambulation with left hip adduction, clubfoot, and ipsilateral scapular elevation that progressed during the following five 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. Next-generation 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 significance (VUS). In the light of these findings the study was also performed to the patient’s uncle and asymptomatic mother, confirming 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.
KMT2B gene mutation as a cause of dystonia was first described in 2016.(2) Since then, 66 mutations in at least 133 patients have been reported.(3–6) Most of them are de novo, embracing delections, nonsense, splice-sice and missense mutations.(4, 5) Our mutation is registered in the database as a variant present in the European population with a prevalence of 0,0004%.(7) Nevertheless, due to the low prevalence of this variant in the general population and the low penetrance and high intrafamilial variability of this entity,(2, 4, 6) we suggest that this mutation might be a pathogenic variant.
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 difficulty to a disease that is already a diagnostic challenge, even more so for clinicians who are not movement disorder specialists.