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Year : 2021  |  Volume : 69  |  Issue : 5  |  Page : 1400--1401

A Novel Mutation in KMT2B Gene Causing Childhood-onset Generalized Dystonia with Expanded Phenotype from India

Hansashree Padmanabha, Akash M Awati, Kurian Thomas, Gosala R K Sarma 
 Department of Neurology, St Johns Medical College and Hospital, Bengaluru, Karnataka, India

Correspondence Address:
Gosala R K Sarma
Department of Neurology, St Johns Medical College and Hospital, Bengaluru, Karnataka


Mutations in KMT2B (lysine-specific methyltransferase 2B) gene, which is primarily involved in methylation of Histone3lys4 (H3K4), has been recently described to cause early-onset generalized progressive dystonia (DYT28) by two independent researchers. Unlike other primary dystonias, mutations in KMT2B gene is associated with additional features like dysmorphism (elongated face, bulbous nose), microcephaly, short stature, and multisystemic involvement. Herein, we describe a 13-year-old boy with early-onset, generalized, progressive complex severe dystonia, along with mild intellectual disability, dysmorphism, and dermatological manifestations associated with a novel missense variation in KMT2B gene and also expand the phenotypic spectrum of the same.

How to cite this article:
Padmanabha H, Awati AM, Thomas K, K Sarma GR. A Novel Mutation in KMT2B Gene Causing Childhood-onset Generalized Dystonia with Expanded Phenotype from India.Neurol India 2021;69:1400-1401

How to cite this URL:
Padmanabha H, Awati AM, Thomas K, K Sarma GR. A Novel Mutation in KMT2B Gene Causing Childhood-onset Generalized Dystonia with Expanded Phenotype from India. Neurol India [serial online] 2021 [cited 2022 Jan 18 ];69:1400-1401
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Full Text

Childhood-onset dystonias are complex hyperkinetic movement disorders, which can be either inheritedor acquired. With the advent of next generation sequencing there has been a drastic increase in the list of identification of novel genes causing complex childhood-onset dystonias.[1] Recently, in 2016, two researchers independently identified loss of function mutations in KMT2B gene as an emerging cause of early childhood-onset progressive complex dystonias.[2],[3] We report a 13-year-old boy with early-onset, generalized, progressive complex dystonia, along with mild intellectual disability, dysmorphism, and dermatological manifestations associated with a novel missense variation in KMT2B gene and recognize additional features to its phenotype. To the best of our knowledge, this is the first reported case of KMT2B mutation from India.


A 13-year-old boy had presented to us with abnormal generalized twisting postures involving the limbs, trunk, and face with onset from 8 years of age. These movements initially started with the left foot, subsequently over an year it progressed to involve the right lower limb, both upper limbs, trunk, neck, and orofacial muscles. These movements disappeared in sleep and there was no diurnal fluctuation. Since the onset of these movements, there has been a decrease in speech output, understanding, play with peers and he had dropped out of the school because of the functional incapacitance. He was first born to a healthy non-consanguineous couple with smooth perinatal transition. Family history was unremarkable. On examination, he had a normal head circumference (53 cm), grey hairs, acne vulgaris, bluedot cataract, and mid-thoracic scoliosis. He had dysmorphic features with an elongated face, bushy eyebrows, and a bulbous nose. Neurologically there was dysarthria, axial, and appendicular dystonia with severe cervical and oro-mandibular dystonia, dystonic tremors involving the head, mild choreiform movements in upper limbs with diminished reflexes. A clinical possibility of a childhood-onset primary generalized dystonia was considered and anti-dystonic measures were initiated. However, he failed levodopa trial. Presenly, on trihexyphenidyl, clonazepam and tetrabenizine at optimal doses, with not much therapeutic response.

His investigations revealed a normal MRI brain, normal nerve conduction, normal serum ceruloplasmin levels, normal plasma ammonia and lactate. Brainstem evoked response audiometry showed evidence of sensorineural hearing loss. Targeted next generation sequencing of dystonia gene panel identified a previously unreported heterozygous missense variation in exon 24 of the KMT2B gene (chr19:36221280G>A; Depth: 99x) that results in the amino acid substitution of Glutamine for Arginine at codon 1705. The pathogenecity of the variant was further confirmed by Sanger sequencing. Parental screening could not be performed for the reported variation. As parents were clinically asymptomatic, a final diagnosis of childhood-onset dystonia caused due to a denovo mutation in KMT2B gene was considered.


Recently, two investigators Zech et al. and Meyer et al. independently have described a novel autosomal dominant, early childhood-onset complex dystonia syndrome caused due to loss of function mutations and microdeletions in the Lysine-Specific Methyltransferase 2B (KMT2B) gene.[2],[3] KMT2B-dystonia (DYT28), though described recently, is emerging as an important cause of childhood-onset primary dystonia accounting for 10% of cases.[4] So far, around 12 missense variations in KMT2B gene have been reported.[4],[5] The present case adds to the list and also expands the phenotype of DYT28.

KMT2B, located on chromosome 19q13.12 belongs to a member of SET/MLL protein family, is ubiquitously expressed with highest expression in the cerbellum.[3] It is involved in the methylation of Histone3lys4 (H3K4) which is an important epigenetic modification essential for gene activation and normal development.[3] The pathophysiology of dystonia in KMT2B gene mutation is uncertain. However, few attribute it to the decreased expression of KMT2B in fibroblasts leading to destabilization of the protein and erratic circuits.[2],[3] Others hypothesize it to the decreased expresssion of dystonia causing genes like THAP1 and TOR1A in fibroblasts secondary to loss of function mutations in KMT2B gene.[3] DYT28 dystonia is inherited as an autosomal-dominant condition mostly denovo and rarely autosomal dominant with incomplete penetrance has been reported.[3] The genotype–phenotype correlation of KMT2B gene suggests a milder and an earlier age of clinical presentation in those with missense variations, as compared to loss of function mutations and microdeletions.[3] Though the index child with missense variation had an earlier age of onset, he had severe generalized dystonia with additional systemic manifestations.

The phenotype described in majority of patients has a mean age of onset of 5.8 years (range 1–23 years).[5] Dystonia typically begins with lower limbs in form of foot deformity, toe walking, or gait disturbances. Subsequently, it becomes generalized overtime (mean 4.4 years, range 1–9 years) with involvement of trunk and upper limbs. Interesting feature of DYT28 dystonia is that it extends to invlove the cervical, oro-mandibular, and facial region unlike other primary dystonias. Few also experience aggravation with intercurent illnesses. Apart from dystonia, additional features described with DYT28 include microcephaly (21%), short stature (21%), preceeding developmental delay, mild to moderate intellectual disability, dermatological manifestations like cutis aplasia, renal involvement, retinal dystrophy, oculomotor abnormalities (impaired saccades, strabismus) and behavioral disturbances like depression and anxiety. Dysmorphic features in form of elongated face, bulbous nasal tip, sparse eyelashes and eyebrows, 5th finger clinodactyly and 2nd and 3rd fingers syndactyly have been reported frequently in those patients with loss of function mutations and microdeletions.[4] In addition, to the previously described features, the index child also had premature grey hairs, blue-dot cataract, profound acne vulgaris, and deafness. Neuroimaging feature described in those who undergo an early imaging (average age of 11.7 years) include bilateral symmetrical hypointensity at the lateral part of globus pallidus externa in T2, diffusion and susceptibility weighted MRI.[3] Nonetheless, imaging of index child was normal. As far as treatment is considered, anti-dystonic medications and levodopa have been proven ineffective. Beneficial reports of globus pallidus interna-deep brain stimulation (GP-DBS) have been reported in around 13 patients so far.[4]


Mutations in KMT2B gene are a novel emerging cause of an autosomal-dominant, complex, progressive, childhood onset dystonia DYT28. Additional manifestations like microcephaly, short stature, dysmorphism, opthalmological, renal, psychiatry and dermatological involvement differentiates DYT28 dystonia from other primary dystonias.

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2Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, et al. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet 2016;99:1377-87.
3Meyer E, Carss KJ, Rankin J, Nichols JM, Grozeva D, Joseph AP, et al. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet 2017;49:223-37.
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