KMT2B-Related Dystonia (DYT-KMT2B) and Isolated Monogenic Dystonias

Childhood-onset dystonia, autosomal dominant and often de novo, caused by haploinsufficiency of the histone methyltransferase KMT2B; it usually begins in the lower limbs, generalises with cervical, cranial and laryngeal involvement and responds partially and heterogeneously to pallidal deep brain stimulation. The article places it within the class of isolated monogenic dystonias.

Literature and regulatory information updated: 31 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition of dystonia and the place of monogenic forms

Dystonia is defined, in the 2025 revision of the international consensus, as a movement disorder characterised by sustained or intermittent muscle contractions causing abnormal movements, abnormal postures or both; dystonic movements and postures are typically patterned and repetitive, may be tremulous or jerky, are often initiated or worsened by voluntary action and are frequently associated with overflow movements into regions not involved in the task [13]. The revision retained, with minor clarifications, the 2013 definition and the two-axis classification: axis I describes the clinical features (age at onset, family history, body distribution, temporal dimensions, phenomenology and presence of other neurological or systemic signs), and axis II organises the aetiology (genetic, acquired or anatomical) and the mechanisms [13, 14]. The 2017 Oxford Desk Reference of clinical genetics still presents the earlier aetiological classification into primary, secondary and heredodegenerative dystonias and estimates the prevalence of dystonia of all causes at between 127 and 329 per million, with the caveat that the true figure is probably higher; the focal form is the most common [15]. The division into primary and secondary was abandoned by the international consensus in favour of the distinction between isolated and combined dystonia, described in subsection 1.4.

1.2. From numerical DYT nomenclature to gene-by-gene designation

For decades the monogenic dystonias were designated by the acronym DYT followed by a number reflecting the chronological order in which the phenotype or locus was described; the list accumulated erroneous, duplicated and never-confirmed loci, as well as phenotypes that were not predominantly dystonic [2]. Marras and colleagues proposed in 2012 a system that combines the phenotype prefix with the gene symbol, and the Task Force on Nomenclature of Genetic Movement Disorders of the International Parkinson and Movement Disorder Society (MDS) formally recommended it in 2016 and revised it in 2022 [2, 16]. KMT2B-related dystonia thus came to be designated DYT-KMT2B, with the numerical designation DYT28 retained in OMIM (Online Mendelian Inheritance in Man) and Orphanet, and the expression "KMT2B-deficient dystonia" in some epigenetics papers [1, 8]. The paroxysmal movement disorders ceased to use the DYT prefix and moved to the PxMD prefix [2].

1.3. Discovery of KMT2B as a dystonia gene

The gene was linked to dystonia almost simultaneously by two independent groups between late 2016 and early 2017 [2]. Zech and colleagues sequenced the exome of an Austrian trio with early-onset generalised dystonia and no family history and identified a de novo frameshift variant, c.6406del p.(Leu2136SerfsTer17); among 30 German-Austrian patients with the same phenotype they found three further variants introducing a premature stop codon, two de novo and one inherited that co-segregated with dystonia in a three-generation family, and they demonstrated reduced total KMT2B messenger RNA in fibroblasts, pointing to haploinsufficiency [17]. The phenotype was dominated by generalised dystonia with onset in the lower limbs in childhood, accompanied by heterogeneous non-motor features, and the family with the inherited variant showed variable expressivity [17]. Meyer and colleagues, in the consortium led by Manju Kurian, described heterozygous variants in 27 unrelated individuals with a complex, progressive childhood-onset dystonia, often with a distinctive facial appearance and characteristic findings on magnetic resonance imaging (MRI); over time most developed prominent cervical, cranial and laryngeal dystonia, and deep brain stimulation (DBS) produced marked benefit, with recovery of independent walking in some patients [18]. Both groups noted that dystonia was frequent in the 19q13.11–q13.12 microdeletion syndromes that include the gene [17, 18]. The Oxford Desk Reference included the entity as early as 2017 as "KMT2B-associated early-onset complex dystonia", predicted that it would become a common cause of childhood dystonia and recommended KMT2B sequencing, alongside testing for the DYT1 variant, in patients with onset before 26 years of age [15].

1.4. Isolated, combined and "complex" dystonia

In isolated dystonia, dystonia is the only motor or neurological manifestation; accompanying dystonic tremor does not count as a separate disorder [2]. Combined dystonia is associated with another movement disorder (myoclonus, tremor, chorea, parkinsonism, ataxia), with other neurological signs (corticospinal signs, epilepsy, developmental delay) or with systemic manifestations; the term "complex dystonia", used for forms with systemic features, ceased to be recommended in 2025 owing to lack of agreement on its boundaries [2, 13]. DYT-KMT2B occupies a borderline position: the GeneReviews overview of the class includes it among the 12 isolated monogenic dystonias with the qualifier "isolated or combined", the ERN-RND flowchart describes it as isolated dystonia with focal lower-limb involvement and secondary progression, occasionally with developmental delay, and Orphanet defines it as persistent combined dystonia [2, 8, 19]. In a cohort of 68 carriers, 58% had combined or complex dystonia and 41% isolated dystonia, and the larger cohorts describe mainly combined forms [1]. The classification therefore depends on the timing of the observation and on the extent of the neurological and developmental assessment.

1.5. Entities covered in this article

KMT2B-related disorders comprise two presentations: DYT-KMT2B, described in 93% of families, and a non-dystonic neurodevelopmental disorder, in 7%, which includes global delay, intellectual disability, growth restriction and ectodermal features and corresponds to the OMIM entry MRD68 [1, 7]. Heterozygous 19q13.11–q13.12 deletions encompassing the gene cause either of the two presentations, with a predominance of systemic features [1]. DYT-KMT2B belongs to the class of the 12 isolated monogenic dystonias, presented in a dedicated table in section 6, with a more detailed description of the forms that are most frequent or most relevant to treatment decisions: DYT-TOR1A, DYT-THAP1, DYT-GNAL, DYT-VPS16 and DYT-PRKRA [2]. The combined dystonias (dopa-responsive dystonia and neurotransmitter defects, X-linked dystonia-parkinsonism due to TAF1, Mohr-Tranebjærg syndrome, neurodegeneration with brain iron accumulation, Wilson disease) appear only in the differential diagnosis.

2. Molecular Genetics and Pathophysiology

2.1. The KMT2B gene and protein

KMT2B lies at 19q13.12 and encodes histone-lysine N-methyltransferase 2B, a ubiquitously expressed protein of the SET/MLL (mixed-lineage leukemia) family, also known by the historical designations MLL2 and MLL4 [1, 3]. The designations MLL2 and MLL4 were applied interchangeably to KMT2B and KMT2D in the older literature, so reports and searches should use only the symbol approved by the HGNC (HUGO Gene Nomenclature Committee) [3]. The protein transfers methyl groups from S-adenosyl-L-methionine to lysine 4 of histone H3 (H3K4), deposits mainly the H3K4me1 and H3K4me2 marks at active promoters and enhancers, partly redundantly with KMT2C, and contains a CXXC zinc finger, three PHD fingers and the catalytic SET domain [3]. H3K4 methylation is associated with transcriptional activation and stability [1]. FitzGerald and Diaz determined in 1999 that the gene has 37 exons and spans about 20 kb and predicted a protein of 2605 or 2716 amino acids with all the MLL domains [5]. The MANE Select transcript is NM_014727.3, with the protein NP_055542.1; the c. numbering of the variants described on version NM_014727.2 coincides with that of the current version for the variants checked [4].

2.2. Disease mechanism

The established mechanism is haploinsufficiency: loss-of-function variants (nonsense, frameshift, splicing and whole-gene deletions) reduce KMT2B dosage, and the four variants of the original study decreased total messenger RNA in fibroblasts [1, 17]. KMT2B deficiency leaves a distinctive DNA methylation signature in blood, with non-random hypermethylation over-represented at promoters and other regulatory regions that positively control gene expression, suggesting widespread transcriptional repression [1]. A classifier based on 113 CpG sites, all hypermethylated in patients, accurately distinguished KMT2B deficiency from the general population and from other deficiencies of the epigenetic machinery, and the mean normalised methylation correlated with age at onset, being lower in cases with late onset or incomplete penetrance [20]. In 2026 a signature of 752 CpG sites, mostly hypermethylated, was validated, with pathogenicity scores above 85% in validation; the signature genes relate to ion transport and enzymatic activity, and some variants located in disordered regions of the protein showed methylation similar to that of controls, suggesting alternative mechanisms for those alleles [21]. How the epigenetic alteration produces dystonia has not been elucidated; GeneReviews allows that other genes and mechanisms may contribute [1]. In a heterozygous mouse model with constitutive Kmt2b inactivation, published in 2026, the animals were smaller and hyperlocomotor, had an acoustic startle response about twice as large, impaired motor coordination with hind-paw clasping and reduced sociability; striatal Kmt2b messenger RNA was reduced to about half and 177 genes were differentially expressed, including Maob; overt dystonia was not observed without an additional challenge [22]. These data are preclinical.

2.3. Variant spectrum

About 88% of patients have a heterozygous intragenic pathogenic or likely pathogenic variant and about 12% a heterozygous 19q13.11–q13.12 deletion that includes the gene; in the methods table of the same GeneReviews, sequencing detects 94% and chromosomal microarray 6% of the alterations, a difference that reflects different denominators [1]. The variants include nonsense, frameshift and splicing alleles (including a synonymous variant with an effect on splicing), small insertions and deletions and missense variants; variants in exon 1 may escape exome sequencing [1]. The following table lists the variants cited in the text, normalised in VariantValidator on the MANE transcript.

Missense hotspots are beginning to be described: residue Arg2565 was affected in two families by NM_014727.3:c.7693C>G p.(Arg2565Gly) and in one patient by de novo NM_014727.3:c.7693C>T p.(Arg2565Cys), with phenotypes ranging from childhood-onset dystonia to non-specific intellectual disability and behavioural symptoms in adulthood; the methylation signature of p.(Arg2565Gly) carriers was typical but less pronounced than that of loss-of-function variants [4, 26].

2.4. Inheritance, penetrance and expressivity

Transmission is autosomal dominant [1]. In families with parental testing, about 84% of patients with DYT-KMT2B and 91% of patients with the neurodevelopmental form have a de novo alteration; among the 16% with an inherited variant, 63.5% received it from an affected parent (36.5% with a dystonic phenotype and 27% with a non-dystonic phenotype) and 36.5% from a clinically asymptomatic parent [1]. Penetrance is reduced: two of 32 variants in the Meyer series were inherited from an apparently unaffected parent, the Milan paediatric cohort identified four asymptomatic carriers and, in some families, the parent has later-onset, milder and non-generalised dystonia compared with the child [1, 9]. Intrafamilial variability includes, within the same family, dystonic phenotypes and neurodevelopmental phenotypes without dystonia [1, 9].

2.5. Genotype-phenotype correlations

The Meyer series showed significantly earlier onset with loss-of-function variants than with missense variants, with no difference in rate of progression, severity or response to DBS [1]. In the pooled analysis of 53 own and 80 published patients, microdeletions and truncating variants were associated with earlier onset of dystonia and a greater burden of systemic disease [27]. A 2026 review of 178 published cases (112 with a truncating variant and 66 missense) associated truncating variants with cervical and laryngeal dystonia, dysmorphic features, microcephaly, endocrinopathies, wheelchair dependence and pallidal hypointensity, and missense variants with later onset and more psychiatric manifestations [28]. In 81 patients, onset was earlier with insertions (mean 4.4 years) than with missense variants (mean 8.7 years) [1]. Rare missense variants were found in 12 individuals from five Italian families with adult-onset focal or segmental dystonia, isolated progressive deafness or intellectual disability with short stature; the methylation profile distinguished these cases both from controls and from early-onset DYT-KMT2B [29].

2.6. Allelic disorders and somatic alterations

No germline phenotypes other than those described are known [1]. The predominant cerebellar ataxia described in a Portuguese adult with the splicing variant c.3334+1G>A broadens the clinical spectrum but results from the same gene and mechanism [24]. Somatic KMT2B variants are frequent in sporadic tumours, including grade II and III gliomas; they do not indicate hereditary predisposition, and a germline finding should not be presented as a tumour risk [1, 3].

2.7. Genetics of the other isolated monogenic dystonias

The 12 genes primarily associated with isolated dystonia together account for less than 10% of isolated dystonia; DYT-TOR1A accounts for about 2% of patients, DYT-ANO3, DYT-GNAL, DYT-THAP1 and DYT-VPS16 for about 1% each, DYT-KMT2B for 0.5–1%, and the remaining six forms for less than 0.1% each [2]. The MDS Task Force recognises more than 50 established dystonia genes and more than 400 candidate genes [2]. In DYT-TOR1A, more than 98% of patients have the in-frame deletion NM_000113.3:c.907_909del p.(Glu303del) in exon 5, historically the "GAG deletion" or "DYT1 mutation", which is a hotspot with de novo occurrences and a founder effect in Ashkenazi Jews; penetrance is about 30%, and the variant NM_000113.3:c.646G>C p.(Asp216His) on the allele in trans reduces it to about 3% [2, 4, 30]. In DYT-THAP1, described in Amish-Mennonite families, heterozygous truncating or missense variants or whole-gene deletions impair the nuclear localisation or DNA binding of this transcription factor; penetrance is about 50% and there are cases of recessive inheritance [2, 31]. In DYT-GNAL, the gene encodes the α subunit of the olfactory G protein, involved in striatal dopaminergic signalling, and the spectrum includes missense and truncating variants and complete deletions [2, 32]. In DYT-VPS16, loss of function of a subunit of the CORVET and HOPS complexes links dystonia to autophagy and lysosomal function [2, 33]. The Saudubray textbook classifies VPS16 and VPS41, core components of the HOPS complex that mediates fusion of the autophagosome and endosome with the lysosome, among the disorders of cellular trafficking and the lysosome-related disorders, with dystonia of onset in childhood or adolescence [33, 34]. In DYT-PRKRA, most patients are homozygous for NM_003690.5:c.665C>T p.(Pro222Leu), first described in Brazilian families [4, 35]. EIF2AK2 has a recurrent variant, NM_001135651.3:c.388G>A p.(Gly130Arg), and all described variants are located in the double-stranded RNA-binding motifs that mediate the interaction with PRKRA [2, 4]. The proteins encoded by EIF2AK2, EIF4A2 and PRKRA participate in translational regulation and the integrated stress response, whereas KMT2B and THAP1 act in transcriptional regulation, pointing to convergent pathways of gene-expression control [2].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Data sources and limitations

The clinical description rests on the GeneReviews synthesis (2025 update), which brings together about 238 patients with an intragenic variant and 33 with a 19q13.11–q13.12 deletion, and on cohorts with their own denominators: 53 patients in the international cohort of Cif and colleagues, 14 of 65 children in the Milan cohort, nine patients followed for up to 20 years in two Austrian centres and 178 published cases reviewed in 2026 [1, 9, 23, 27, 28]. Most data come from reports and series from referral centres, which receive the most severe patients, and the frequencies in the following table are proportions among published cases, not population estimates. The totals cited by GeneReviews vary between sections (246, 258 or 271 patients with DYT-KMT2B), owing to aggregation of series at different dates [1].

Sources: GeneReviews [1] and Austrian cohort [23].

3.2. Age at onset and first manifestation

Onset typically occurs in the first decade, with a median of 6 years and a range of 0 to 43 years; at least 13 patients had onset in the second decade and at least 17 between the third and the sixth [1]. The most common presentation is dystonia of one lower limb, with abnormal foot posturing, recent-onset toe walking or gait disturbance, in about 66% of patients; this is followed by upper-limb dystonia (abnormal hand or arm posturing, dystonic tremor, difficulty with writing and manual dexterity) in about 15%, laryngeal or oromandibular dystonia in about 10%, cervical in 5.5%, axial in 2% and isolated dystonic tremor in 2% [1]. In the Milan cohort, dystonia affected the lower limbs at onset in 78.5% of carriers [9]. The Austrian cohort drew attention to asymmetry of dystonia at onset, observed in all nine patients and maintained or accentuated with progression [23].

3.3. Motor progression

The typical course follows a caudocranial pattern: lower-limb dystonia spreads to the upper limbs, trunk and, finally, to the cervical and cranial regions, with retrocollis, torticollis and oromandibular and laryngeal dystonia [1, 27]. Dystonia generalises in about 68% of patients within 2 to 11 years of presentation, and the earlier the onset the greater the likelihood of generalisation, according to the analysis of 81 patients [1]. In the Austrian cohort, with follow-up of 5 to 20 years in six of the nine patients, all generalised and all developed bulbar involvement, which the authors attribute to the duration of observation [23]. Gross motor disability ranges from minimal gait disturbance to wheelchair dependence, corresponding to levels II to V of the Gross Motor Function Classification System (GMFCS) [1]. About 27% of patients have another movement disorder: spasticity in about 10%, myoclonus in 7%, tremor in 7%, chorea in 2% and ataxia in 1.5% [1]. Parkinsonism and bilateral mirror movements have been described in isolated patients [1]. Choreoathetosis of the right arm in an Austrian boy led to an initial diagnosis of Sydenham chorea [23].

3.4. Atypical and adult-onset forms

A growing number of patients present with milder or atypical forms: prominent cervical dystonia, especially with onset between the second and fifth decades; upper-limb dystonia or dystonic hand tremor; oromandibular or laryngeal dystonia without clinical limb dystonia [1]. A Portuguese report described early-onset oromandibular-laryngeal dystonia with a "Charlot" gait as a new phenotype [36]. Adult-onset forms are rare: a 2025 report counted 20 described patients, with mean onset at 34 years, focal presentation (mainly cervical) in 70% and additional features in 30% [25]. Rare missense variants were associated with adult focal or segmental dystonia in seven individuals from five Italian families [29].

3.5. Speech, swallowing and airway

Laryngeal dystonia produces dysarthria, anarthria and hypophonia or spasmodic dysphonia, and bulbar dysfunction impairs chewing and swallowing, with a risk of aspiration and the need for gastrostomy in some patients [1]. The frequency of bulbar dysfunction is probably higher than the 30% recorded, because it is counted only when the paper mentions it explicitly [1]. All Austrian patients had oromandibular dystonia, with or without tongue involvement, and dysarthria from childhood or adolescence; two had dysphonia or stridor due to laryngeal involvement [23]. Progressive bulbar dysfunction caused malnutrition and recurrent aspiration pneumonia in an Austrian patient who declined gastrostomy and died at 34 years of age [23].

3.6. Neurodevelopment, cognition and behaviour

Developmental delay, described in about 26% of patients with DYT-KMT2B, usually precedes dystonia and is not progressive; isolated language delay occurs in about 5% [1]. Intellectual disability, in about 42%, ranges from mild to severe, and most of those affected acquire variable functional independence in adolescence and adulthood [1]. Neurobehavioural and psychiatric manifestations, in about 26%, include anxiety and obsessive-compulsive disorder (11%), attention deficit hyperactivity disorder (ADHD; 10%), autism spectrum disorder (ASD; 4%) and depression or unspecified behavioural changes (1.5%) [1]. The Austrian cohort, assessed in a structured way before DBS, found developmental delay and intellectual disability in 56% and epilepsy in 22%, figures above those in the literature that the authors explain by systematic assessment and recruitment in referral centres [23].

3.7. Growth, endocrine system, skin and eyes

Microcephaly is described in about 44% of patients, and possibly endocrine features in about 38%, including short stature, precocious puberty and hypothyroidism [1]. The Cif cohort added intrauterine growth restriction and endocrinopathies to the comorbidities of the disease [27], and central precocious puberty has been described as the first manifestation in a patient with a de novo KMT2B variant and a concomitant STS deletion [37]. Ophthalmological abnormalities (refractive errors, nystagmus in extreme gaze positions, strabismus, slow saccades) occur in about 8%, and eye movement abnormalities include delayed saccade initiation, hypometric vertical saccades and oculomotor apraxia [1]. About 4% have features of ectodermal dysplasia: aplasia cutis, sparse hair, sparse or absent eyelashes and eyebrows, hypertrichosis and ichthyotic skin with a cross-hatched pattern on the soles and knees [1]. Meyer and colleagues described a characteristic facial appearance in some patients, which OMIM summarises as an elongated face with a bulbous nose; OMIM also mentions motor or cognitive delay with mild intellectual disability in about half of patients [6, 18]. In the neurodevelopmental form, OMIM records epicanthus, posteriorly rotated ears, syndactyly or clinodactyly of the toes and fifth-finger clinodactyly [7].

3.8. Neuroimaging and ancillary investigations

MRI is normal in about 40% of patients [1]. In about 27%, aged between 3 and 44 years, subtle, symmetrical lateral hypointense streaks are seen in the globus pallidus externus on T2-weighted, T2* and susceptibility-weighted (SWI) sequences [1]. The pattern appears to be age-dependent: it became less evident on successive MRIs in five patients and is often absent in adults, so a normal MRI in an adult does not exclude the diagnosis [1]. None of the nine Austrian patients had typical changes [23]. Cerebellar atrophy has been described in three patients, one of them Portuguese with predominant ataxia [1, 24]. DaTscan was normal in four patients and showed reduced striatal uptake in two, without diagnostic value [1, 3]. There is no measurable biochemical marker of the deficiency [3].

3.9. Acute complications: dystonic storm and status dystonicus

The Cif cohort identified the risk of status dystonicus as a comorbidity of the disease [27]. An Austrian patient had two infection-triggered dystonic storms at 20 years of age, which prompted genetic reassessment of a diagnosis of dyskinetic cerebral palsy [23]. In the 2026 review, status dystonicus was more frequent in European and American series than in Asian ones [28]. Status dystonicus is an emergency with a reported mortality of 10.3% to 11.4%, mainly affecting children and adolescents [38].

3.10. KMT2B-related neurodevelopmental disorder

The non-dystonic form has been described in 26 patients, 17 with an intragenic variant and nine with a 19q13.11–q13.12 deletion; other sections of the same GeneReviews count 27 patients from 25 families [1]. They share prenatal and postnatal growth restriction, feeding difficulties, microcephaly, developmental delay with language delay, intellectual disability, ectodermal dysplasia and genital malformations in males [1]. Early delay occurs in about 81%, intellectual disability (mild to severe) in 89%, bulbar dysfunction requiring a feeding tube or gastrostomy in 44%, behavioural manifestations in 21% (ASD 7%, ADHD 7%, other 7%), nystagmus or strabismus in 11% and febrile seizures in 11%; ectodermal dysplasia is present in almost all patients with a deletion [1]. Imaging is normal or non-specific (enlarged ventricles, Dandy-Walker variant, posterior periventricular hyperintensity with pituitary hypoplasia, thin corpus callosum) [1]. This form appears both in relatives of patients with dystonia and in isolated cases, and 19q13.11–q13.12 deletions add faltering growth, short stature and skin changes [1]. The prognosis is poorly known owing to the lack of longitudinal follow-up [1].

3.11. Natural history and treated disease

The natural history without DBS is that of a progressive dystonia that generalises in most patients, with accumulating bulbar involvement [1, 23]. In patients treated with DBS, the improvement of the first months and years is followed, in series with long follow-up, by mild to moderate secondary worsening, attributed to disease progression; in the Cif cohort no patient maintained fully independent walking in the long term, whereas in the Austrian cohort three patients regained lost walking and maintained it 12 to 20 years after surgery [23, 27]. Life expectancy is not known; patients in their seventh decade have been described [1].

3.12. Phenotypes of the other isolated monogenic dystonias

The most frequent forms of the class have distinct profiles [2, 39]. DYT-TOR1A begins at around 9 years (interquartile range 7–12) as twisting of one extremity, mainly the upper limb, generalises in most and only rarely affects the craniofacial and laryngeal regions [2]. DYT-THAP1 begins at around 14 years (8–25) in the upper limb, neck or craniofacial and laryngeal region, with segmental, multifocal or generalised distribution and frequent dysphonia or dysarthria [2]. DYT-GNAL begins at around 40 years (25–47) in the neck, spreads to the cranial region or one arm and rarely generalises [2]. DYT-VPS16 begins at around 14 years (9–24) in the upper half of the body and generalises in most, with cognitive impairment in about 10% and anxiety in 5% [2]. DYT-PRKRA begins at around 7 years (3–13), almost always in a limb, and generalises with laryngeal, craniofacial, cervical and axial involvement; the parkinsonism initially described is not constant, and one third have cognitive delay or impairment [2]. The MDSGene systematic review confirmed that carriers of variants in TOR1A, THAP1, PRKRA, KMT2B and HPCA have onset mainly in childhood and adolescence, whereas GNAL and ANO3 often begin in adulthood, and that KMT2B and GNAL have a predominant site of onset (lower limbs and neck, respectively) [39].

4. Clinical Recognition and Red Flags

4.1. When to suspect DYT-KMT2B

Suspicion should arise in a child with progressive dystonia beginning in the first decade, especially if it starts with abnormal posturing of one foot, recent-onset toe walking or gait disturbance and then spreads to the upper limbs, neck and face, with dysarthria, hypophonia or swallowing difficulty [1]. Suspicion is reinforced by developmental delay, particularly of language, preceding the dystonia, intellectual disability, neurobehavioural manifestations, microcephaly, short stature and endocrinopathies [1]. The GeneReviews overview of the class stresses that the combination of dystonia with developmental delay or cognitive impairment makes DYT-KMT2B or DYT-EIF2AK2 more likely among the monogenic dystonias [2]. The neurodevelopmental form should be considered in a child with global delay, intellectual disability, intrauterine growth restriction, short stature, endocrinopathies (hypothyroidism, precocious puberty) and ectodermal features, especially if there are relatives with dystonia [1]. The absence of a family history does not exclude the diagnosis, because most variants are de novo and penetrance is reduced [1].

4.2. Childhood dystonia as a possible combined disorder

Whereas most gradual-onset focal or segmental dystonias in adults are isolated, fewer than half of childhood-onset dystonias are; therefore, dystonia in a child should be regarded as a possible sign of a combined disorder and requires a full assessment [2]. The Oxford Desk Reference lists as suggestive of non-primary dystonia an abnormal perinatal history, dysmorphic features, developmental delay, seizures, hemidystonia, sudden onset or rapid progression, prominent oro-bulbar dystonia, the presence of another movement disorder (except tremor), signs of other neurological systems (pyramidal, cerebellar, neuropathy, cognitive decline) and extraneurological disease, such as hepatomegaly or splenomegaly [15]. In DYT-KMT2B, oro-bulbar dystonia and developmental delay are frequent, so these signs do not rule out a monogenic dystonia and should lead, simultaneously, to genetic testing and to the exclusion of treatable metabolic disorders. The Saudubray textbook adds that an inborn error of metabolism should be suspected when several types of abnormal movement coexist, when dystonia is associated with other neurological signs, when it involves the orofacial region, when there are bilateral basal ganglia lesions on MRI and when there are paroxysmal disorders triggered by fasting or exercise [40].

4.3. The child with a diagnosis of dyskinetic cerebral palsy

Cerebral palsy (CP) affects about 1 in 400 births, and the dyskinetic form (athetoid, dystonic or choreoathetoid) is a frequent differential diagnosis of genetic dystonia [41]. Two of the nine Austrian patients with DYT-KMT2B had a previous diagnosis of dyskinetic CP, in one case attributed to prematurity at 32 weeks; reassessment was prompted by infection-triggered dystonic storms in one case and by the response to DBS and the course of bulbar dysfunction in the other [23]. The authors point to the following clues for testing KMT2B in a person with dyskinetic CP: absence of a demonstrated perinatal injury, progression (incompatible with the clinical stability of CP), hyperkinetic crises and progressive bulbar dysfunction [23]. The Oxford Desk Reference recommends that all children with an athetoid CP phenotype undergo a levodopa trial, because dopa-responsive dystonia can mimic it [15, 41].

4.4. Red flags and urgent situations

Urgent situations are rapid worsening of dystonia with pain, hyperthermia, rhabdomyolysis or respiratory compromise (status dystonicus), often triggered by infection, and dysphagia with weight loss or aspiration pneumonia [23, 27, 38]. A dystonic crisis requiring intensive care has been described in the postoperative period after DBS [25]. Abrupt withdrawal of anticholinergics or benzodiazepines can worsen dystonia, and abrupt withdrawal of trihexyphenidyl has been associated with neuroleptic malignant syndrome [38, 42].

4.5. Newborn screening

There is no newborn screening for the isolated monogenic dystonias, and the sources consulted do not describe biochemical markers that would allow it [3].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No consensus clinical criteria have been published for KMT2B-related disorders [1]. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic variant in KMT2B or a heterozygous 19q13.11–q13.12 deletion that includes the gene; a variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis [1]. There is no confirmatory biochemical, imaging or neurophysiological test [3].

5.2. Clinical assessment and scales

Characterisation follows axis I of the consensus: age at onset (infancy 0–2 years, childhood 3–12, adolescence 13–20, early adulthood 21–40, late adulthood above 40), distribution (focal, segmental, multifocal, hemidystonia, generalised), temporal pattern (acute, subacute or gradual onset; static, progressive or fluctuating course; paroxysmal or diurnal variability) and association with other signs [2, 13]. Severity is measured with validated scales, mainly the Burke-Fahn-Marsden scale, with its movement (BFMDRS-M) and disability (BFMDRS-D) subscales, the Unified Dystonia Rating Scale and the Global Dystonia Rating Scale; in children the Barry-Albright Dystonia Scale and the Movement Disorder-Childhood Rating Scale are also used, none of them validated across the whole developmental range [2, 38]. ERN-RND maintains a compilation of dystonia scales, updated in May 2025 [12].

5.3. Non-genetic investigations

Brain MRI with T2, T2* and SWI sequences looks for the pallidal streaks (present in about 27%) and excludes structural lesions, basal ganglia calcifications (Fahr, Aicardi-Goutières, mitochondrial disorders) and the "eye-of-the-tiger" sign of pantothenate kinase-associated neurodegeneration [1, 15]. The signal pattern guides the metabolic differential diagnosis: T2 hyperintensity of the basal ganglia suggests a defect of energy metabolism, T2 hypointensity of the pallidum suggests iron accumulation and T1 hyperintensity suggests a disorder of manganese metabolism or portosystemic shunting [40]. When MRI is normal, diurnal fluctuation suggests a neurotransmitter defect and exercise-induced paroxysmal dystonia suggests glucose transporter GLUT1 deficiency or pyruvate dehydrogenase deficiency [40]. The Oxford Desk Reference proposes, as second line, plasma and urine amino acids, urine organic acids (L-2-hydroxyglutaric and glutaric acidurias), leucocyte enzymes (GM2, Niemann-Pick C, Krabbe), lipoproteins, testing for neuronal ceroid lipofuscinoses, cerebrospinal fluid (CSF) pyruvate and lactate, CSF neurotransmitters, thyroid function with free T3 (Allan-Herndon-Dudley syndrome), a search for acanthocytes, copper studies (Wilson disease), manganese, creatine kinase and, if there is a dominant history, Huntington disease, spinocerebellar ataxias and dentatorubral-pallidoluysian atrophy [15]. Videofluoroscopy assesses the risk of aspiration, and psychoeducational and developmental assessment documents the cognitive profile [1].

5.4. Genetic testing

The KMT2B GeneReviews considers two approaches: a multigene panel that includes KMT2B and the genes in the differential diagnosis, or comprehensive genomic testing, with chromosomal microarray for deletions and exome sequencing (the most widely used) or genome sequencing; single-gene testing is rarely useful and is not recommended [1]. The GeneReviews overview of the class, updated in December 2025, goes further and advises against panels, as they are inflexible in the face of new genes and may omit differentials, preferring exome or genome with targeted analysis of a virtual panel and periodic reanalysis of the data [2]. Short-read sequencing is considered sufficient, because no repeat expansions are known in isolated dystonia and structural rearrangements are rare; long-read sequencing is under evaluation, including a French prospective multicentre study started in 2026 (NCT06999096) [2, 43]. The paediatric flowchart adopted by ERN-RND in 2019 and retained in the February 2026 update proposes the following sequence: confirm that the disorder is dystonia and not a mimic; exclude a drug-induced or toxic cause; perform MRI and look for clues to acquired forms; and, if no cause is identified, carry out in parallel biochemical investigations targeting treatable metabolic disorders, start a levodopa trial and request next-generation sequencing [19, 44]. The 2011 EFNS guideline, which predates the discovery of KMT2B, recommended TOR1A testing in patients with primary dystonia beginning in a limb before 30 years of age or with an affected relative with early onset, THAP1 testing in early-onset or familial cases with craniocervical involvement and SGCE testing in early-onset myoclonus [45]. The Oxford Desk Reference recommends, for onset before 26 years of age, testing for the DYT1 variant and KMT2B sequencing, as well as GCH1 and TH in the dopa-responsive forms [15].

5.5. Diagnostic yield

In an exome study of 1924 genetically unsolved patients, mostly with late-onset isolated dystonia, recruited from the DysTract and Dystonia Coalition registries, the yield was 8.1% (153 of 1895 index cases), with 137 pathogenic or likely pathogenic variants in 51 genes; the yield rose to 28.6% in generalised dystonia and to 20.4% with onset before 30 years of age, and KMT2B was among the most implicated genes, with one de novo variant [46]. In a Milan cohort of 65 children with dystonia beginning before 18 years of age and negative for the known genes, 14 (21.5%) had variants in KMT2B and the definitive diagnostic rate reached 23% [9]. In a Turkish national cohort of 81 patients with childhood-onset dystonia of genetic cause, KMT2B was the most common aetiology (16%), followed by GCH1 and SLC2A1 (11.1% each), GNAO1 and TOR1A (8.6%) and GNAL (6.2%); the diagnosis was obtained by exome in 49.4%, single gene in 25.9% and panel in 23.5%, and 21 patients had deletions or duplications [47]. The family history is positive in about 25% of patients with dystonia, but the overall yield of genome sequencing is below 50% and is lower in isolated than in combined dystonia [2].

5.6. Limitations of testing and interpretation

Sequencing does not usually detect single-exon or whole-gene deletions, so a negative exome requires copy-number variant analysis or microarray, whose resolution in the 19q13.11–q13.12 region depends on probe density [1]. Exon 1 may have insufficient coverage in the exome, and deep intronic or synonymous splicing variants may be missed [1]. Analysis of leucocyte DNA does not detect all somatic mosaicism nor exclusively gonadal mosaicism [1]. In a 2026 study that combined nanopore long reads with the episignature classifier, two previously undetected or uninterpreted variants were resolved and an ambiguous insertion-deletion call was refuted [48]. Interpretation of missense variants is difficult, and the proportion of variants detectable by a method is not equivalent to the clinical sensitivity of the test.

5.7. Methylation episignature

Analysis of the epigenetic signature in peripheral blood, or in stored DNA, should be considered when genetic testing does not identify a variant or deletion in a patient with a suggestive picture and is useful for reclassifying VUS [1]. In a Brazilian study that compared, with the EPIC methylation array in peripheral blood, the 144 probes of the EpiSign KMT2B episignature between two patients and 14 controls, the variant NP_055542.1:p.(Tyr2515Cys) produced a hypermethylated profile compatible with pathogenicity, which allowed it to be reclassified, the family to be counselled and the patient to be stratified for DBS, whereas NP_055542.1:p.(Leu1720Phe) had methylation similar to that of controls, which practically excluded the diagnosis [4, 49]. The signature also distinguishes cases of moderate effect and mosaics [50], and in the Austrian cohort it allowed the variant NM_014727.3:c.3229C>T p.(Arg1077Trp), with an intermediate pattern, to be reclassified as likely pathogenic [4, 23]. Missense variants associated with adult onset produce subtler methylation changes than truncating ones [23, 29].

5.8. Content of the genetic report

The report should state the gene, the transcript with version (NM_014727.3), the HGVS description (c. and p.), the genomic coordinate with the genome build, the zygosity, the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), the method and its limitations and, where available, the result of segregation and episignature analysis [1, 4]. For deletions, the genomic boundaries and the genes included should be stated [1]. Parental testing is recommended in all apparently isolated cases, to confirm de novo occurrence and inform the recurrence risk [1].

5.9. Practical algorithm

5.10. Prenatal and preimplantation diagnosis

Once the familial variant or deletion has been identified, prenatal diagnosis and preimplantation genetic testing are technically possible [1]. Their use, the limitations arising from reduced penetrance and variable expressivity and the diversity of perspectives among professionals and families are discussed in section 8.

6. Differential Diagnosis

6.1. Principles

The differential diagnosis of DYT-KMT2B includes the other early-onset generalised dystonias, isolated or combined, the metabolic and neurodegenerative disorders with dystonia and the dystonias acquired through brain injury (notably dyskinetic CP), drugs (neuroleptics and anticonvulsants) or of functional nature [1, 2]. The first priority is not to miss disorders with specific treatment: dopa-responsive dystonia due to GTP cyclohydrolase 1 deficiency and the other defects of dopamine synthesis, Wilson disease, GLUT1 deficiency, disorders of manganese metabolism and organic acidurias [2, 15, 40]. Variants in genes usually associated with combined dystonia (GCH1, PRKN, SGCE, SLC2A1, CACNA1A) are also found, rarely, in patients with isolated dystonia, and among them DYT/PARK-GCH1 is the most important because it responds to levodopa [2].

6.2. The class of isolated monogenic dystonias

Sources: GeneReviews overview of the class and MDSGene review [2, 39]; OMIM numbers of genes and phenotypes confirmed in the entries [5, 6, 51–70].

The clinical clues that guide targeted testing, when resources do not allow an exome, are as follows: DYT-ANO3 and DYT-GNAL often begin in adulthood and remain focal with cervical predominance, which makes them difficult to distinguish from each other and from non-genetic dystonias; myoclonus is recurrent in DYT-ANO3 and frequent in DYT-VPS16, but rare in DYT-GNAL; dystonia with developmental delay or cognitive impairment points to DYT-KMT2B or DYT-EIF2AK2; onset in infancy suggests DYT-HPCA; all, except DYT-GNAL and DYT-TUBB4A, frequently affect the limbs; and laryngeal dystonia is more frequent in DYT-THAP1 and DYT-TUBB4A [2]. Ancestry points to TOR1A in Ashkenazi Jews, in whom early-onset dystonia is 5 to 10 times more frequent, and to PRKRA in Brazilian patients [2, 15].

6.3. Genetic differentials of DYT-KMT2B with early-onset generalised dystonia

Sources: GeneReviews of KMT2B and of the class, Oxford Desk Reference, Saudubray, ERN-RND flowchart and review by Gorodetsky and Fasano [1, 2, 15, 19, 38, 40, 71, 72].

6.4. Differentials of the neurodevelopmental form

The manifestations of KMT2B-related neurodevelopmental disorder do not allow a clinical diagnosis, and all intellectual disabilities without distinctive features enter the differential [1]. The combination of growth restriction, microcephaly and ectodermal features brings it close to Silver-Russell syndrome (11p15.5 hypomethylation, maternal uniparental disomy of chromosome 7), Seckel syndrome (ATR, CPAP, CEP152, CEP63, DNA2, NIN, NSMCE2, RBBP8, TRAIP; autosomal recessive), Kleefstra syndrome (EHMT1 or 9q34.3 deletion), Wiedemann-Steiner syndrome (KMT2A), Kabuki syndrome (KMT2D, autosomal dominant; KDM6A, X-linked) and SETD1A-related disorders [1]. The methylation signatures of KMT2A and KMT2B have limited overlap and allow the two genes to be distinguished in doubtful cases [21].

6.5. Metabolic differentials and epilepsy with dystonia

Inborn errors of metabolism produce movement disorders in about 70% of paediatric cases, and MRI is usually normal in neurotransmitter defects, GLUT1 deficiency and the primary genetic dystonias, which makes it necessary to consider these groups when imaging is normal [73]. In children with metabolic disease, dystonia often precedes parkinsonism [73]. The Oxford Desk Reference highlights as epilepsy-with-dystonia syndromes GLUT1 deficiency (SLC2A1; low CSF glucose and lactate; response to the ketogenic diet), ARX-related disorders (infantile spasms or Partington syndrome with focal dystonia and dysarthria), Allan-Herndon-Dudley syndrome (SLC16A2; profound hypotonia evolving into dystonic posturing in males; raised free T3) and the congenital variant of Rett syndrome due to FOXG1 [15]. Synaptic vesicle disorders are another group to consider in a child with dystonia and parkinsonism: biallelic variants of SYNJ1 (synaptojanin 1) cause paediatric or juvenile parkinsonism with dystonia and cognitive deterioration, with a transient response to levodopa, and those of DNAJC6 (auxilin) parkinsonism-dystonia from 7 years of age, with a partial response to levodopa; in both, low CSF homovanillic acid has been described, which brings them close to the neurotransmitter defects [72].

6.6. Acquired and functional dystonias

Acquired causes of isolated dystonia include hypoxic injury (CP, bronchopulmonary dysplasia), infections (Creutzfeldt-Jakob disease, Mycoplasma pneumoniae, Japanese encephalitis, tuberculosis), parainfectious disorders (Reye syndrome, subacute sclerosing panencephalitis), autoimmune disorders (multiple sclerosis, antiphospholipid syndrome), metabolic disorders (kernicterus, hypoparathyroidism, central pontine myelinolysis), vascular disorders (stroke, arteriovenous malformation), head trauma, space-occupying lesions, intoxications (carbon monoxide, manganese), drugs (neuroleptics, anticonvulsants) and functional dystonia [2]. Acute onset, over minutes, suggests a functional form, and subacute onset, over days to weeks, an autoimmune process [2]. Drug-induced dystonia includes acute reactions to dopamine-antagonist antiemetics, a risk also to be borne in mind in carriers of genetic dystonia [1].

7. Treatment and Risk-Management Strategies

7.1. Principles and evidence base

There is no cure or mechanism-directed treatment for KMT2B-related disorders or for any isolated monogenic dystonia; treatment is symptomatic and multidisciplinary and should involve, early on, a neurologist specialising in movement disorders to discuss pharmacological and surgical options [1, 2]. There are no KMT2B-specific clinical guidelines: the GeneReviews recommendations are based on the authors' experience, the DBS figures come from pooled series and not from randomised trials, and the recommendation of anticholinergics rests on cohort observation [1, 3]. ClinGen has no actionability assessment for KMT2B, in either the paediatric or the adult context; this absence means only that the gene has not gone through that process, and not that effective interventions, such as DBS, are lacking [3]. The general references are the 2011 EFNS guideline on primary dystonia, the ERN-RND treatment and diagnostic algorithms (updated in 2025 and 2026) and the 2026 European consensus on DBS in monogenic dystonia, endorsed by ERN-RND in July 2026 [11, 19, 45, 74, 75]. The ERN-RND algorithm, adapted from Balint and colleagues, guides treatment by distribution: botulinum toxin in focal or segmental forms, oral drugs mainly in generalised forms and DBS in refractory generalised, segmental or focal forms, complemented by physical therapies; syndromes with their own treatment (paroxysmal disorders, dopa-responsive dystonia, Wilson disease) follow specific regimens [74, 76]. The classic pharmacological strategy is "start low and go slow": titration every 3–4 days in children and young adults and weekly in older people or those prone to adverse effects, up to the lowest effective dose without adverse effects [77].

7.2. Levodopa trial

A levodopa trial is indicated in all children with dystonia of unexplained cause, because dopa-responsive dystonia can mimic other forms, including dyskinetic CP, and responds markedly [15, 38, 45]. In DYT-KMT2B, dopaminergic drugs are generally ineffective, although some patients have had partial improvement, and in an Austrian cohort two patients had a mixed response [2, 23]. The trial dose differs between sources: the review by Gorodetsky and Fasano proposes, in children, levodopa 1 mg/kg/day (combined with carbidopa) in three doses, with weekly increases of 1 mg/kg/day up to a maximum of 10 mg/kg/day or 600 mg/day, for at least three months [38]; Termsarasab and colleagues propose up to 300–400 mg/day in adults or 4–5 mg/kg/day in children for at least one month and advise against high doses (up to 1000 mg/day or 16–20 mg/kg/day) before genetic confirmation [77]; the GeneReviews overview of the class mentions doses of up to 600–1000 mg/day in adults and 20 mg/kg/day in children with partial benefit in some patients with DYT-ANO3, DYT-EIF2AK2 and DYT-VPS16 [2]. The EFNS guideline recommends the trial in all patients with early-onset dystonia without an alternative diagnosis, without specifying the dose [45].

7.3. Anticholinergics

Antimuscarinics significantly improved motor manifestations in about 50% of patients with KMT2B-related disorders and should be considered the first-line pharmacological treatment once the diagnosis has been confirmed, starting at a low dose according to paediatric and adult guidance and titrating slowly to the lowest effective dose without adverse effects [1]. Three of the nine Austrian patients had a significant response to trihexyphenidyl, which they maintained after DBS, and in two others the drug was withdrawn because of adverse effects [23]. The general evidence in dystonia comes from older studies: in a prospective, double-blind crossover trial, 22 of 31 patients with torsion dystonia (71%) had a clinically significant response to trihexyphenidyl at doses up to 30 mg, and 42% maintained considerable benefit after 2.4 years [78]; in an open-label study by Fahn, a response occurred in 61% of children and 38% of adults, with mean doses of 41 and 24 mg/day, and the benefit was greater when treatment began within the first five years of disease [77]. The drug may take two to four weeks to reach its maximum effect at a stable dose and can paradoxically worsen dystonia at low doses [77]. In dystonic CP, a systematic review showed no relevant difference [38].

Trihexyphenidyl is licensed only for parkinsonism and for drug-induced extrapyramidal disorders; in dystonia, at any age, its use is off-label, and the US and Portuguese labels state that safety and efficacy in children have not been established [42, 79]. The paediatric doses in the following table come from a review that compiles them from paediatric formularies (Lexicomp and AHFS) and that GeneReviews indicates as the reference for titration; they constitute an extrapolation to DYT-KMT2B [1, 38].

In DYT-KMT2B, levodopa, baclofen, gabapentin, tetrabenazine and benzodiazepines did not give lasting benefit to most patients, but a trial of them is considered reasonable; botulinum toxin, benzodiazepines, baclofen, neuroleptics and antiepileptics had variable effects [1, 2]. In the United Kingdom, among 139 children and young people treated with DBS, 96 were receiving one to six tone-reducing drugs, mainly gabapentin (n=58), clonidine (n=50) and benzodiazepines (n=43) [80]. Neuroleptics, formerly part of the so-called "Marsden cocktail", are now rarely used because of the risk of tardive dystonia [38].

7.4. Botulinum toxin

Botulinum toxin type A is first line in cranial (except oromandibular) and cervical focal dystonias according to the EFNS, and is effective in cervical, eyelid, oromandibular, laryngeal and focal limb dystonia, without systemic effects [2, 45]. The 2016 guideline of the American Academy of Neurology (AAN), since retired, classified abobotulinumtoxinA and rimabotulinumtoxinB as established (level A) and onabotulinumtoxinA and incobotulinumtoxinA as probably effective (level B) in cervical dystonia [81]. In DYT-KMT2B, the toxin is an adjunct, useful for residual cervical dystonia after DBS, blepharospasm, pain and localised functional goals, with variable effect; in laryngeal and oromandibular dystonia it may be considered, although in one Austrian patient it was abandoned because of pain and insufficient effect [2, 23, 25, 38]. The units of the different preparations are not interchangeable [82].

There are no systematic studies of botulinum toxin in paediatric hereditary dystonia, and paediatric doses are extrapolated from CP spasticity and adult dystonia [38].

7.5. Pallidal deep brain stimulation

Bilateral GPi-DBS is the intervention with the largest documented effect in DYT-KMT2B. GeneReviews counts about 80 patients treated with GPi-DBS and two with subthalamic nucleus stimulation; in 45 patients with data, the mean reduction was about 49.2% (2–98%) on the BFMDRS-M between 2 and 16 months and 38.3% (9–91%) on the BFMDRS-D between 2 and 12 months, with the effect maintained at five years in the trunk, neck, upper limbs and oromandibular region [1]. The meta-analysis by Rajan and colleagues (10 studies, 42 patients, mean age at onset 6.4 years, median follow-up 12 months) found a median improvement of 42.7% on the BFMDRS-M (range −103.5% to 95.9%) and a pooled proportion of 41% (95% CI 27–57%) of patients with improvement greater than 50%; male sex and greater preoperative severity were associated with a better outcome [10]. The 2026 European systematic review, with individual data on 14 of the 34 patients with DYT-KMT2B identified, recorded a median improvement of 42.1% (interquartile range 35.3–75%), with 35.7% good responders and 85.7% total responders, compared with 72.8% median improvement and 76% good responders in DYT-TOR1A and 71.8% and 81.8% in SGCE myoclonus-dystonia [11, 75]. The GeneReviews overview of the class summarises the mean response as 43% in DYT-KMT2B, 68% in DYT-TOR1A, 37% in DYT-THAP1 and 42% in DYT-VPS16 [2].

Distribution influences the outcome. In the Cif cohort (18 patients with longitudinal data, median age at surgery 11.5 years, follow-up of 0.25 to 22 years), improvement was significant at 6 months, at 1 year and at last follow-up, and more than half had an improvement greater than 30% on the BFMDRS-M and BFMDRS-D at 1 year; in the eight patients with more than five years of DBS, an improvement greater than 30% was maintained in five on the motor scale and in three on the disability scale [27]. The greatest improvements were in the trunk (53.2%) and neck (50.5%), and improvement in swallowing on the disability scale was maintained (52.9%); improvement in gait fell from 20.9% at 1 year to 16.2% at last follow-up and no patient maintained fully independent walking; laryngeal dystonia benefited little; five patients developed mild parkinsonism after DBS [27]. DBS is not effective in laryngeal dystonia, and an effect on speech has been described only in a minority [1]. Freezing of gait is a recognised complication of GPi-DBS in carriers of truncating variants and occurred in two of the nine Austrian patients [1, 23]. The Austrian cohort added data from 5 to 20 years: an initial improvement of 23% to 47% on the BFMDRS-M, followed in all by mild to moderate secondary worsening; three patients regained lost walking and maintained it 12 to 20 years later, and surgical correction of equinovarus foot was decisive in preserving walking in two [23]. Dysarthria did not improve or worsened [23].

The timing of surgery weighs on the outcome. In the European review, the mean age at surgery (21.2 years) was about ten years above the mean age at symptom onset (11.2 years), a delay that may miss the window of greatest benefit; in DYT-TOR1A, long disease duration with fixed skeletal deformities, and not age itself, is the main predictor of a poor outcome [11, 75]. The GeneReviews overview of the class associates worse outcomes with longer disease duration and higher baseline score, whereas the Rajan meta-analysis associated a higher baseline score with greater percentage improvement [2, 10]. In children, the factors associated with a good outcome are a short time lived with dystonia, monogenic aetiology (better than neurodegenerative, and this better than acquired), mobile rather than tonic dystonia, involvement of the neck, trunk and limbs without bulbar predominance, the absence of fixed skeletal deformities and the absence of neurological comorbidities such as ataxia, spasticity or weakness [38]. In a paediatric series, the duration of dystonia and, above all, the ratio of duration to age at surgery correlated negatively with the outcome at 6 and 12 months in primary dystonia (Spearman coefficients of −0.614 and −0.559 for the ratio) [38]. The Austrian authors conclude that DBS should be offered before loss of walking and that the possibility of secondary worsening should be discussed to avoid unrealistic expectations [23].

The usual target is the bilateral GPi, used in 91% of children in a systematic review; the subthalamic nucleus is reserved for selected cases [38]. DBS has been described from 4 years of age, and the mean age at paediatric surgery is around 13.8 years [38]. In the United Kingdom, among 139 children and young people with DBS, the median age at surgery was 9.8 years and 13 (9.4%) had DYT-KMT2B, the second cause after dyskinetic CP (49.6%) [80]. The adverse effects described in monogenic dystonia include bradykinesia, dysarthria, swallowing and chewing difficulties and freezing of gait; more rarely, intracerebral haemorrhage and tonic-clonic seizures; and, device-related, battery depletion, stimulator malfunction, lead fracture, electrode migration and infection [11]. In DYT-KMT2B, one of the two children with improvement below 25% had an intracerebral haemorrhage and both required several surgical revisions [11]. A dystonic crisis in the immediate postoperative period, requiring intensive care and midazolam, has been described [25].

The 2026 European consensus, endorsed by ERN-RND, recommends DBS in generalised or segmental dystonia due to TOR1A, SGCE, TAF1 and PANK2 after failure of non-invasive therapies, and considers that DBS "may be effective" in generalised or segmental dystonia due to THAP1 and KMT2B under the same conditions; it also recommends genetic testing in the preoperative work-up and a systematic assessment before and after surgery with at least one dystonia scale, one scale for each concomitant movement disorder and one patient-reported outcome scale, with case-by-case decision-making [11, 75]. There is a difference of degree between this formulation and that of the KMT2B GeneReviews, which describes substantial clinical and functional improvement, and that of the paediatric review, which groups KMT2B with TOR1A and SGCE among the forms with a favourable outcome [1, 38]; the difference reflects the heterogeneity of individual responses and the inclusion of long-term data in the European review. The 2011 EFNS guideline already considered pallidal DBS a good option in generalised or cervical primary dystonia after failure of drugs or toxin, to be performed by a specialised multidisciplinary team [45]. The Oxford Desk Reference recommends referral to a specialised centre to consider DBS for patients with DYT1, KMT2B, GNAO1 and secondary forms such as PANK2 [15].

7.6. Ablative surgery and intrathecal baclofen

In 2026 the first simultaneous bilateral radiofrequency pallidotomy was described in a 9-year-old child with refractory generalised DYT-KMT2B, with a BFMDRS-M of 88 before surgery, 72 immediately afterwards and 60 at follow-up, transient hypophonia resolved within one month and a stable outcome at 18 months; the authors present it as an alternative when DBS is not feasible because of access, cost or concerns about implanted hardware [84]. In DYT-TOR1A, thalamotomy and pallidotomy were effective in about half of the few patients treated [2]. Intrathecal baclofen has been used in axial dystonia and in lower-limb dystonia in CP and is an option in refractory status dystonicus; it should not be withdrawn abruptly, because of the risk of withdrawal syndrome [38, 77].

7.7. Rehabilitation, orthopaedics, communication and nutrition

Early physiotherapy with an adapted exercise programme helps maintain function and prevent contractures, hip dislocation and kyphoscoliosis; ankle-foot orthoses and walkers support walking, and occupational therapy works on fine motor skills, feeding, hygiene, dressing and writing [1]. Orthopaedic surgery for fixed deformities and scoliosis is part of treatment, and in the Austrian cohort correction of equinovarus foot preserved walking in patients with DBS [2, 23]. Speech and language therapy supports feeding and communication, and augmentative and alternative communication (writing boards, digital devices) benefits patients with expressive difficulties [1, 2]. In dysphagia, videofluoroscopy or endoscopic assessment identifies the risk of aspiration and guides texture modification and the decision on tube or gastrostomy feeding; clinical nutrition ensures caloric intake [1, 2]. In patients with respiratory compromise due to chest deformity, GeneReviews suggests considering prophylactic antibiotics in winter, regular chest physiotherapy and influenza vaccination [1]. Pain should be assessed with scales and, when necessary, treated in an interdisciplinary centre [2].

7.8. Neurodevelopment, behaviour and mental health

Developmental delay requires early intervention (occupational, physical, speech and feeding therapy, infant mental health and special education) and follow-up by developmental paediatrics; individual education plans, school adjustments and the transition plan in adolescence follow the rules of each country [1]. Behavioural and psychiatric manifestations (ADHD, anxiety, obsessive-compulsive disorder, depression, ASD) are treated according to standard practice, with behavioural intervention, psychotherapy, neuropsychological rehabilitation and drugs when indicated [1, 2]. Structured neuropsychological assessment before and after DBS is recommended, because data on the cognitive and behavioural effects of stimulation in DYT-KMT2B are scarce [23]. The Austrian cohort, in which epilepsy was more frequent than in the literature, recommends early electroencephalography and surveillance for epileptic activity [23]. An Austrian patient developed excessive alcohol consumption and benzodiazepine dependence during worsening of dystonia, which illustrates the need for psychological support and monitoring of sedative use [23].

7.9. Status dystonicus

Status dystonicus is an emergency defined by the need for urgent hospital admission because of life-threatening complications of the movements; 60% to 80% of episodes occur in children and adolescents, it may affect up to 10% of children with dystonia (34 of 336 in one series, with 63 episodes), the most common underlying causes are CP, monogenic dystonias and PKAN, and the reported mortality is 10.3% to 11.4% [38]. Treatment begins with identification and correction of the trigger (infection, pain, change in medication), followed by optimisation of oral antidystonic drugs, sedation with intravenous midazolam and, if necessary, anaesthesia with propofol; in refractory cases, GPi-DBS or intrathecal baclofen is indicated [38]. In a series of 40 patients who underwent GPi-DBS for status dystonicus, 60% of them children, stimulation resolved 90% of episodes; 56.6% of the children had lasting improvement and 36.7% returned to baseline [38, 85]. The occurrence of dystonic storms was one of the reasons for the DBS indication in an Austrian patient [23].

7.10. Agents to avoid, intercurrent illness and the perioperative period

Dopamine-antagonist antiemetics (metoclopramide, domperidone) and ondansetron can induce dystonia and should be avoided or used with caution, a recommendation that GeneReviews makes for pregnancy and that applies at any age [1]. Neuroleptics are a cause of acute and tardive dystonia [2, 38]. Trihexyphenidyl is contraindicated in angle-closure glaucoma, requires caution in hot environments because of the risk of anhidrosis and hyperthermia and should not be withdrawn abruptly; benzodiazepines and intrathecal baclofen should not be stopped abruptly either [38, 42, 77, 79]. Infections can trigger dystonic crises and should be treated early [23, 38]. In patients with DBS, surgical procedures require planning: during gastrostomy placement with the stimulator switched off, lower-limb dystonia worsened markedly [23]. The sources consulted do not describe specific anaesthetic recommendations for DYT-KMT2B.

7.11. Pregnancy, lactation and transition

Before conception, a woman with DYT-KMT2B should discuss the possible effects of antidystonic drugs and plan their management; data are limited, but isolated reports of treatment with trihexyphenidyl, levodopa/carbidopa and clonazepam during pregnancy did not describe maternal or fetal adverse effects, and GeneReviews recommends reducing oral drugs to the lowest effective dose [1]. The US label for trihexyphenidyl assigns it the former category C and reserves it for clear need [42]. No maternal or fetal adverse effects have been described in women with DBS implanted before conception [1]. The sources consulted do not provide lactation data specific to this disease. Transition to adult care is a practical problem: in the United Kingdom, 26.6% of young people with DBS followed by paediatric services were over 18 years of age [80].

7.12. Regulatory status

7.13. Available treatment studies

There are no randomised trials in DYT-KMT2B; the evidence consists of series, meta-analyses and a systematic review with consensus [3, 75].

The series are not comparable with one another: they use different scales and assessment times, include patients with different disease durations and incomplete individual data, and selection for DBS favours the most severe patients [10, 75]. The percentages of improvement are relative to the baseline score; an improvement of 42% on a BFMDRS-M of 88 has a different functional meaning from the same percentage on a score of 30. The European review notes the low quality of the evidence, the non-systematic assessment of response and the pooling of patients with different aetiologies [75].

7.14. Discrepancies between sources

The sources diverge on four points: the classification of DYT-KMT2B as isolated (GeneReviews overview of the class, ERN-RND) or combined (Orphanet); the strength of the DBS recommendation, "may be effective" in the 2026 European consensus versus "substantial improvement" in GeneReviews; the dose of the levodopa trial (maximum of 10 mg/kg/day in the paediatric review, 4–5 mg/kg/day in Termsarasab, up to 20 mg/kg/day in the GeneReviews overview of the class); and the place of genetic panels, accepted by the KMT2B GeneReviews and discouraged by the GeneReviews overview of the class [1, 2, 8, 19, 38, 75, 77]. The DBS recommendation adopted follows the European consensus, the levodopa trial dose follows the paediatric review, and the genetic strategy favours exome or genome with copy-number variant analysis.

7.15. Developments in the last 6–12 months

Between November 2025 and October 2026 the following were published, with different levels of evidence: the systematic review with expert consensus on DBS in monogenic dystonia (Eur J Neurol, January 2026), endorsed by ERN-RND on 10 July 2026 [11, 75]; the February 2026 update of the ERN-RND diagnostic flowcharts [19]; the Austrian cohort with 5 to 20 years of follow-up after DBS (observational study, n=9) [23]; the review of 178 published cases comparing Asian and European/American series and truncating and missense variants [28]; the Turkish national cohort in which KMT2B was the most frequent genetic cause of childhood dystonia [47]; the British survey of children with DBS [80]; the first report of paediatric bilateral pallidotomy [84]; the validation of a methylation signature of 752 CpG sites [21]; the integration of nanopore sequencing with the episignature [48]; and the first heterozygous mouse model with dystonia-oriented phenotyping (preclinical) [22]. On ClinicalTrials.gov there are no therapeutic trials registered for KMT2B; registered studies include an observational international collaboration study on DBS for rare movement disorders (DBS MatchMaker, NCT06912841, Boston, planned until 2030) and a diagnostic study of long-read sequencing in dystonia (NCT06999096, France, recruitment planned from April 2026) [43, 89]. Pharmacological inhibition of DNA methylation has been mentioned as a future therapeutic hypothesis, without human studies [20]. The absence of registered trials in the searches performed does not prove that no studies are in preparation.

8. Reproductive Options and Family Counselling

8.1. Recurrence risks in DYT-KMT2B

DYT-KMT2B and the neurodevelopmental form are autosomal dominant, and each child of an affected person has a 50% chance of inheriting the variant or deletion [1]. The risk to siblings depends on the status of the parents, as shown in the following table.

In the families studied, about 84% of DYT-KMT2B cases result from de novo alterations and 16% from an inherited variant; of these, 63.5% came from an affected parent and 36.5% from a clinically asymptomatic parent, and, among affected parents, about 58% had a dystonic phenotype and 42% a neurodevelopmental phenotype; some parents had later-onset and milder dystonia than their children [1]. In the neurodevelopmental form, GeneReviews reports about 91% de novo alterations, from 13 series, and about 11% inherited alterations, 7% from an affected parent in cases with data, from only two series; the two estimates come from different sets of patients and therefore add up to more than 100% [1]. A parent with somatic and gonadal mosaicism may be mildly or minimally affected, and leucocyte DNA does not detect all mosaicism [1]. In the Austrian cohort, one patient inherited the p.(Gln810Ter) variant from her father, who had focal arm dystonia, and another inherited p.(Arg1077Trp) from her father, also present in a sister, both with mild developmental features [23]. The lower mean methylation in carriers with late onset or incomplete penetrance suggests a potential future use as a predictor, not yet validated for individual counselling [20].

8.2. Risks in the other isolated monogenic dystonias

In the autosomal dominant forms of the class (ANO3, EIF2AK2, EIF4A2, KMT2B, TOR1A, TUBB4A and, usually, GNAL, THAP1 and VPS16), the risk of transmission is 50%, but the probability of disease depends on penetrance: in DYT-TOR1A, about 30% of carriers of the c.907_909del deletion develop dystonia, and only about 3% if the p.(Asp216His) variant is on the other allele [2]. Before the era of genetic testing, empirical sibling recurrence risks in early-onset torsion dystonia were 21% in familial cases and 14% in isolated cases [15]. In the recessive forms (AOPEP, HPCA, PRKRA and rare cases of GNAL, THAP1 and VPS16), each sibling has a 25% chance of being affected and 50% of being an asymptomatic carrier; in the face of apparent homozygosity, an undetected deletion and uniparental isodisomy should be excluded [2].

8.3. Testing of relatives and minors

Parental testing is recommended in all apparently isolated cases [1, 2]. Testing of asymptomatic relatives requires counselling that explains reduced penetrance, the impossibility of predicting age at onset and severity and the possibility of non-dystonic phenotypes [1]. In minor siblings with compatible signs (toe walking, language delay, postural abnormalities), testing has diagnostic value; in asymptomatic siblings, the decision should weigh the benefit of early surveillance against the child's right to decide later. Affected or at-risk young adults should receive counselling on the risks to offspring and reproductive options [1].

8.4. Prenatal and preimplantation diagnosis

Once the familial variant or deletion has been identified, prenatal diagnosis and preimplantation genetic testing are possible; the ideal time to discuss them is before pregnancy, and the use of these techniques is seen by most professionals as a personal decision, with differing perspectives among professionals and families [1]. Reduced penetrance and variable expressivity limit prediction of the phenotype of a carrier fetus. In probands without a molecular diagnosis, DNA should be stored for future studies [2, 15].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

The population prevalence of DYT-KMT2B has not been established; the approximately 250–270 patients with dystonia and 26–27 with the neurodevelopmental form described up to 2025 are literature counts and not prevalence estimates [1]. The proportion in isolated dystonia is 0.5–1% according to the large exome study by Thomsen and colleagues, conducted mainly in patients with late-onset dystonia; in that study, KMT2B was among the six most implicated genes [2, 46]. In selected paediatric populations the proportion is much higher: 21.5% of Italian children with dystonia beginning before 18 years of age and negative for other genes, 16% of Turkish patients with childhood dystonia of genetic cause and 9.4% of British children and young people treated with DBS [9, 47, 80]. These figures measure relative frequencies in referral cohorts, not incidence. The Oxford Desk Reference estimates the prevalence of dystonia in general at between 127 and 329 per million [15].

9.2. Geographical distribution and differences between series

Published series come mainly from Europe (United Kingdom, Germany, Austria, Italy, France, Czechia, Greece, Portugal), the USA and, increasingly, Asia (China, India, Japan) [1, 28]. In the 2026 comparison between 53 Asian and 125 European and American patients, the Asian series had a male predominance and more generalised dystonia, and the European/American series a female predominance, more segmental dystonia, intellectual disability, psychiatric manifestations, status dystonicus and pallidal hypointensity [28]. No founder variants of KMT2B are known. In the class, the founder variants of practical relevance are the TOR1A deletion in Ashkenazi Jews, in whom early-onset torsion dystonia is 5 to 10 times more frequent, the PRKRA p.(Pro222Leu) variant in Brazilian families and the Amish-Mennonite families in the original description of THAP1; X-linked dystonia-parkinsonism is concentrated in Filipino patients [2, 15, 31, 35].

9.3. Portugal and Brazil

Two Portuguese cases of DYT-KMT2B have been published: a report from Coimbra with early-onset oromandibular-laryngeal dystonia and a "Charlot" gait, presented as a new phenotype [36], and an adult from Porto with adult-onset cerebellar ataxia, mild dystonia, neuropathy, an epileptic seizure and ophthalmological abnormalities, carrying the splicing variant c.3334+1G>A with exon 8 skipping [24]. In Brazil, a group from São Paulo validated the clinical use of the methylation episignature to reclassify KMT2B VUS and to stratify patients for DBS [49], and DYT-PRKRA was first described in Brazilian families [35]. The sources consulted do not provide frequency estimates for either country. Trihexyphenidyl is available in both (Artane®), as are several botulinum toxins [79, 82, 86].

9.4. European network and patient organisations

The relevant European Reference Network is ERN-RND, whose dystonia, paroxysmal disorders and NBIA group brings together 64 centres and 4 affiliated partners in 24 Member States and provides diagnostic flowcharts, scales, treatment algorithms and the consensus on DBS in monogenic dystonia; the list of centres in the 2026 document does not include Portuguese centres [12, 19]. The patient organisations listed by GeneReviews are Dystonia Europe (dystonia-europe.org), Dystonia UK (dystonia.org.uk), the Dystonia Medical Research Foundation (dystonia-foundation.org), the Dystonia Coalition (dc.rarediseasesnetwork.org), the Global Dystonia Registry (globaldystoniaregistry.org) and the German dystonia registry [1]. The DBS MatchMaker platform connects clinicians who treat rare movement disorders with DBS [43, 89].

9.5. Special populations

Children with a diagnosis of dyskinetic CP without a demonstrated perinatal injury, with progression or with progressive bulbar dysfunction, constitute a group in which DYT-KMT2B is underdiagnosed, including young adults with a longstanding diagnosis [23]. Patients with intellectual disability and dystonia need adapted neuropsychological assessment before DBS [2, 23]. In settings with limited access to DBS, radiofrequency pallidotomy has been described as an alternative in one case [84].

10. Illustrative Clinical Case

10.1. Generalised dystonia inherited from a father with focal dystonia

Indelicato and colleagues described in 2026 the course of nine Austrian patients with DYT-KMT2B followed in Innsbruck and Vienna, including the patient designated 3V, who corresponds to a member of the fourth family of the original 2016 description [17, 23]. She was born by caesarean section at 37 weeks, in a twin pregnancy, to non-consanguineous parents; she walked unsupported at 13 months but had language delay [23]. At 6 years of age, dystonic inversion of the left foot and dysarthria appeared; the following year the dystonia generalised and the child became wheelchair-dependent [23]. At the first examination she had microcephaly, strabismus and mild intellectual disability [23]. The levodopa trial had no effect [23]. Genetic testing identified the variant NM_014727.3:c.2428C>T p.(Gln810Ter), inherited from her father, who had focal dystonia of the right arm [4, 23]. Because of the progression and the molecular diagnosis, she underwent bilateral GPi-DBS at 7 years of age; she regained mobility and walked again with a stick or even unsupported, with mild improvement in dysarthria [23]. Two years later, limb dystonia progressed and trihexyphenidyl had a stabilising effect [23]. In the last year of follow-up, progression again increased the need for a wheelchair, and she underwent surgery for a persistent left equinovarus foot; dysarthria remained stable, without dysphagia, and weight and height remained below the 3rd centile [23]. Figure 1 of the paper shows the KMT2B variants of the Austrian cohort, marking in blue those that presented as a CP mimic (https://pmc.ncbi.nlm.nih.gov/articles/PMC12926133/figure/F1/) [23].

10.2. Long-term course in the index case of the discovery

In the same cohort, patient 1I is the index patient of the Austrian family in which the gene was identified: carrying the de novo variant c.6406del p.(Leu2136SerfsTer17), absent in her parents and four healthy siblings, she had normal early development and dystonia at 7 years, with internal rotation of the left foot, which generalised in a caudorostral manner to the right hand (writer's cramp), trunk and neck [17, 23]. At 23 years of age she was in a wheelchair, with a normal MRI, and had stopped trihexyphenidyl because of adverse effects; after GPi-DBS she regained walking and writing, residual cervical dystonia was treated with botulinum toxin, and surgery for equinovarus foot improved her gait [23]. Seventeen years after implantation, she walks long distances with sticks and lives independently, although in the last four years mild dysarthria due to oromandibular dystonia and right-sided worsening have appeared [23].

10.3. Clinical interpretation

The two cases illustrate central features of the disease: onset in the lower limbs in the first decade, caudocranial generalisation, initial response to DBS with recovery of walking and secondary worsening years later, absence of effect of DBS on speech, the contribution of foot surgery and complementary anticholinergic medication and extreme intrafamilial variability (father with focal dystonia and daughter with generalised dystonia) [1, 23]. DBS at 7 years of age coincides with the lower age limit of the US device exemption [87]. The approaches described are those of two referral centres and not a routine regimen; the indication for DBS should follow the European consensus, after failure of non-invasive therapies and with systematic assessment before and after surgery [11, 75]. A third report, from France, shows the opposite end of the spectrum: a woman with cervical dystonia from the age of 33, controlled with toxin for 14 years, generalised at 50 with myoclonic dystonia, a 25 kg weight loss and gastrostomy; the genome revealed the likely pathogenic variant c.631T>G p.(Cys211Gly), and GPi-DBS reduced the BFMDRS-M from 30 to 5 at two months, after a postoperative dystonic crisis that required intensive care [25].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

DYT-KMT2B is a progressive disease: dystonia generalises in about 68% of patients within 2 to 11 years, more often the earlier the onset, and laryngeal and bulbar dysfunction accumulates over time [1, 23]. Truncating variants and deletions are associated with earlier onset and more systemic disease [27, 28]. Motor disability ranges from minimal gait disturbance to wheelchair dependence [1]. DBS improves dystonia of the trunk, neck and upper limbs in a sustained manner, but has a limited and declining effect on gait and no effect on laryngeal dystonia; in the long term, all Austrian patients had secondary worsening, although three maintained recovered walking for 12 to 20 years [23, 27]. The causes of severe morbidity include status dystonicus, malnutrition and aspiration; an Austrian patient died at 34 years of age in palliative care, after progressive dysphagia and aspiration pneumonia [23, 27]. Life expectancy is not known, but patients in their seventh decade have been described; the neurodevelopmental form has a poorly characterised prognosis [1]. Intellectual disability, when present, is compatible with variable functional independence in adolescence and adulthood [1].

11.2. Assessment after diagnosis

After diagnosis, the following are recommended: a full neurological examination with a standardised scale and assessment of eligibility for DBS; assessment by physical and rehabilitation medicine, physiotherapy and occupational therapy, with prescription of equipment; orthopaedic assessment of contractures, dislocations and kyphoscoliosis; speech and language therapy and assessment of the need for alternative communication; videofluoroscopic or endoscopic swallowing assessment; nutritional assessment; developmental or neuropsychological and psychiatric assessment; ophthalmological examination with study of eye movements; dermatological examination; pain assessment; genetic counselling; and assessment of the family's social needs [1, 2]. The Austrian cohort adds early electroencephalography [23].

11.3. Surveillance table

11.4. Transition and adult care

The disease spans childhood and adulthood, and a significant proportion of young people with DBS continue to be followed in paediatric services after 18 years of age [80]. Transition should include DBS programming, management of the battery and hardware, surveillance of swallowing and nutrition, psychological support and reproductive planning [1, 11].

12. Summary and Concluding Remarks

KMT2B-related dystonia is one of the most frequent monogenic causes of childhood-onset dystonia and is caused by haploinsufficiency of a histone methyltransferase that deposits the H3K4 mark of active transcription. Transmission is autosomal dominant, de novo in most cases, with reduced penetrance and an intrafamilial variability that ranges from severe generalised dystonia to adult focal dystonia and a neurodevelopmental disorder without dystonia. The typical picture is that of a child with toe walking or abnormal posturing of one foot at around 6 years of age, which over the following years generalises with cervical, oromandibular and laryngeal involvement, dysarthria, hypophonia and dysphagia, often against a background of language delay, intellectual disability, microcephaly, short stature and endocrinopathies; MRI is normal in about 40% and shows subtle pallidal streaks in about 27%, mainly in children. The diagnosis is made by exome or genome with copy-number variant analysis, because about 12% of patients have 19q13.11–q13.12 deletions, and the DNA methylation episignature has become a validated tool for reclassifying variants of uncertain significance. The molecular diagnosis changes management: it ends the metabolic work-up, redirects children labelled as having dyskinetic CP, indicates anticholinergics as first-line pharmacological treatment and places pallidal DBS under discussion before loss of walking. DBS improves the motor scale by about 42–49% on average, more sustainably in the trunk, neck and upper limbs, but little or not at all for gait in the long term and for speech, and the disease continues to progress; the 2026 European consensus considers that it may be effective after failure of non-invasive therapies, with systematic assessment before and after surgery. Neurological surveillance two to four times a year, continuous attention to swallowing, nutrition, communication, the skeleton and mental health, and genetic counselling that integrates reduced penetrance complete the approach. Within the class of isolated monogenic dystonias, DYT-KMT2B is distinguished from DYT-TOR1A by onset in the lower limbs, bulbar involvement and neurodevelopmental features, and from DYT-THAP1 by its earlier age at onset; the response to DBS is intermediate between DYT-TOR1A and the acquired dystonias.

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