KMT2B-Related Dystonia

Mendelian MONDO:0015004 Pathograph 36 Show in embeddings browser dystonic disorder movement disorder autosomal dominant disease chromatinopathy

KMT2B-related dystonia (DYT-KMT2B, dystonia 28) is a childhood-onset, progressive, generalized dystonia caused by heterozygous loss-of-function variants in KMT2B or by heterozygous 19q13.11-19q13.12 deletions encompassing the gene. KMT2B encodes a histone H3 lysine 4 (H3K4) methyltransferase, so haploinsufficiency both removes an activating chromatin mark and permits aberrant, non-random DNA hypermethylation at promoters and other positive regulatory elements. The result is broad transcriptional dysregulation at KMT2B target loci rather than failure of any single effector pathway; no patient transcriptomic data establish the direction of that change, so the entry does not claim one. Dystonia characteristically begins as a focal lower-limb disorder in early childhood and ascends in a caudocranial pattern to a generalized form with prominent cervical, oromandibular and laryngeal involvement, producing dysarthria, hypophonia and bulbar dysfunction. Most affected individuals also have developmental delay or intellectual disability, short stature, additional movement disorders, and neurobehavioral features; a milder adult-onset focal or segmental form and a non-dystonic neurodevelopmental presentation are both recognized. Oral antimuscarinic agents help about half of individuals, and bilateral deep brain stimulation of the globus pallidus internus produces substantial, long-lasting motor improvement, making this one of the more treatable monogenic dystonias — though laryngeal dystonia and gait respond poorly and are the residual burden.

Ask OpenScientist

Ask a research question about KMT2B-Related Dystonia. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
6
Pathophys.
28
Phenotypes
3
Gaps
36
Pathograph
1
Genes
4
Medical Actions
1
Subtypes
1
Models
1
References
1
Deep Research
🏷

Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
KMT2B-related dystonia is autosomal dominant with incomplete penetrance and variable expressivity: relatives carrying the same variant may present with generalized dystonia, with short stature or intellectual disability alone, or remain asymptomatic. Most probands carry a de novo variant, but inherited variants occur and a transmitting parent may be mildly affected or clinically asymptomatic, so reduced penetrance and variable expressivity must be assumed when counselling families.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (5 references)
PMID:29697234 SUPPORT Human Clinical
"DYT-KMT2B and KMT2B-related NDD are autosomal dominant disorders."
GeneReviews states the mode of inheritance for KMT2B-related dystonia.
PMID:29697234 SUPPORT Human Clinical
"The majority of individuals reported to date with a KMT2B-related disorder whose parents have undergone molecular genetic testing have the disorder as a result of a de novo genetic alteration."
Supports the predominantly de novo origin of the causal variant.
PMID:31216378 SUPPORT Human Clinical
"We also report on 4 asymptomatic carriers, suggesting that some KMT2B mutations may be associated with incomplete disease penetrance."
Directly evidences incomplete penetrance, which is why an apparently unaffected parent cannot be assumed to be a non-carrier.
+ 2 more references
◆

Subtypes

1
Adult-onset focal or segmental DYT-KMT2B
A milder, later-onset form presenting in adulthood as focal or segmental dystonia — blepharospasm, cervical dystonia, writer's cramp or spasmodic dysphonia — usually without the developmental delay of the classic childhood-onset disease. It is not simply a late presentation of the same process: on genome-wide methylation profiling the adult-onset cases cluster with controls rather than with early-onset DYT-KMT2B, and the probes that do distinguish them do not overlap the early-onset episignature, which the authors read as a different molecular mechanism. This entry's pathophysiology chain is therefore not asserted to apply to the subtype. Two of the four missense alleles involved (p.S640T, p.R2339Q) are described by the reporting authors as lacking segregation proof, so the subtype rests on a smaller evidence base than the childhood-onset disease.
Show evidence (4 references)
PMID:36483457 SUPPORT Human Clinical
"Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature."
Establishes the adult-onset focal/segmental presentation as a distinct subtype.
PMID:36483457 SUPPORT Human Clinical
"Genome-wide DNA methylation profiling allowed to discriminate these adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients."
Supports treating adult-onset disease as separable from the classic form rather than as the same entity presenting late.
PMID:36483457 SUPPORT Human Clinical
"These specific probes did not overlap with early-onset DYT-KMT2B episignature, suggesting a different molecular mechanism underlying this late-onset phenotype."
States directly that the adult-onset signature does not overlap the early-onset one and implies a different mechanism, which is why this entry does not extend its causal chain to the subtype.
+ 1 more reference
?

Discussions and Knowledge Gaps

3
Which KMT2B target genes, in which neurons, translate genome-wide promoter hypermethylation into dystonia rather than into a purely neurodevelopmental phenotype?
KNOWLEDGE GAP OPEN kmt2b_effector_genes
Attached to
pathophysiology#Transcriptional Dysregulation at KMT2B Target Loci
The chain from KMT2B haploinsufficiency to broad transcriptional dysregulation is measured directly in patients, and the circuit endpoint is inferred from deep brain stimulation response and from the pallidal imaging sign, but nothing connects the two. No patient-derived, cell-type-resolved transcriptomic dataset for striatal neurons was identified, so the step from a genome-wide epigenetic lesion to a motor-specific phenotype is currently an unknown-intermediates edge. This is what would have to be closed before any disease-modifying therapy could be targeted upstream of the pallidum.
What determines whether a KMT2B variant carrier develops dystonia, an isolated neurodevelopmental or growth phenotype, or nothing at all?
OPEN QUESTION OPEN kmt2b_dystonic_vs_ndd_branch
Attached to
pathophysiology#Pallidal Motor Circuit Dysfunction inheritance#Autosomal dominant
Relatives carrying the identical variant diverge between generalized dystonia, isolated short stature or intellectual disability, and clinically asymptomatic carriage, and the Arg2565 hotspot spans that whole range on one codon. Variant class predicts onset age and systemic burden but not this branch, so the determinant is neither the allele alone nor a described modifier locus. Until it is identified, predictive testing in a family cannot say what an at-risk carrier will actually develop.
Is there any whole-organism model of KMT2B-related dystonia, and if not, what would one have to reproduce to be useful?
KNOWLEDGE GAP OPEN kmt2b_no_in_vivo_model
Attached to
animal_models# pathophysiology#Pallidal Motor Circuit Dysfunction
The animal_models section of this entry is empty, and that is a finding rather than an omission: a literature search for this curation found no published Kmt2b animal model of the dystonic phenotype. The contrast with TOR1A/DYT1, where rodent models have carried most of the mechanistic work, is what makes the absence worth recording. The consequence is concrete. The one in vivo-adjacent system available is a mouse embryonic stem cell line (see experimental_models), which reports the enzyme's generic chromatin function and cannot report a motor phenotype at all, so the step from the epigenetic lesion to pallidal dysfunction has no experimental system in which it can currently be tested. A useful model would have to carry heterozygous rather than complete loss of function, and be assayed for motor output rather than for methylation alone. Recording the gap here is also meant to stop the next curator repeating the same fruitless search.
⚙

Pathophysiology

6
KMT2B Haploinsufficiency
Heterozygous loss-of-function variants in KMT2B, or heterozygous deletions of 19q13.11-19q13.12 that remove one copy of the gene, halve the dose of the KMT2B histone methyltransferase. Truncating alleles introduce a premature termination codon and reduce KMT2B transcript in patient fibroblasts; microdeletion carriers show the same dystonic presentation, which is the independent argument that gene dosage rather than a mutant protein product is the lesion. Missense alleles are presumed to act by the same route, but for those the haploinsufficiency claim is inferred rather than measured.
KMT2B hgnc:15840 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KMT2B (hgnc:15840). hgnc:15840 is a gene from the HUGO Gene Nomenclature Committee.
histone H3K4 methyltransferase activity GO:0042800 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves histone H3K4 methyltransferase activity (GO:0042800), qualified as loss of function. GO:0042800 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
Downstream
Promoter DNA Hypermethylation Drawn from the haploinsufficiency node rather than from the reduced-mark node because the barrier function KMT2B provides against repressive machinery is reported to be independent of its methyltransferase catalysis: what is lost is protein occupancy, not the mark.
Reduced H3K4 Methylation at Target Promoters
Show evidence (4 references)
PMID:27839873 SUPPORT In Vitro
"Suggestive of haploinsufficiency, we found significantly decreased total mRNA levels of KMT2B in mutant fibroblasts."
Patient-derived fibroblasts show the reduced KMT2B transcript dose that this node asserts.
PMID:27839873 SUPPORT Computational
"Each of the four mutations was predicted to mediate a loss-of-function effect by introducing a premature termination codon."
In-silico consequence prediction for the founding alleles; graded COMPUTATIONAL because the sentence reports a prediction, not a measurement. The measured half of the claim is the fibroblast transcript result above.
PMID:27839873 SUPPORT Human Clinical
"Independent support for pathogenicity of the mutations comes from the observation of high rates of dystonic presentations in KMT2B-involving microdeletion syndromes."
Whole-gene deletions producing the same phenotype is the dosage argument that distinguishes haploinsufficiency from a dominant-negative mechanism.
+ 1 more reference
Reduced H3K4 Methylation at Target Promoters
KMT2B is one of the SET1/MLL-family enzymes that deposit methyl marks on histone H3 lysine 4 at promoters and enhancers. Reduced enzyme dose lowers H3K4 methylation across the loci KMT2B normally licenses, changing chromatin state rather than deleting any single downstream gene. Note that the loss of the activating mark is only half the lesion: the same loss of KMT2B occupancy also removes a barrier to repressive machinery, and that arm is drawn as a parallel branch from the haploinsufficiency node rather than from here.
chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Transcriptional Dysregulation at KMT2B Target Loci
Show evidence (1 reference)
PMID:34380541 SUPPORT Human Clinical
"Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28)."
Establishes KMT2B as the histone H3 methyltransferase whose activity this node describes.
Promoter DNA Hypermethylation
KMT2B haploinsufficiency produces non-random genome-wide DNA hypermethylation that is selectively enriched at promoters and other positively acting regulatory elements. This is the one step in the chain measured directly in patients rather than inferred: the pattern is reproducible enough in peripheral blood to serve as a diagnostic episignature, which is also why it can reclassify variants of uncertain significance.
Experimental models
Mll2 (Kmt2b) conditional-knockout mouse embryonic stem cells CELL LINE Establishes the causal direction the patient data cannot: loss of KMT2B precedes promoter DNA methylation rather than accompanying it, and restoring the enzyme reverses the silencing. What it does not establish is that this is what happens in a KMT2B variant carrier.
Downstream
Transcriptional Dysregulation at KMT2B Target Loci
Show evidence (1 reference)
PMID:34380541 SUPPORT Human Clinical
"Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression."
Directly supports promoter-enriched DNA hypermethylation as a measured consequence of KMT2B dysfunction in patients.
Transcriptional Dysregulation at KMT2B Target Loci
Loss of the activating H3K4 mark together with gain of promoter DNA methylation disturbs transcription at a broad set of KMT2B target loci, including neurodevelopmental and neuronal-identity programs. Which of those targets actually drives the dystonic phenotype is not established, and this is the weakest link in the chain — the epigenetic lesion is well characterized while its motor-specific effectors are not.
regulation of transcription by RNA polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Pallidal Motor Circuit Dysfunction
Intellectual disability
Short stature
Intrauterine growth retardation
Microcephaly
Endocrinopathy
Characteristic facial appearance
Myoclonus
Tremor
Spasticity
Ataxia
Eye movement abnormality
Attention deficit hyperactivity disorder
Anxiety
Depression
Obsessive-compulsive behavior
Show evidence (1 reference)
PMID:27839873 SUPPORT Human Clinical
"Moreover, we provide evidence for a causative role of disordered histone modification, chromatin states, and transcriptional deregulation in dystonia pathogenesis."
Supports transcriptional deregulation, rather than a signalling defect, as the mechanism linking the chromatin lesion to dystonia.
Pallidal Motor Circuit Dysfunction
Transcriptional dysregulation disturbs basal-ganglia motor output at the level of pallidal outflow. The circuit-level location of the lesion is inferred clinically rather than molecularly: no cell-type-resolved patient data localize it. Two independent lines of clinical evidence point at the pallidum — the substantial and sustained response to bilateral globus pallidus internus deep brain stimulation, and the symmetrical hypointense streaks reported on MRI in about a quarter of published cases. Neither is decisive alone, and they do not agree on segment: the imaging sign is in the external pallidum while stimulation targets the internal.
Downstream
Ascending Generalization of Dystonic Posturing
Show evidence (2 references)
PMID:27992417 SUPPORT INDIRECT Human Clinical
"These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement."
Supports KMT2B loss acting on motor-control circuitry. The sentence names no anatomy, so its bearing on a specifically pallidal node is inferential.
PMID:27992417 SUPPORT INDIRECT Human Clinical
"Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS)."
Response to pallidal stimulation localizes an actionable node to this circuit; the inference from therapeutic response to lesion site is why this is graded INDIRECT.
Ascending Generalization of Dystonic Posturing
Abnormal basal-ganglia output produces sustained co-contraction of agonist and antagonist muscles. The disorder characteristically starts focally in a lower limb during early childhood, then spreads caudocranially to trunk, upper limbs, neck, oromandibular musculature and larynx. This rostral progression is the clinical signature of the disease and generates the bulbar and speech burden that dominates long-term disability.
Downstream
Generalized dystonia
Cervical dystonia
Oromandibular dystonia
Laryngeal dystonia
Dysarthria
Hypophonia
Dysphagia
Gait disturbance
Show evidence (2 references)
PMID:33150406 SUPPORT Human Clinical
"Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement."
Describes the caudocranial ascent this node represents.
PMID:31216378 SUPPORT Human Clinical
"In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization."
Quantifies lower-limb onset followed by caudocranial generalization.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for KMT2B-Related Dystonia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

28
Digestive 1
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
No frequency band recorded: the cited source says impaired swallowing needs gastrostomy "in some" without giving a proportion, and guessing a band from that phrasing is what the frequency vocabulary is meant to prevent.
Sequelae: Aspiration
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"Bulbar dysfunction can lead to impaired swallowing with an increased risk of aspiration and need for gastrostomy tube placement in some."
GeneReviews reports impaired swallowing from bulbar dysfunction.
Ear 1
Sensorineural hearing loss Sensorineural hearing impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing loss, annotated with Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36483457 SUPPORT Human Clinical
"Sensorineural hearing loss has also been rarely reported."
Records sensorineural hearing loss as a rare feature of the disorder.
PMID:36483457 SUPPORT Human Clinical
"Seven affected subjects presented with adult-onset focal or segmental dystonia, three developed isolated progressive hearing loss, and one displayed intellectual disability and short stature."
Documents isolated progressive hearing loss as a presenting phenotype in carriers.
Endocrine 1
Endocrinopathy Abnormality of the endocrine system HP:0000818 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Endocrinopathy, annotated with Abnormality of the endocrine system (HP:0000818). HP:0000818 is a phenotype from the Human Phenotype Ontology.
Bound at the level the source states. The cohort reports "endocrinopathies" without naming which axes, so the general endocrine-abnormality term is co-extensive with the claim; a specific axis term would assert more.
Show evidence (1 reference)
PMID:33150406 SUPPORT Human Clinical
"In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies."
Identifies endocrinopathies as a recognized co-morbidity.
Eye 1
Eye movement abnormality Abnormality of eye movement HP:0000496 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of eye movement (HP:0000496). HP:0000496 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities)"
GeneReviews lists eye movement abnormalities.
Head and Neck 3
Cervical dystonia Torticollis HP:0000473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cervical dystonia, annotated with Torticollis (HP:0000473). HP:0000473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"typically evolving from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement"
GeneReviews lists prominent cervical involvement.
Microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
No frequency band: the only citable source here is a single pre-symptomatic proband, not a cohort proportion.
Show evidence (1 reference)
PMID:38425714 SUPPORT Human Clinical
"The proband, a 4-year-old female of Jewish-Israeli descent, presented with speech delay, microcephaly, poor weight gain, attention-deficit and hyperactivity disorder, dysmorphism, intellectual disabilities and joint hyperlaxity, but presented no signs of dystonia at initial evaluation."
Documents microcephaly in a KMT2B variant carrier, and does so before dystonia onset, which is why it hangs off the transcriptional node rather than off the motor chain.
Characteristic facial appearance FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Characteristic facial appearance, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27992417 SUPPORT Human Clinical
"Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings."
Reports a typical facial appearance in the founding cohort.
Musculoskeletal 1
Spasticity HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities)"
GeneReviews lists spasticity among the additional manifestations.
Nervous System 15
Lower-limb focal dystonia at onset FREQUENT Leg dystonia HP:0031959 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower-limb focal dystonia, annotated with Leg dystonia (HP:0031959). HP:0031959 is a phenotype from the Human Phenotype Ontology.
Sequelae: Ascending Generalization of Dystonic Posturing
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"DYT-KMT2B is a complex childhood-onset progressive movement disorder (median age of onset: 6 years; range: 0-43 years) typically evolving from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement."
GeneReviews names lower-limb focal dystonia as the typical presentation.
Generalized dystonia VERY_FREQUENT HP:0007325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized dystonia (HP:0007325), qualified as course progressive. HP:0007325 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Sequelae: Status dystonicus
Show evidence (3 references)
PMID:29697234 SUPPORT Human Clinical
"DYT-KMT2B is a complex childhood-onset progressive movement disorder (median age of onset: 6 years; range: 0-43 years) typically evolving from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement."
Supports progression to generalized dystonia as the characteristic course.
PMID:38425714 SUPPORT Human Clinical
"which is reported to develop in more than 80% of KMT2B-related disorder cases"
The only quantified frequency available for dystonia in this disorder, and the basis for the VERY_FREQUENT band.
PMID:41738007 SUPPORT Human Clinical
"All patients developed generalized dystonia and bulbar involvement over time, emphasizing the progressive nature of the disease."
Independent long-term cohort in which generalization and bulbar involvement were universal.
Laryngeal dystonia HP:0012049 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Laryngeal dystonia (HP:0012049). HP:0012049 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"typically evolving from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement"
GeneReviews lists prominent laryngeal involvement.
Dysarthria FREQUENT HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"Communication difficulties secondary to articulation difficulties (dysarthria) and low speech volume (hypophonia) are common."
GeneReviews reports dysarthria as a common feature.
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"Most individuals have additional neurologic or systemic manifestations including intellectual disability (ID) / developmental delay (DD), other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities), and neurobehavioral/psychiatric manifestations"
GeneReviews lists intellectual disability among additional manifestations.
Myoclonus HP:0001336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonus (HP:0001336). HP:0001336 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities)"
GeneReviews lists myoclonus among the additional movement disorders.
Tremor HP:0001337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tremor (HP:0001337). HP:0001337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities)"
GeneReviews lists tremor among the additional movement disorders.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"other movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement abnormalities)"
GeneReviews lists ataxia among the additional movement disorders.
Attention deficit hyperactivity disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder.)"
GeneReviews lists ADHD among the neurobehavioral manifestations.
Anxiety HP:0000739 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anxiety (HP:0000739). HP:0000739 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder.)"
GeneReviews lists anxiety among the neurobehavioral manifestations.
Depression HP:0000716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Depression (HP:0000716). HP:0000716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder.)"
GeneReviews lists depression among the neurobehavioral manifestations.
Obsessive-compulsive behavior Compulsive behaviors HP:0000722 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obsessive-compulsive disorder, annotated with Compulsive behaviors (HP:0000722). HP:0000722 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder.)"
GeneReviews lists obsessive-compulsive disorder among the neurobehavioral manifestations.
Oromandibular dystonia HP:0012048 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oromandibular dystonia (HP:0012048). HP:0012048 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33150406 SUPPORT Human Clinical
"Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement."
Names prominent oromandibular involvement as a key disease characteristic.
Gait disturbance FREQUENT HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31216378 SUPPORT Human Clinical
"In 78.5% of cases, dystonia involved the lower limbs at onset, with later caudocranial generalization."
Lower-limb onset is what produces the presenting gait disturbance.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41738007 SUPPORT Human Clinical
"Non-motor features such as developmental delay, intellectual disability, and epilepsy were more frequent in our cohort than in earlier reports."
Reports epilepsy among the non-motor features and states that the literature under-reports it.
Respiratory 1
Aspiration HP:0002835 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aspiration (HP:0002835). HP:0002835 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"Bulbar dysfunction can lead to impaired swallowing with an increased risk of aspiration and need for gastrostomy tube placement in some."
GeneReviews reports increased aspiration risk.
Voice 1
Hypophonia FREQUENT Weak voice HP:0001621 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypophonia, annotated with Weak voice (HP:0001621). HP:0001621 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"Communication difficulties secondary to articulation difficulties (dysarthria) and low speech volume (hypophonia) are common."
GeneReviews reports hypophonia as a common feature.
Growth 2
Short stature FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31216378 SUPPORT Human Clinical
"KMT2B mutations are frequent in childhood-onset dystonia and cause a complex neurodevelopmental syndrome, often featuring growth retardation and intellectual disability as additional phenotypic features."
Reports growth retardation as a frequent additional feature.
PMID:36483457 SUPPORT Human Clinical
"KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal dominant neurological disorder characterized by varying combinations of generalized dystonia, psychomotor developmental delay, mild-to-moderate intellectual disability and short stature."
Lists short stature among the defining combination of features.
Intrauterine growth retardation HP:0001511 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intrauterine growth retardation (HP:0001511). HP:0001511 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33150406 SUPPORT Human Clinical
"In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies."
Identifies intrauterine growth retardation as a recognized co-morbidity.
Other 1
Status dystonicus
HPO has no term for status dystonicus; binding the generic Dystonia term here would lose the acute-emergency meaning that is the whole point of recording it, so the phenotype is left unbound.
Show evidence (1 reference)
PMID:33150406 SUPPORT Human Clinical
"In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies."
Identifies risk of status dystonicus as a co-morbidity of the disorder.
🧬

Genetic Associations

1
KMT2B
Gene: KMT2B hgnc:15840 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KMT2B (hgnc:15840). hgnc:15840 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: DE_NOVO
Show evidence (5 references)
PMID:29697234 SUPPORT Human Clinical
"a heterozygous pathogenic variant involving KMT2B (~88% of affected individuals) or a heterozygous deletion of 19q13.11-19q13.12 involving KMT2B (~12% of affected individuals)"
Quantifies the two causal lesion classes at the KMT2B locus.
PMID:33150406 SUPPORT Human Clinical
"Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants."
Supports the genotype-phenotype correlation between lesion class, onset age and systemic burden.
PMID:39933316 SUPPORT Human Clinical
"We established the existence of a KMT2B missense-mutation hotspot associated with varying degrees of disease severity and expression, providing information for patient counseling and elucidation of pathomechanisms."
Establishes the Arg2565 missense hotspot and its variable expressivity.
+ 2 more references
💊

Medical Actions

4
Antimuscarinic (Anticholinergic) Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: trihexyphenidyl CHEBI:9720 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses trihexyphenidyl (CHEBI:9720). CHEBI:9720 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Oral antimuscarinic agents, principally trihexyphenidyl, are the recommended first-line pharmacologic treatment and significantly improve motor manifestations in roughly half of individuals.
Mechanism Target:
Pallidal Motor Circuit Dysfunction
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"Antimuscarinic (anticholinergic) agents have significantly improved motor manifestations in about 50% of individuals and should be considered a first-line pharmacologic treatment in individuals with a KMT2B-related disorder."
GeneReviews recommends antimuscarinic agents as first-line therapy.
Bilateral Globus Pallidus Internus Deep Brain Stimulation
Action: bilateral globus pallidus internus deep brain stimulationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is bilateral globus pallidus internus deep brain stimulation, annotated with Deep Brain Stimulation (NCIT:C21024). NCIT:C21024 is a clinical intervention from the NCI Thesaurus. Ontology label: Deep Brain Stimulation NCIT:C21024
Platform: Device
Bilateral deep brain stimulation of the globus pallidus pars interna is the most effective intervention reported and produces a dramatic, long-lasting reduction in dystonia severity, in some cases restoring independent ambulation. Its benefit is regionally uneven: trunk and cervical dystonia improve most, laryngeal dystonia responds poorly, and gait improvement decays over years, with no patient in the longest-followed cohort maintaining a fully independent gait. Male sex and greater preoperative severity predict better response. Post-operative complications reported in the KMT2B cohorts are mild parkinsonism and freezing of gait, the latter compounding the poor and decaying gait response above rather than being a separate problem.
Mechanism Target:
Pallidal Motor Circuit Dysfunction
Ascending Generalization of Dystonic Posturing
Target Phenotypes: Generalized dystonia HP:0007325 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Generalized dystonia (HP:0007325). HP:0007325 is a phenotype from the Human Phenotype Ontology.
Show evidence (10 references)
PMID:29697234 SUPPORT Human Clinical
"Bilateral globus pallidus pars interna deep brain stimulation, performed in about 80 individuals to date, has resulted in substantial clinical and functional improvement."
GeneReviews reports substantial benefit from bilateral GPi DBS.
PMID:35005062 SUPPORT Human Clinical
"GPi-DBS resulted in median BFMDRS-M improvement of 42.7% (range: -103.5% to 95.9%) postoperatively."
Pooled effect size for pallidal stimulation across ten studies.
PMID:35005062 SUPPORT Human Clinical
"KMT2B-associated dystonia responds effectively to pallidal stimulation. The outcome is better in males and those with more severe dystonia at baseline."
Identifies male sex and baseline severity as predictors of response.
+ 7 more references
Botulinum Toxin Injection
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: botulinum toxin Relation: this treatment uses this therapeutic agent This treatment uses botulinum toxin.
Platform: Small molecule
Focal chemodenervation of the affected muscle group. It does nothing to the underlying epigenetic lesion and acts at the neuromuscular junction, far downstream of everything this entry models, but it is the practical option for the focal and segmental presentations — blepharospasm, cervical dystonia, spasmodic dysphonia — where generalized measures are disproportionate. Reported benefit in the adult-onset series is partial and, in one subject, short-lived.
Show evidence (1 reference)
PMID:36483457 SUPPORT Human Clinical
"Anticholinergics did not bring any benefit. Botulinum toxin injections led to moderate improvement of dystonia."
Records partial benefit from chemodenervation in an adult-onset carrier in whom the first-line antimuscarinic failed.
Levodopa Trial
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: levodopa CHEBI:15765 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses levodopa, annotated with L-dopa (CHEBI:15765). CHEBI:15765 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
A trial of levodopa and other anti-dystonic agents is reasonable, chiefly to exclude a dopa-responsive dystonia, but long-term benefit is not obtained in most individuals. This is a diagnostically important negative: unlike GCH1-related dopa-responsive dystonia, KMT2B-related dystonia does not show a sustained levodopa response.
Show evidence (2 references)
PMID:29697234 SUPPORT Human Clinical
"Although use of anti-dystonic agents (levodopa and other agents) has not resulted in long-term benefit for most individuals, a trial of these agents would be considered reasonable."
Supports the recommendation to trial levodopa.
PMID:29697234 REFUTE Human Clinical
"Although use of anti-dystonic agents (levodopa and other agents) has not resulted in long-term benefit for most individuals, a trial of these agents would be considered reasonable."
The same sentence refutes sustained levodopa efficacy, which is the claim a reader coming from dopa-responsive dystonia would otherwise assume.
🔬

Diagnosis

3
Molecular genetic testing for a KMT2B variant or 19q13 deletion (PRESENT)
The confirmatory test. Either a heterozygous pathogenic KMT2B sequence variant or a heterozygous 19q13.11-19q13.12 deletion encompassing the gene establishes the diagnosis in a proband with suggestive findings. The two lesion classes need different assays, which is why sequencing alone is not sufficient: a deletion carrier is missed by a test that only reads sequence.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"The diagnosis of a KMT2B-related disorder is established in a proband with suggestive findings and either of the following identified by molecular genetic testing: a heterozygous pathogenic variant involving KMT2B (~88% of affected individuals) or a heterozygous deletion of 19q13.11-19q13.12..."
The GeneReviews diagnostic criterion, with the yield of each lesion class.
KMT2B DNA methylation episignature (PRESENT)
Genome-wide peripheral-blood DNA methylation profiling resolves a disorder-specific episignature for KMT2B haploinsufficiency. Its practical value is variant reclassification: it distinguishes carriers from controls and from other dystonic and neurodevelopmental disorders, so a KMT2B variant of uncertain significance can be resolved functionally rather than left open. The signature is attenuated in Arg2565 missense carriers relative to loss-of-function carriers, so a weak result does not exclude the diagnosis.
Show evidence (3 references)
PMID:34380541 SUPPORT Human Clinical
"We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches."
Establishes the episignature as a diagnostic and variant-reclassification tool.
PMID:39933316 SUPPORT Human Clinical
"Samples bearing p.Arg2565Gly had a KMT2B-typical episignature, although the effect on methylation was less pronounced than in carriers of loss-of-function KMT2B variants."
Supports the caveat that signature strength varies with allele class, so a muted signature is not a negative result.
PMID:38425714 SUPPORT Human Clinical
"Episignature screening in this pre-symptomatic patient enabled accurate genetic diagnosis and timely and actionable intervention earlier in the natural history of Childhood-onset Dystonia-28."
Demonstrates the episignature diagnosing a carrier before dystonia onset, which is the case conventional phenotype-led testing cannot reach.
Misdiagnosis as dyskinetic cerebral palsy (PRESENT)
A progressive childhood movement disorder with developmental delay is routinely labelled dyskinetic cerebral palsy, and KMT2B carriers are found on genetic re-evaluation of that diagnosis. This matters more than a nomenclature point: the cerebral palsy label closes the diagnostic pathway and, with it, access to the pallidal stimulation that works here.
Show evidence (1 reference)
PMID:41738007 SUPPORT Human Clinical
"Notably, KMT2B variants were identified upon genetic re-evaluation in two patients previously diagnosed with dyskinetic cerebral palsy."
Documents KMT2B disease presenting under a cerebral palsy label until genetic re-evaluation.
🩻

Imaging Findings

1
Symmetrical hypointense lateral streaks in the external globus pallidus
Subtle, symmetrical hypointense lateral streaks in the external globus pallidus on T2-weighted and susceptibility-sensitive sequences, reported in roughly a quarter of published cases and treated as a feature of the disease. It is the one structural correlate described for KMT2B-related dystonia, and it is anatomically independent of the therapeutic evidence, which is what makes it worth recording even though it is neither sensitive nor required for diagnosis.
Mri Bilateral
Abnormal globus pallidus morphology HP:0002453 Human Phenotype Ontology (HP) external globus pallidus UBERON:0002476 Uberon multi-species anatomy ontology (UBERON)
Recorded with its negative alongside it. The same cohort that reports the ~27% literature figure saw no indicative MRI abnormality in any of its own nine patients, and attributes that to the sign being age-dependent and often absent in adults. A normal MRI therefore argues nothing. Note also that the streaks are in the external segment while deep brain stimulation targets the internal segment, so this corroborates pallidal involvement without confirming that the internal segment is where the lesion sits. The frequency slot is deliberately left empty: a single band would flatten the conflict between the ~27% literature figure and the zero-of-nine cohort result that this record exists to preserve.
Show evidence (3 references)
PMID:41738007 SUPPORT Human Clinical
"Brain MRI in ~27% of the patients with DYT-KMT2B in the literature showed abnormalities considered features of the disease (subtle and symmetrical hypointense lateral streaks in the external globus pallidus)."
Names the imaging sign and its published frequency, and treats it as a feature of the disease rather than an incidental finding.
PMID:41738007 REFUTE Human Clinical
"We did not see any indicative MRI-abnormalities in our cohort. This may be explained by the observed age-dependency of these MRI changes which may become less prominent over time and are often not evident in adults."
The same paper reports the sign absent throughout its own cohort, which refutes any reading of it as a reliable or age-independent marker.
PMID:27992417 SUPPORT Human Clinical
"Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings."
The founding cohort already described characteristic brain MRI findings as part of the recognizable syndrome.
📈

Progression

1
Long-term survival
Age: Adulthood
Formal survival statistics have not been published. What is documented is that the disorder is not classically fatal and that affected individuals have been reported living into the seventh decade, against a background of progressive motor and bulbar disability rather than early mortality.
Show evidence (1 reference)
PMID:29697234 SUPPORT Human Clinical
"Life expectancy is not known; however, individuals in the seventh decade of life have been reported."
The only life-expectancy statement available, and it is explicitly an absence of data rather than an estimate.
📊

Prevalence

1
Worldwide
Unknown Not yet documented
No population-based prevalence or incidence estimate exists. What is available is a diagnostic yield in selected cohorts — KMT2B variants in 21.5% of childhood-onset dystonia patients already negative for other dystonia genes — which is a testing statistic, not an occurrence rate, and is recorded on the genetic entry rather than converted into a rate here.
Show evidence (1 reference)
PMID:41738007 SUPPORT Human Clinical
"Since its initial description in 2016, DYT-KMT2B has emerged as one of the most common genetic causes of early-onset dystonia."
Establishes relative importance among monogenic early-onset dystonias without supplying a population rate, which is the state of the evidence.
🧫

Experimental Models

1
Mll2 (Kmt2b) conditional-knockout mouse embryonic stem cells CELL_LINE
Mouse embryonic stem cells carrying a conditional Mll2 allele, the gene encoding KMT2B, in which the enzyme can be depleted and then re-expressed while the chromatin state and DNA methylation of a CpG island promoter are followed over time. This is the experimental basis for the claim that KMT2B occupancy protects promoters from DNA methylation, and it is recorded here so that the mechanism the hypermethylation node declines to assert as human biology has a structural home rather than living only in that node's notes.
Organism
mouse NCBITaxon:10090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in mouse, annotated with Mus musculus (NCBITaxon:10090). NCBITaxon:10090 is an organism from the NCBI Taxonomy.
Cell source
Mouse embryonic stem cell line with a conditional Mll2 (Kmt2b) allele
Culture
Monolayer embryonic stem cell culture with inducible Mll2 deletion and rescue by KMT2B re-expression
Publication
PMID:23358417
Pathograph links
Promoter DNA Hypermethylation partially recapitulates fidelity: low observes: molecular Establishes the causal direction the patient data cannot: loss of KMT2B precedes promoter DNA methylation rather than accompanying it, and restoring the enzyme reverses the silencing. What it does not establish is that this is what happens in a KMT2B variant carrier.
Limitations: A single CpG island promoter in mouse embryonic stem cells, under complete conditional loss of the gene, stands in for genome-wide promoter hypermethylation measured in the peripheral blood of humans carrying one working copy. Nothing in the system is neural, human, or heterozygous, and no dystonia-relevant readout exists in it.
Divergences from the human mechanism
species mismatch qualifying
The measurements are in mouse cells. Mouse and human differ in CpG island methylation dynamics at exactly the class of promoter under study, so the direction of the effect transfers more safely than its magnitude or its target set.
boundary omission qualifying
Neurons, the pallidum and the whole developmental trajectory of the disease lie outside the model. Embryonic stem cells report the enzyme's generic chromatin function, not its function in the cell types whose failure produces dystonia.
population mismatch qualifying
The model applies complete conditional loss of Mll2, whereas the disease is heterozygous loss of function. Whether one remaining copy leaves the protective function partially intact is the quantitative question the model is not set up to answer.
Readouts
MagohB CpG island promoter DNA methylation after KMT2B depletion
Direction: INCREASED
Interpretation: Promoter methylation rises once KMT2B is lost and the active marks have gone, which is the molecular event the human episignature measures at genome scale.
Show evidence (1 reference)
PMID:23358417 SUPPORT In Vitro
"KMT2B depletion was followed by the loss of the active chromatin marks and progressive loss of RNA polymerase II binding with a concomitant downregulation of MagohB expression. Once the active chromatin marks were lost, the MagohB promoter was rapidly methylated."
The kinetic measurement behind this readout, and the sentence that orders the two events.
Promoter reactivation after KMT2B re-expression
Direction: RESTORED
Interpretation: The rescue arm, which is what makes the relationship causal rather than correlative in this system.
Show evidence (1 reference)
PMID:23358417 SUPPORT In Vitro
"Reexpression of KMT2B was sufficient to reinstate an active MagohB promoter."
Reports the rescue measurement behind this readout.
Show evidence (1 reference)
PMID:23358417 SUPPORT In Vitro
"Our study provides a paradigm for the idea that KMT2 proteins are crucial components for establishing and maintaining the transcriptionally active and unmethylated state of CpG island promoters."
The authors' own statement of scope, and the reason this model is treated as informative for the hypermethylation node while its fidelity is graded LOW.
Notes
Recorded as an experimental model rather than an animal model because the system is a cultured cell line, not a whole organism. The wider claim often made from this literature, that KMT2B loss lets Polycomb repressive complex 2 and DNA methyltransferases reach loci they are normally excluded from, is not asserted here: this paper measures protection from DNA methylation and does not name PRC2, and no cited reference does so in quotable form.
{ }

Source YAML

click to show 
name: KMT2B-Related Dystonia
creation_date: "2026-09-04T04:30:00Z"
category: Mendelian
description: >-
  KMT2B-related dystonia (DYT-KMT2B, dystonia 28) is a childhood-onset,
  progressive, generalized dystonia caused by heterozygous loss-of-function
  variants in KMT2B or by heterozygous 19q13.11-19q13.12 deletions encompassing
  the gene. KMT2B encodes a histone H3 lysine 4 (H3K4) methyltransferase, so
  haploinsufficiency both removes an activating chromatin mark and permits
  aberrant, non-random DNA hypermethylation at promoters and other positive
  regulatory elements. The result is broad transcriptional dysregulation at
  KMT2B target loci rather than failure of any single effector pathway; no
  patient transcriptomic data establish the direction of that change, so the
  entry does not claim one. Dystonia characteristically begins as a
  focal lower-limb disorder in early childhood and ascends in a caudocranial
  pattern to a generalized form with prominent cervical, oromandibular and
  laryngeal involvement, producing dysarthria, hypophonia and bulbar dysfunction.
  Most affected individuals also have developmental delay or intellectual
  disability, short stature, additional movement disorders, and neurobehavioral
  features; a milder adult-onset focal or segmental form and a non-dystonic
  neurodevelopmental presentation are both recognized. Oral antimuscarinic agents
  help about half of individuals, and bilateral deep brain stimulation of the
  globus pallidus internus produces substantial, long-lasting motor improvement,
  making this one of the more treatable monogenic dystonias — though laryngeal
  dystonia and gait respond poorly and are the residual burden.
synonyms:
- DYT-KMT2B
- DYT28
- dystonia 28, childhood-onset
- KMT2B dystonic disorder
- complex childhood-onset dystonia due to KMT2B mutation
disease_term:
  preferred_term: KMT2B-related dystonia
  term:
    id: MONDO:0015004
    label: dystonia 28, childhood-onset
parents:
- dystonic disorder
- movement disorder
- autosomal dominant disease
- chromatinopathy
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      A movement disorder presenting and managed in neurology; the clinical
      chapter that covers it is the dystonia chapter.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      Monogenic autosomal dominant disorder whose lesion is gene dosage, and
      whose diagnosis, counselling and predictive-testing problems are those of
      a Mendelian disease rather than of a movement disorder.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence or incidence estimate exists. What is
    available is a diagnostic yield in selected cohorts — KMT2B variants in
    21.5% of childhood-onset dystonia patients already negative for other
    dystonia genes — which is a testing statistic, not an occurrence rate, and is
    recorded on the genetic entry rather than converted into a rate here.
  evidence:
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Since its initial description in 2016, DYT-KMT2B has emerged as one of the
      most common genetic causes of early-onset dystonia.
    explanation: >-
      Establishes relative importance among monogenic early-onset dystonias
      without supplying a population rate, which is the state of the evidence.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    KMT2B-related dystonia is autosomal dominant with incomplete penetrance and
    variable expressivity: relatives carrying the same variant may present with
    generalized dystonia, with short stature or intellectual disability alone, or
    remain asymptomatic. Most probands carry a de novo
    variant, but inherited variants occur and a transmitting parent may be mildly
    affected or clinically asymptomatic, so reduced penetrance and variable
    expressivity must be assumed when counselling families.
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DYT-KMT2B and KMT2B-related NDD are autosomal dominant disorders.
    explanation: GeneReviews states the mode of inheritance for KMT2B-related dystonia.
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of individuals reported to date with a KMT2B-related disorder
      whose parents have undergone molecular genetic testing have the disorder as
      a result of a de novo genetic alteration.
    explanation: Supports the predominantly de novo origin of the causal variant.
  - reference: PMID:31216378
    reference_title: "Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also report on 4 asymptomatic carriers, suggesting that some KMT2B
      mutations may be associated with incomplete disease penetrance.
    explanation: >-
      Directly evidences incomplete penetrance, which is why an apparently
      unaffected parent cannot be assumed to be a non-carrier.
  - reference: PMID:31216378
    reference_title: "Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observed a spectrum of clinical manifestations in KMT2B variant carriers,
      ranging from generalized dystonia to short stature or intellectual
      disability alone, even within the same family.
    explanation: Documents the intrafamilial variable expressivity recorded above.
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each child of an individual with a KMT2B-related disorder has a 50% chance
      of inheriting the genetic alteration. Once the KMT2B pathogenic variant or
      deletion of 19q13.12 involving KMT2B has been identified in an affected
      family member, prenatal and preimplantation genetic testing are possible.
    explanation: >-
      The transmission risk and the availability of prenatal and preimplantation
      testing once the familial variant is known — the two facts a counselling
      conversation turns on.
has_subtypes:
- name: Adult-onset
  display_name: Adult-onset focal or segmental DYT-KMT2B
  review_notes: >-
    Left without a subtype_term deliberately. MONDO has no term for adult-onset
    KMT2B-related dystonia; the nearest candidate, MONDO:0100015 adult-onset
    segmental dystonia, is a clinical category rather than a KMT2B entity, so
    binding it would drop the gene identity and admit unrelated cases. Bind a
    term here if MONDO later mints one.
  description: >-
    A milder, later-onset form presenting in adulthood as focal or segmental
    dystonia — blepharospasm, cervical dystonia, writer's cramp or spasmodic
    dysphonia — usually without the developmental delay of the classic
    childhood-onset disease. It is not simply a late presentation of the same
    process: on genome-wide methylation profiling the adult-onset cases cluster
    with controls rather than with early-onset DYT-KMT2B, and the probes that do
    distinguish them do not overlap the early-onset episignature, which the
    authors read as a different molecular mechanism. This entry's
    pathophysiology chain is therefore not asserted to apply to the subtype.
    Two of the four missense alleles involved (p.S640T, p.R2339Q) are described
    by the reporting authors as lacking segregation proof, so the subtype rests
    on a smaller evidence base than the childhood-onset disease.
  evidence:
  - reference: PMID:36483457
    reference_title: Adult-onset KMT2B-related dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven affected subjects presented with adult-onset focal or segmental
      dystonia, three developed isolated progressive hearing loss, and one
      displayed intellectual disability and short stature.
    explanation: Establishes the adult-onset focal/segmental presentation as a distinct subtype.
  - reference: PMID:36483457
    reference_title: Adult-onset KMT2B-related dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genome-wide DNA methylation profiling allowed to discriminate these
      adult-onset dystonia cases from controls and early-onset DYT-KMT2B patients.
    explanation: >-
      Supports treating adult-onset disease as separable from the classic form
      rather than as the same entity presenting late.
  - reference: PMID:36483457
    reference_title: Adult-onset KMT2B-related dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These specific probes did not overlap with early-onset DYT-KMT2B
      episignature, suggesting a different molecular mechanism underlying this
      late-onset phenotype.
    explanation: >-
      States directly that the adult-onset signature does not overlap the
      early-onset one and implies a different mechanism, which is why this entry
      does not extend its causal chain to the subtype.
  - reference: PMID:36483457
    reference_title: Adult-onset KMT2B-related dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in particular, at the current time, the p.S640T and p.R2339Q lack proof of
      disease segregation and need additional evidence to support their
      pathogenicity
    explanation: >-
      The reporting authors' own caveat on two of the four alleles underpinning
      this subtype.
pathophysiology:
- name: KMT2B Haploinsufficiency
  description: >-
    Heterozygous loss-of-function variants in KMT2B, or heterozygous deletions of
    19q13.11-19q13.12 that remove one copy of the gene, halve the dose of the
    KMT2B histone methyltransferase. Truncating alleles introduce a premature
    termination codon and reduce KMT2B transcript in patient fibroblasts;
    microdeletion carriers show the same dystonic presentation, which is the
    independent argument that gene dosage rather than a mutant protein product is
    the lesion. Missense alleles are presumed to act by the same route, but for
    those the haploinsufficiency claim is inferred rather than measured.
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  biological_scale: MOLECULAR
  genes:
  - preferred_term: KMT2B
    term:
      id: hgnc:15840
      label: KMT2B
  molecular_functions:
  - preferred_term: histone H3K4 methyltransferase activity
    term:
      id: GO:0042800
      label: histone H3K4 methyltransferase activity
    modifier: LOSS_OF_FUNCTION
  downstream:
  - target: Promoter DNA Hypermethylation
    causal_link_type: DIRECT
    description: >-
      Drawn from the haploinsufficiency node rather than from the reduced-mark
      node because the barrier function KMT2B provides against repressive
      machinery is reported to be independent of its methyltransferase
      catalysis: what is lost is protein occupancy, not the mark.
  - target: Reduced H3K4 Methylation at Target Promoters
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27839873
      reference_title: Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Our findings thus establish generalized dystonia as the human phenotype
        associated with haploinsufficiency of KMT2B.
      explanation: >-
        Establishes haploinsufficiency as the disease-initiating lesion. The step
        to a reduced H3K4 mark follows from KMT2B's enzyme identity rather than
        from this genotype-phenotype statement, hence INDIRECT.
  evidence:
  - reference: PMID:27839873
    reference_title: Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Suggestive of haploinsufficiency, we found significantly decreased total
      mRNA levels of KMT2B in mutant fibroblasts.
    explanation: >-
      Patient-derived fibroblasts show the reduced KMT2B transcript dose that this
      node asserts.
  - reference: PMID:27839873
    reference_title: Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Each of the four mutations was predicted to mediate a loss-of-function
      effect by introducing a premature termination codon.
    explanation: >-
      In-silico consequence prediction for the founding alleles; graded
      COMPUTATIONAL because the sentence reports a prediction, not a measurement.
      The measured half of the claim is the fibroblast transcript result above.
  - reference: PMID:27839873
    reference_title: Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Independent support for pathogenicity of the mutations comes from the
      observation of high rates of dystonic presentations in KMT2B-involving
      microdeletion syndromes.
    explanation: >-
      Whole-gene deletions producing the same phenotype is the dosage argument
      that distinguishes haploinsufficiency from a dominant-negative mechanism.
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of a KMT2B-related disorder is established in a proband with
      suggestive findings and either of the following identified by molecular
      genetic testing: a heterozygous pathogenic variant involving KMT2B (~88% of
      affected individuals) or a heterozygous deletion of 19q13.11-19q13.12
      involving KMT2B (~12% of affected individuals).
    explanation: Quantifies the two lesion classes that converge on reduced KMT2B dose.
- name: Reduced H3K4 Methylation at Target Promoters
  description: >-
    KMT2B is one of the SET1/MLL-family enzymes that deposit methyl marks on
    histone H3 lysine 4 at promoters and enhancers. Reduced enzyme dose lowers
    H3K4 methylation across the loci KMT2B normally licenses, changing chromatin
    state rather than deleting any single downstream gene. Note that the loss of
    the activating mark is only half the lesion: the same loss of KMT2B occupancy
    also removes a barrier to repressive machinery, and that arm is drawn as a
    parallel branch from the haploinsufficiency node rather than from here.
  notes: >-
    The reduction in H3K4 methylation is inferred from enzyme identity and gene
    dosage, not measured in patients or patient tissue. No cited reference
    quantifies the mark in KMT2B variant carriers, which is why the incoming
    edge is graded INDIRECT and why the adjacent hypermethylation node — which
    is measured — carries the weight of the chain.
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance"
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: DECREASED
  downstream:
  - target: Transcriptional Dysregulation at KMT2B Target Loci
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34380541
    reference_title: Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a
      histone H3 methyltransferase, have been associated with a childhood-onset,
      progressive and complex form of dystonia (dystonia 28, DYT28).
    explanation: Establishes KMT2B as the histone H3 methyltransferase whose activity this node describes.
- name: Promoter DNA Hypermethylation
  description: >-
    KMT2B haploinsufficiency produces non-random genome-wide DNA
    hypermethylation that is selectively enriched at promoters and other
    positively acting regulatory elements. This is the one step in the chain
    measured directly in patients rather than inferred: the pattern is
    reproducible enough in peripheral blood to serve as a diagnostic
    episignature, which is also why it can reclassify variants of uncertain
    significance.
  notes: >-
    The mechanism usually offered for this step — that loss of KMT2B occupancy
    lets DNA methyltransferases and Polycomb machinery act at loci they would
    normally be excluded from — comes from mouse embryonic stem cell work and
    has not been shown in human neurons or patient tissue. It is therefore left
    out of the description rather than asserted as human mechanism; what is
    curated here is the measured hypermethylation, not its proposed cause. No
    current GO biological-process term fits: GO has obsoleted histone H3-K4
    methylation, histone lysine methylation and DNA methylation alike, so the
    node is left without a process annotation rather than reusing the generic
    chromatin-organization term already carried by the adjacent node.
  biological_scale: MOLECULAR
  downstream:
  - target: Transcriptional Dysregulation at KMT2B Target Loci
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:34380541
    reference_title: Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, defective KMT2B function in DYT28 causes a non-random DNA
      hypermethylation across the genome, selectively involving promoters and
      other regulatory regions positively controlling gene expression.
    explanation: >-
      Directly supports promoter-enriched DNA hypermethylation as a measured
      consequence of KMT2B dysfunction in patients.
- name: Transcriptional Dysregulation at KMT2B Target Loci
  description: >-
    Loss of the activating H3K4 mark together with gain of promoter DNA
    methylation disturbs transcription at a broad set of KMT2B target loci,
    including neurodevelopmental and neuronal-identity programs. Which of those
    targets actually drives the dystonic phenotype is not established, and this
    is the weakest link in the chain — the epigenetic lesion is well
    characterized while its motor-specific effectors are not.
  notes: >-
    The node deliberately claims dysregulation rather than repression. The
    chromatin changes are individually repressive, and repression is the usual
    reading, but no patient transcriptomic data were found for this disorder and
    the cited sources say "transcriptional deregulation" without a direction, so
    the modifier is ABNORMAL rather than DECREASED.
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Dysregulated Neurodevelopmental Transcriptional Program"
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: ABNORMAL
  downstream:
  - target: Pallidal Motor Circuit Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intrauterine growth retardation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Endocrinopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Characteristic facial appearance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Myoclonus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Eye movement abnormality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Attention deficit hyperactivity disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Anxiety
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Depression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Obsessive-compulsive behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:27839873
    reference_title: Haploinsufficiency of KMT2B, Encoding the Lysine-Specific Histone Methyltransferase 2B, Results in Early-Onset Generalized Dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Moreover, we provide evidence for a causative role of disordered histone
      modification, chromatin states, and transcriptional deregulation in dystonia
      pathogenesis.
    explanation: >-
      Supports transcriptional deregulation, rather than a signalling defect, as
      the mechanism linking the chromatin lesion to dystonia.
- name: Pallidal Motor Circuit Dysfunction
  description: >-
    Transcriptional dysregulation disturbs basal-ganglia motor output at the
    level of pallidal outflow. The circuit-level location of the lesion is
    inferred clinically rather than molecularly: no cell-type-resolved patient
    data localize it. Two independent lines of clinical evidence point at the
    pallidum — the substantial and sustained response to bilateral globus
    pallidus internus deep brain stimulation, and the symmetrical hypointense
    streaks reported on MRI in about a quarter of published cases. Neither is
    decisive alone, and they do not agree on segment: the imaging sign is in the
    external pallidum while stimulation targets the internal.
  notes: >-
    Named for the pallidum alone, and left without a cell-type binding, because
    that is as far as the evidence reaches. Striatal medium spiny neurons are the
    usual candidate by circuit logic and by the choice of DBS target, but nothing
    cited here reports striatal or cell-type-resolved data in KMT2B variant
    carriers, so binding CL:1001474 would assert a localization no source makes.
    The imaging corroboration is real but weak: the sign is absent in roughly
    three quarters of published cases and was absent throughout the one cohort
    that looked for it prospectively.
  biological_scale: TISSUE
  downstream:
  - target: Ascending Generalization of Dystonic Posturing
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:27992417
    reference_title: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings highlight a clinically recognizable and potentially treatable
      form of genetic dystonia, demonstrating the crucial role of KMT2B in the
      physiological control of voluntary movement.
    explanation: >-
      Supports KMT2B loss acting on motor-control circuitry. The sentence names
      no anatomy, so its bearing on a specifically pallidal node is inferential.
  - reference: PMID:27992417
    reference_title: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Marked clinical benefit, including the restoration of independent
      ambulation in some cases, was observed following deep brain stimulation
      (DBS).
    explanation: >-
      Response to pallidal stimulation localizes an actionable node to this
      circuit; the inference from therapeutic response to lesion site is why this
      is graded INDIRECT.
- name: Ascending Generalization of Dystonic Posturing
  description: >-
    Abnormal basal-ganglia output produces sustained co-contraction of agonist
    and antagonist muscles. The disorder characteristically starts focally in a
    lower limb during early childhood, then spreads caudocranially to trunk,
    upper limbs, neck, oromandibular musculature and larynx. This rostral
    progression is the clinical signature of the disease and generates the bulbar
    and speech burden that dominates long-term disability.
  biological_scale: ORGANISM
  downstream:
  - target: Generalized dystonia
    causal_link_type: DIRECT
  - target: Cervical dystonia
    causal_link_type: DIRECT
  - target: Oromandibular dystonia
    causal_link_type: DIRECT
  - target: Laryngeal dystonia
    causal_link_type: DIRECT
  - target: Dysarthria
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hypophonia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Dysphagia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Gait disturbance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key characteristics of typical disease include focal motor features at
      disease presentation, evolving through a caudocranial pattern into
      generalized dystonia, with prominent oromandibular, laryngeal and cervical
      involvement.
    explanation: Describes the caudocranial ascent this node represents.
  - reference: PMID:31216378
    reference_title: "Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 78.5% of cases, dystonia involved the lower limbs at onset, with later
      caudocranial generalization.
    explanation: Quantifies lower-limb onset followed by caudocranial generalization.
imaging_findings:
- name: Symmetrical hypointense lateral streaks in the external globus pallidus
  modality: MRI
  imaging_finding_term:
    preferred_term: Abnormal globus pallidus morphology
    term:
      id: HP:0002453
      label: Abnormal globus pallidus morphology
  located_in:
    preferred_term: external globus pallidus
    term:
      id: UBERON:0002476
      label: lateral globus pallidus
  laterality: BILATERAL
  diagnostic: false
  description: >-
    Subtle, symmetrical hypointense lateral streaks in the external globus
    pallidus on T2-weighted and susceptibility-sensitive sequences, reported in
    roughly a quarter of published cases and treated as a feature of the disease.
    It is the one structural correlate described for KMT2B-related dystonia, and
    it is anatomically independent of the therapeutic evidence, which is what
    makes it worth recording even though it is neither sensitive nor required for
    diagnosis.
  notes: >-
    Recorded with its negative alongside it. The same cohort that reports the
    ~27% literature figure saw no indicative MRI abnormality in any of its own
    nine patients, and attributes that to the sign being age-dependent and often
    absent in adults. A normal MRI therefore argues nothing. Note also that the
    streaks are in the external segment while deep brain stimulation targets the
    internal segment, so this corroborates pallidal involvement without
    confirming that the internal segment is where the lesion sits. The
    frequency slot is deliberately left empty: a single band would flatten the
    conflict between the ~27% literature figure and the zero-of-nine cohort
    result that this record exists to preserve.
  evidence:
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI in ~27% of the patients with DYT-KMT2B in the literature showed
      abnormalities considered features of the disease (subtle and symmetrical
      hypointense lateral streaks in the external globus pallidus).
    explanation: >-
      Names the imaging sign and its published frequency, and treats it as a
      feature of the disease rather than an incidental finding.
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We did not see any indicative MRI-abnormalities in our cohort. This may be
      explained by the observed age-dependency of these MRI changes which may
      become less prominent over time and are often not evident in adults.
    explanation: >-
      The same paper reports the sign absent throughout its own cohort, which
      refutes any reading of it as a reliable or age-independent marker.
  - reference: PMID:27992417
    reference_title: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report heterozygous variants in the gene KMT2B (also known as MLL4)
      in 27 unrelated individuals with a complex progressive childhood-onset
      dystonia, often associated with a typical facial appearance and
      characteristic brain magnetic resonance imaging findings.
    explanation: >-
      The founding cohort already described characteristic brain MRI findings as
      part of the recognizable syndrome.
phenotypes:
- category: Neurological
  name: Lower-limb focal dystonia at onset
  description: >-
    The presenting feature in most individuals is focal dystonia of a lower limb,
    typically causing gait disturbance in early childhood.
  phenotype_term:
    preferred_term: Lower-limb focal dystonia
    term:
      id: HP:0031959
      label: Leg dystonia
  frequency: FREQUENT
  sequelae:
  - target: Ascending Generalization of Dystonic Posturing
    description: >-
      Focal lower-limb onset is the first step of the caudocranial march that the
      pathophysiology node describes.
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DYT-KMT2B is a complex childhood-onset progressive movement disorder
      (median age of onset: 6 years; range: 0-43 years) typically evolving from
      lower-limb focal dystonia into generalized dystonia with prominent
      cervical, cranial, and laryngeal involvement.
    explanation: GeneReviews names lower-limb focal dystonia as the typical presentation.
- category: Neurological
  name: Generalized dystonia
  description: >-
    Focal dystonia generalizes over months to years, involving trunk, limbs, neck
    and cranial musculature.
  phenotype_term:
    preferred_term: Generalized dystonia
    term:
      id: HP:0007325
      label: Generalized dystonia
    clinical_course: PROGRESSIVE
  frequency: VERY_FREQUENT
  sequelae:
  - target: Status dystonicus
    description: >-
      Status dystonicus is the acute decompensation of established generalized
      dystonia, not an independent manifestation.
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DYT-KMT2B is a complex childhood-onset progressive movement disorder
      (median age of onset: 6 years; range: 0-43 years) typically evolving from
      lower-limb focal dystonia into generalized dystonia with prominent
      cervical, cranial, and laryngeal involvement.
    explanation: Supports progression to generalized dystonia as the characteristic course.
  - reference: PMID:38425714
    reference_title: "Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which is reported to develop in more than 80% of KMT2B-related disorder
      cases
    explanation: >-
      The only quantified frequency available for dystonia in this disorder, and
      the basis for the VERY_FREQUENT band.
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients developed generalized dystonia and bulbar involvement over
      time, emphasizing the progressive nature of the disease.
    explanation: >-
      Independent long-term cohort in which generalization and bulbar
      involvement were universal.
- category: Neurological
  name: Cervical dystonia
  description: Prominent involvement of the neck musculature with abnormal head posture.
  phenotype_term:
    preferred_term: Cervical dystonia
    term:
      id: HP:0000473
      label: Torticollis
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      typically evolving from lower-limb focal dystonia into generalized dystonia
      with prominent cervical, cranial, and laryngeal involvement
    explanation: GeneReviews lists prominent cervical involvement.
- category: Neurological
  name: Laryngeal dystonia
  description: >-
    Dystonic involvement of the laryngeal musculature contributing to strained,
    low-volume speech.
  phenotype_term:
    preferred_term: Laryngeal dystonia
    term:
      id: HP:0012049
      label: Laryngeal dystonia
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      typically evolving from lower-limb focal dystonia into generalized dystonia
      with prominent cervical, cranial, and laryngeal involvement
    explanation: GeneReviews lists prominent laryngeal involvement.
- category: Neurological
  name: Dysarthria
  description: Articulation difficulty producing communication impairment.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  frequency: FREQUENT
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Communication difficulties secondary to articulation difficulties
      (dysarthria) and low speech volume (hypophonia) are common.
    explanation: GeneReviews reports dysarthria as a common feature.
- category: Neurological
  name: Hypophonia
  description: Abnormally low speech volume.
  phenotype_term:
    preferred_term: Hypophonia
    term:
      id: HP:0001621
      label: Weak voice
  frequency: FREQUENT
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Communication difficulties secondary to articulation difficulties
      (dysarthria) and low speech volume (hypophonia) are common.
    explanation: GeneReviews reports hypophonia as a common feature.
- category: Neurological
  name: Dysphagia
  description: >-
    Bulbar dysfunction impairs swallowing, with aspiration risk and a need for
    gastrostomy in some individuals.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  sequelae:
  - target: Aspiration
    description: Impaired swallowing is what produces the aspiration risk.
  notes: >-
    No frequency band recorded: the cited source says impaired swallowing needs
    gastrostomy "in some" without giving a proportion, and guessing a band from
    that phrasing is what the frequency vocabulary is meant to prevent.
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bulbar dysfunction can lead to impaired swallowing with an increased risk of
      aspiration and need for gastrostomy tube placement in some.
    explanation: GeneReviews reports impaired swallowing from bulbar dysfunction.
- category: Neurological
  name: Aspiration
  description: Consequence of bulbar dysfunction and impaired swallowing.
  phenotype_term:
    preferred_term: Aspiration
    term:
      id: HP:0002835
      label: Aspiration
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bulbar dysfunction can lead to impaired swallowing with an increased risk of
      aspiration and need for gastrostomy tube placement in some.
    explanation: GeneReviews reports increased aspiration risk.
- category: Neurodevelopmental
  name: Intellectual disability
  description: >-
    Intellectual disability or developmental delay, ranging from mild to severe,
    accompanies the movement disorder in most individuals.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most individuals have additional neurologic or systemic manifestations
      including intellectual disability (ID) / developmental delay (DD), other
      movement disorders (myoclonus, spasticity, tremor, ataxia, eye movement
      abnormalities), and neurobehavioral/psychiatric manifestations
    explanation: GeneReviews lists intellectual disability among additional manifestations.
- category: Neurological
  name: Myoclonus
  description: Additional movement disorder co-occurring with dystonia.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other movement disorders (myoclonus, spasticity, tremor, ataxia, eye
      movement abnormalities)
    explanation: GeneReviews lists myoclonus among the additional movement disorders.
- category: Neurological
  name: Tremor
  description: Additional movement disorder co-occurring with dystonia.
  phenotype_term:
    preferred_term: Tremor
    term:
      id: HP:0001337
      label: Tremor
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other movement disorders (myoclonus, spasticity, tremor, ataxia, eye
      movement abnormalities)
    explanation: GeneReviews lists tremor among the additional movement disorders.
- category: Neurological
  name: Spasticity
  description: Additional pyramidal feature co-occurring with dystonia.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other movement disorders (myoclonus, spasticity, tremor, ataxia, eye
      movement abnormalities)
    explanation: GeneReviews lists spasticity among the additional manifestations.
- category: Neurological
  name: Ataxia
  description: Additional movement disorder co-occurring with dystonia.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other movement disorders (myoclonus, spasticity, tremor, ataxia, eye
      movement abnormalities)
    explanation: GeneReviews lists ataxia among the additional movement disorders.
- category: Ophthalmological
  name: Eye movement abnormality
  description: Oculomotor abnormalities reported alongside the movement disorder.
  phenotype_term:
    preferred_term: Abnormality of eye movement
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other movement disorders (myoclonus, spasticity, tremor, ataxia, eye
      movement abnormalities)
    explanation: GeneReviews lists eye movement abnormalities.
- category: Psychiatric
  name: Attention deficit hyperactivity disorder
  description: Neurobehavioral manifestation reported in KMT2B-related disorders.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity
      disorder, anxiety, depression, and obsessive-compulsive disorder.)
    explanation: GeneReviews lists ADHD among the neurobehavioral manifestations.
- category: Psychiatric
  name: Anxiety
  description: Neurobehavioral manifestation reported in KMT2B-related disorders.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity
      disorder, anxiety, depression, and obsessive-compulsive disorder.)
    explanation: GeneReviews lists anxiety among the neurobehavioral manifestations.
- category: Psychiatric
  name: Depression
  description: Neurobehavioral manifestation reported in KMT2B-related disorders.
  phenotype_term:
    preferred_term: Depression
    term:
      id: HP:0000716
      label: Depression
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity
      disorder, anxiety, depression, and obsessive-compulsive disorder.)
    explanation: GeneReviews lists depression among the neurobehavioral manifestations.
- category: Psychiatric
  name: Obsessive-compulsive behavior
  description: Neurobehavioral manifestation reported in KMT2B-related disorders.
  phenotype_term:
    preferred_term: Obsessive-compulsive disorder
    term:
      id: HP:0000722
      label: Compulsive behaviors
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      neurobehavioral/psychiatric manifestations (e.g., attention-deficit/hyperactivity
      disorder, anxiety, depression, and obsessive-compulsive disorder.)
    explanation: GeneReviews lists obsessive-compulsive disorder among the neurobehavioral manifestations.
- category: Neurological
  name: Oromandibular dystonia
  description: >-
    Cranial involvement of the jaw and lower facial musculature, part of the
    prominent oromandibular-laryngeal-cervical triad of established disease.
  phenotype_term:
    preferred_term: Oromandibular dystonia
    term:
      id: HP:0012048
      label: Oromandibular dystonia
  evidence:
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Key characteristics of typical disease include focal motor features at
      disease presentation, evolving through a caudocranial pattern into
      generalized dystonia, with prominent oromandibular, laryngeal and cervical
      involvement.
    explanation: Names prominent oromandibular involvement as a key disease characteristic.
- category: Neurological
  name: Gait disturbance
  description: >-
    Gait difficulty from lower-limb dystonia is usually the presenting complaint,
    and progressive gait failure is the main determinant of loss of independence.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  frequency: FREQUENT
  evidence:
  - reference: PMID:31216378
    reference_title: "Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 78.5% of cases, dystonia involved the lower limbs at onset, with later
      caudocranial generalization.
    explanation: Lower-limb onset is what produces the presenting gait disturbance.
- category: Growth
  name: Short stature
  description: >-
    Growth restriction is a recurrent systemic feature and can be the only
    manifestation in a variant carrier who never develops dystonia.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: FREQUENT
  evidence:
  - reference: PMID:31216378
    reference_title: "Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KMT2B mutations are frequent in childhood-onset dystonia and cause a complex
      neurodevelopmental syndrome, often featuring growth retardation and
      intellectual disability as additional phenotypic features.
    explanation: Reports growth retardation as a frequent additional feature.
  - reference: PMID:36483457
    reference_title: Adult-onset KMT2B-related dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KMT2B-related dystonia (DYT-KMT2B, also known as DYT28) is an autosomal
      dominant neurological disorder characterized by varying combinations of
      generalized dystonia, psychomotor developmental delay, mild-to-moderate
      intellectual disability and short stature.
    explanation: Lists short stature among the defining combination of features.
- category: Growth
  name: Intrauterine growth retardation
  description: >-
    Prenatal growth restriction identified as a co-morbidity in the largest
    phenotyping cohort, indicating that the systemic effect of KMT2B
    haploinsufficiency begins before birth.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the previously reported systemic features, our study has
      identified co-morbidities, including the risk of status dystonicus,
      intrauterine growth retardation, and endocrinopathies.
    explanation: Identifies intrauterine growth retardation as a recognized co-morbidity.
- category: Endocrine
  name: Endocrinopathy
  description: >-
    Endocrine co-morbidity reported alongside growth restriction in the expanded
    phenotype.
  phenotype_term:
    preferred_term: Endocrinopathy
    term:
      id: HP:0000818
      label: Abnormality of the endocrine system
  notes: >-
    Bound at the level the source states. The cohort reports "endocrinopathies"
    without naming which axes, so the general endocrine-abnormality term is
    co-extensive with the claim; a specific axis term would assert more.
  evidence:
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the previously reported systemic features, our study has
      identified co-morbidities, including the risk of status dystonicus,
      intrauterine growth retardation, and endocrinopathies.
    explanation: Identifies endocrinopathies as a recognized co-morbidity.
- category: Neurological
  name: Status dystonicus
  description: >-
    A dystonic emergency of severe, generalized, refractory dystonic spasms,
    identified as a specific risk in this disorder.
  phenotype_term:
    preferred_term: Status dystonicus
  notes: >-
    HPO has no term for status dystonicus; binding the generic Dystonia term here
    would lose the acute-emergency meaning that is the whole point of recording
    it, so the phenotype is left unbound.
  evidence:
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition to the previously reported systemic features, our study has
      identified co-morbidities, including the risk of status dystonicus,
      intrauterine growth retardation, and endocrinopathies.
    explanation: Identifies risk of status dystonicus as a co-morbidity of the disorder.
- category: Otological
  name: Sensorineural hearing loss
  description: >-
    Progressive sensorineural hearing loss is rarely reported in classic disease
    but was the isolated presenting feature in three of twelve carriers in one
    adult-onset series. The reporting authors caution that the association with
    KMT2B rests on few observations and may be coincidental, so this is recorded
    as a reported feature rather than an established one. It is deliberately
    left off the pathograph for the same reason: drawing an edge to it would
    assert a causal link to KMT2B that the reporting authors themselves decline
    to claim.
  phenotype_term:
    preferred_term: Sensorineural hearing loss
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:36483457
    reference_title: Adult-onset KMT2B-related dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sensorineural hearing loss has also been rarely reported.
    explanation: Records sensorineural hearing loss as a rare feature of the disorder.
  - reference: PMID:36483457
    reference_title: Adult-onset KMT2B-related dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven affected subjects presented with adult-onset focal or segmental
      dystonia, three developed isolated progressive hearing loss, and one
      displayed intellectual disability and short stature.
    explanation: Documents isolated progressive hearing loss as a presenting phenotype in carriers.
- category: Neurological
  name: Seizure
  description: >-
    Epilepsy occurs in a minority and was more frequent in a prospectively
    followed national cohort than the published literature suggests, so the
    literature figure is probably an undercount.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Non-motor features such as developmental delay, intellectual disability,
      and epilepsy were more frequent in our cohort than in earlier reports.
    explanation: >-
      Reports epilepsy among the non-motor features and states that the
      literature under-reports it.
- category: Neurological
  name: Microcephaly
  description: >-
    Reduced head circumference is part of the neurodevelopmental arm of the
    disorder and can be present before any dystonia appears.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  notes: >-
    No frequency band: the only citable source here is a single pre-symptomatic
    proband, not a cohort proportion.
  evidence:
  - reference: PMID:38425714
    reference_title: "Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband, a 4-year-old female of Jewish-Israeli descent, presented with
      speech delay, microcephaly, poor weight gain, attention-deficit and
      hyperactivity disorder, dysmorphism, intellectual disabilities and joint
      hyperlaxity, but presented no signs of dystonia at initial evaluation.
    explanation: >-
      Documents microcephaly in a KMT2B variant carrier, and does so before
      dystonia onset, which is why it hangs off the transcriptional node rather
      than off the motor chain.
- category: Craniofacial
  name: Characteristic facial appearance
  description: >-
    A recognizable facial gestalt accompanies the movement disorder in many
    individuals and contributed to the original clinical delineation of the
    syndrome.
  phenotype_term:
    preferred_term: Characteristic facial appearance
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: FREQUENT
  evidence:
  - reference: PMID:27992417
    reference_title: Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report heterozygous variants in the gene KMT2B (also known as MLL4)
      in 27 unrelated individuals with a complex progressive childhood-onset
      dystonia, often associated with a typical facial appearance and
      characteristic brain magnetic resonance imaging findings.
    explanation: Reports a typical facial appearance in the founding cohort.
genetic:
- name: KMT2B
  gene_term:
    preferred_term: KMT2B
    term:
      id: hgnc:15840
      label: KMT2B
  relationship_type: CAUSATIVE
  variant_origin: DE_NOVO
  presence: PRESENT
  notes: >-
    variant_origin records the majority case only; the slot is single-valued and
    inherited alleles are well documented, including a nonsense variant
    co-segregating through a three-generation kindred.
    Heterozygous loss-of-function variants involving KMT2B account for
    approximately 88% of affected individuals; a heterozygous 19q13.11-19q13.12
    deletion encompassing KMT2B accounts for approximately 12%. Variant class
    carries prognostic information for onset and systemic burden: deletions and
    protein-truncating variants give earlier dystonia onset and more systemic
    disease than missense variants. Whether it predicts deep brain stimulation
    response is not settled by anything cited here — the pooled analysis in this
    entry identifies sex and baseline severity as predictors and does not test
    genotype.
    A recurrent missense hotspot at Arg2565 produces a strikingly wide range of
    severity, from childhood-onset dystonia to unrecognized behavioral symptoms
    in adulthood, with a correspondingly attenuated methylation signature.
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a heterozygous pathogenic variant involving KMT2B (~88% of affected
      individuals) or a heterozygous deletion of 19q13.11-19q13.12 involving
      KMT2B (~12% of affected individuals)
    explanation: Quantifies the two causal lesion classes at the KMT2B locus.
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of this study cohort (n = 53) in tandem with published cases (n =
      80) revealed that patients with chromosomal deletions and protein
      truncating variants had a significantly higher burden of systemic disease
      (with earlier onset of dystonia) than those with missense variants.
    explanation: >-
      Supports the genotype-phenotype correlation between lesion class, onset age
      and systemic burden.
  - reference: PMID:39933316
    reference_title: Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We established the existence of a KMT2B missense-mutation hotspot associated
      with varying degrees of disease severity and expression, providing
      information for patient counseling and elucidation of pathomechanisms.
    explanation: Establishes the Arg2565 missense hotspot and its variable expressivity.
  - reference: PMID:39933316
    reference_title: Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observed phenotypic spectrum ranged from childhood-onset dystonia (N =
      2) over unspecific intellectual disability syndromes (N = 2) to undiagnosed
      behavioral symptoms in adulthood (N = 1).
    explanation: Quantifies how wide the expressivity range is at a single recurrent codon.
  - reference: PMID:31216378
    reference_title: "Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified 14 patients (21.5%) carrying KMT2B variants, of which 1 was
      classified as a variant of unknown significance.
    explanation: >-
      Diagnostic yield in a childhood-onset dystonia cohort already negative for
      other dystonia genes, supporting KMT2B as a common monogenic cause.
diagnosis:
- name: Molecular genetic testing for a KMT2B variant or 19q13 deletion
  description: >-
    The confirmatory test. Either a heterozygous pathogenic KMT2B sequence
    variant or a heterozygous 19q13.11-19q13.12 deletion encompassing the gene
    establishes the diagnosis in a proband with suggestive findings. The two
    lesion classes need different assays, which is why sequencing alone is not
    sufficient: a deletion carrier is missed by a test that only reads sequence.
  presence: PRESENT
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of a KMT2B-related disorder is established in a proband with
      suggestive findings and either of the following identified by molecular
      genetic testing: a heterozygous pathogenic variant involving KMT2B (~88% of
      affected individuals) or a heterozygous deletion of 19q13.11-19q13.12
      involving KMT2B (~12% of affected individuals).
    explanation: The GeneReviews diagnostic criterion, with the yield of each lesion class.
- name: KMT2B DNA methylation episignature
  description: >-
    Genome-wide peripheral-blood DNA methylation profiling resolves a
    disorder-specific episignature for KMT2B haploinsufficiency. Its practical
    value is variant reclassification: it distinguishes carriers from controls
    and from other dystonic and neurodevelopmental disorders, so a KMT2B variant
    of uncertain significance can be resolved functionally rather than left open.
    The signature is attenuated in Arg2565 missense carriers relative to
    loss-of-function carriers, so a weak result does not exclude the diagnosis.
  presence: PRESENT
  evidence:
  - reference: PMID:34380541
    reference_title: Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate a distinctive DNA hypermethylation pattern associated with
      DYT28, provide an epigenetic signature for this disorder enabling accurate
      diagnosis and reclassification of ambiguous genetic findings and suggest
      potential therapeutic approaches.
    explanation: Establishes the episignature as a diagnostic and variant-reclassification tool.
  - reference: PMID:39933316
    reference_title: Variable expressivity of KMT2B variants at codon 2565 in patients with dystonia and developmental disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Samples bearing p.Arg2565Gly had a KMT2B-typical episignature, although the
      effect on methylation was less pronounced than in carriers of
      loss-of-function KMT2B variants.
    explanation: >-
      Supports the caveat that signature strength varies with allele class, so a
      muted signature is not a negative result.
  - reference: PMID:38425714
    reference_title: "Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Episignature screening in this pre-symptomatic patient enabled accurate
      genetic diagnosis and timely and actionable intervention earlier in the
      natural history of Childhood-onset Dystonia-28.
    explanation: >-
      Demonstrates the episignature diagnosing a carrier before dystonia onset,
      which is the case conventional phenotype-led testing cannot reach.
- name: Misdiagnosis as dyskinetic cerebral palsy
  description: >-
    A progressive childhood movement disorder with developmental delay is
    routinely labelled dyskinetic cerebral palsy, and KMT2B carriers are found on
    genetic re-evaluation of that diagnosis. This matters more than a
    nomenclature point: the cerebral palsy label closes the diagnostic pathway
    and, with it, access to the pallidal stimulation that works here.
  presence: PRESENT
  evidence:
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, KMT2B variants were identified upon genetic re-evaluation in two
      patients previously diagnosed with dyskinetic cerebral palsy.
    explanation: >-
      Documents KMT2B disease presenting under a cerebral palsy label until
      genetic re-evaluation.
treatments:
- name: Antimuscarinic (Anticholinergic) Therapy
  description: >-
    Oral antimuscarinic agents, principally trihexyphenidyl, are the recommended
    first-line pharmacologic treatment and significantly improve motor
    manifestations in roughly half of individuals.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: trihexyphenidyl
      term:
        id: CHEBI:9720
        label: Trihexyphenidyl
  target_mechanisms:
  - target: Pallidal Motor Circuit Dysfunction
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Antimuscarinic (anticholinergic) agents have significantly improved motor
      manifestations in about 50% of individuals and should be considered a
      first-line pharmacologic treatment in individuals with a KMT2B-related
      disorder.
    explanation: GeneReviews recommends antimuscarinic agents as first-line therapy.
- name: Bilateral Globus Pallidus Internus Deep Brain Stimulation
  description: >-
    Bilateral deep brain stimulation of the globus pallidus pars interna is the
    most effective intervention reported and produces a dramatic, long-lasting
    reduction in dystonia severity, in some cases restoring independent
    ambulation. Its benefit is regionally uneven: trunk and cervical dystonia
    improve most, laryngeal dystonia responds poorly, and gait improvement decays
    over years, with no patient in the longest-followed cohort maintaining a fully
    independent gait. Male sex and greater preoperative severity predict better
    response. Post-operative complications reported in the KMT2B cohorts are
    mild parkinsonism and freezing of gait, the latter compounding the poor and
    decaying gait response above rather than being a separate problem.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: bilateral globus pallidus internus deep brain stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  target_mechanisms:
  - target: Pallidal Motor Circuit Dysfunction
  - target: Ascending Generalization of Dystonic Posturing
  target_phenotypes:
  - preferred_term: Generalized dystonia
    term:
      id: HP:0007325
      label: Generalized dystonia
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bilateral globus pallidus pars interna deep brain stimulation, performed in
      about 80 individuals to date, has resulted in substantial clinical and
      functional improvement.
    explanation: GeneReviews reports substantial benefit from bilateral GPi DBS.
  - reference: PMID:35005062
    reference_title: "GPi-DBS for KMT2B-Associated Dystonia: Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GPi-DBS resulted in median BFMDRS-M improvement of 42.7% (range: -103.5% to
      95.9%) postoperatively.
    explanation: Pooled effect size for pallidal stimulation across ten studies.
  - reference: PMID:35005062
    reference_title: "GPi-DBS for KMT2B-Associated Dystonia: Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      KMT2B-associated dystonia responds effectively to pallidal stimulation. The
      outcome is better in males and those with more severe dystonia at baseline.
    explanation: Identifies male sex and baseline severity as predictors of response.
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The greatest BFMDRS-M improvements were observed for trunk (53.2%) and
      cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia.
    explanation: Documents the regional unevenness of benefit, including poor laryngeal response.
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at
      last assessment; no patient maintained a fully independent gait.
    explanation: >-
      Refutes any claim that pallidal stimulation restores durable independent
      ambulation, the outcome families most often expect from it.
  - reference: PMID:33150406
    reference_title: "KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Five patients developed mild parkinsonism following deep brain stimulation.
    explanation: Records a treatment-emergent adverse movement disorder.
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Freezing of gait as a side effect of the DBS was seen in two patients in
      our cohort (4I and 2V).
    explanation: >-
      A second treatment-emergent gait complication, and one that compounds the
      poor gait response already recorded above.
  - reference: PMID:31216378
    reference_title: "Frequency and phenotypic spectrum of KMT2B dystonia in childhood: A single-center cohort study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eight patients underwent pallidal DBS with a median decrease of
      Burke-Fahn-Marsden Dystonia Rating Scale-Motor score of 38.5% in the long
      term.
    explanation: Independent cohort reporting sustained long-term motor benefit.
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite secondary symptom worsening during long-term follow-up, GPi DBS
      preserved ambulation in three patients and enabled sustained recovery of
      walking ability in two, maintaining functional independence.
    explanation: >-
      Qualifies the gait result above: stimulation did not restore a fully
      independent gait in the Cif cohort, but in this cohort it preserved or
      recovered ambulation, so the honest reading is that gait benefit is real
      and unreliable rather than absent.
  - reference: PMID:41738007
    reference_title: "KMT2B-related disorders in Austria: clinical features and long-term outcome after deep brain stimulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GPi DBS offers durable clinical benefits, particularly when initiated
      before loss of ambulation.
    explanation: >-
      Supports timing of surgery, before ambulation is lost, as a determinant of
      long-term benefit.
- name: Botulinum Toxin Injection
  description: >-
    Focal chemodenervation of the affected muscle group. It does nothing to the
    underlying epigenetic lesion and acts at the neuromuscular junction, far
    downstream of everything this entry models, but it is the practical option
    for the focal and segmental presentations — blepharospasm, cervical dystonia,
    spasmodic dysphonia — where generalized measures are disproportionate.
    Reported benefit in the adult-onset series is partial and, in one subject,
    short-lived.
  notes: >-
    therapeutic_agent is left unbound. The cited report says "botulinum toxin"
    without a serotype; CHEBI codes only type A, and NCIT's generic
    NCIT:C163032 Botulinum Toxin is not reachable from the ChemicalEntityTerm
    roots (CHEBI:24431, NCIT:C1909), so the only bindable options would assert a
    serotype the source does not give.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: botulinum toxin
  evidence:
  - reference: PMID:36483457
    reference_title: Adult-onset KMT2B-related dystonia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anticholinergics did not bring any benefit. Botulinum toxin injections led
      to moderate improvement of dystonia.
    explanation: >-
      Records partial benefit from chemodenervation in an adult-onset carrier in
      whom the first-line antimuscarinic failed.
- name: Levodopa Trial
  description: >-
    A trial of levodopa and other anti-dystonic agents is reasonable, chiefly to
    exclude a dopa-responsive dystonia, but long-term benefit is not obtained in
    most individuals. This is a diagnostically important negative: unlike
    GCH1-related dopa-responsive dystonia, KMT2B-related dystonia does not show a
    sustained levodopa response.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although use of anti-dystonic agents (levodopa and other agents) has not
      resulted in long-term benefit for most individuals, a trial of these agents
      would be considered reasonable.
    explanation: Supports the recommendation to trial levodopa.
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although use of anti-dystonic agents (levodopa and other agents) has not
      resulted in long-term benefit for most individuals, a trial of these agents
      would be considered reasonable.
    explanation: >-
      The same sentence refutes sustained levodopa efficacy, which is the claim a
      reader coming from dopa-responsive dystonia would otherwise assume.
experimental_models:
- name: Mll2 (Kmt2b) conditional-knockout mouse embryonic stem cells
  experimental_model_type: CELL_LINE
  description: >-
    Mouse embryonic stem cells carrying a conditional Mll2 allele, the gene
    encoding KMT2B, in which the enzyme can be depleted and then re-expressed
    while the chromatin state and DNA methylation of a CpG island promoter are
    followed over time. This is the experimental basis for the claim that KMT2B
    occupancy protects promoters from DNA methylation, and it is recorded here
    so that the mechanism the hypermethylation node declines to assert as human
    biology has a structural home rather than living only in that node's notes.
  cell_source: Mouse embryonic stem cell line with a conditional Mll2 (Kmt2b) allele
  culture_system: Monolayer embryonic stem cell culture with inducible Mll2 deletion and rescue by KMT2B re-expression
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:23358417
  modeled_mechanisms:
  - target: Promoter DNA Hypermethylation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: MOLECULAR
    description: >-
      Establishes the causal direction the patient data cannot: loss of KMT2B
      precedes promoter DNA methylation rather than accompanying it, and
      restoring the enzyme reverses the silencing. What it does not establish is
      that this is what happens in a KMT2B variant carrier.
    limitations: >-
      A single CpG island promoter in mouse embryonic stem cells, under complete
      conditional loss of the gene, stands in for genome-wide promoter
      hypermethylation measured in the peripheral blood of humans carrying one
      working copy. Nothing in the system is neural, human, or heterozygous, and
      no dystonia-relevant readout exists in it.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The measurements are in mouse cells. Mouse and human differ in CpG
        island methylation dynamics at exactly the class of promoter under study,
        so the direction of the effect transfers more safely than its magnitude
        or its target set.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Neurons, the pallidum and the whole developmental trajectory of the
        disease lie outside the model. Embryonic stem cells report the enzyme's
        generic chromatin function, not its function in the cell types whose
        failure produces dystonia.
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        The model applies complete conditional loss of Mll2, whereas the disease
        is heterozygous loss of function. Whether one remaining copy leaves the
        protective function partially intact is the quantitative question the
        model is not set up to answer.
    readouts:
    - name: MagohB CpG island promoter DNA methylation after KMT2B depletion
      target: Promoter DNA Hypermethylation
      direction: INCREASED
      interpretation: >-
        Promoter methylation rises once KMT2B is lost and the active marks have
        gone, which is the molecular event the human episignature measures at
        genome scale.
      evidence:
      - reference: PMID:23358417
        reference_title: "The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          KMT2B depletion was followed by the loss of the active chromatin marks
          and progressive loss of RNA polymerase II binding with a concomitant
          downregulation of MagohB expression. Once the active chromatin marks
          were lost, the MagohB promoter was rapidly methylated.
        explanation: >-
          The kinetic measurement behind this readout, and the sentence that
          orders the two events.
    - name: Promoter reactivation after KMT2B re-expression
      target: Promoter DNA Hypermethylation
      direction: RESTORED
      interpretation: >-
        The rescue arm, which is what makes the relationship causal rather than
        correlative in this system.
      evidence:
      - reference: PMID:23358417
        reference_title: "The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Reexpression of KMT2B was sufficient to reinstate an active MagohB
          promoter.
        explanation: Reports the rescue measurement behind this readout.
    evidence:
    - reference: PMID:23358417
      reference_title: "The histone methyltransferase KMT2B is required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our study provides a paradigm for the idea that KMT2 proteins are
        crucial components for establishing and maintaining the
        transcriptionally active and unmethylated state of CpG island promoters.
      explanation: >-
        The authors' own statement of scope, and the reason this model is
        treated as informative for the hypermethylation node while its fidelity
        is graded LOW.
  notes: >-
    Recorded as an experimental model rather than an animal model because the
    system is a cultured cell line, not a whole organism. The wider claim often
    made from this literature, that KMT2B loss lets Polycomb repressive complex
    2 and DNA methyltransferases reach loci they are normally excluded from, is
    not asserted here: this paper measures protection from DNA methylation and
    does not name PRC2, and no cited reference does so in quotable form.
discussions:
- discussion_id: kmt2b_effector_genes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which KMT2B target genes, in which neurons, translate genome-wide promoter
    hypermethylation into dystonia rather than into a purely neurodevelopmental
    phenotype?
  attaches_to:
  - pathophysiology#Transcriptional Dysregulation at KMT2B Target Loci
  rationale: >-
    The chain from KMT2B haploinsufficiency to broad transcriptional
    dysregulation is measured directly in patients, and the circuit endpoint is
    inferred from deep brain stimulation response and from the pallidal imaging
    sign, but nothing connects the two. No patient-derived,
    cell-type-resolved transcriptomic dataset for striatal neurons was identified,
    so the step from a genome-wide epigenetic lesion to a motor-specific
    phenotype is currently an unknown-intermediates edge. This is what would have
    to be closed before any disease-modifying therapy could be targeted upstream
    of the pallidum.
- discussion_id: kmt2b_dystonic_vs_ndd_branch
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    What determines whether a KMT2B variant carrier develops dystonia, an
    isolated neurodevelopmental or growth phenotype, or nothing at all?
  attaches_to:
  - pathophysiology#Pallidal Motor Circuit Dysfunction
  - inheritance#Autosomal dominant
  rationale: >-
    Relatives carrying the identical variant diverge between generalized
    dystonia, isolated short stature or intellectual disability, and clinically
    asymptomatic carriage, and the Arg2565 hotspot spans that whole range on one
    codon. Variant class predicts onset age and systemic burden but not this
    branch, so the determinant is neither the allele alone nor a described
    modifier locus. Until it is identified, predictive testing in a family cannot
    say what an at-risk carrier will actually develop.
- discussion_id: kmt2b_no_in_vivo_model
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is there any whole-organism model of KMT2B-related dystonia, and if not,
    what would one have to reproduce to be useful?
  attaches_to:
  - animal_models#
  - pathophysiology#Pallidal Motor Circuit Dysfunction
  rationale: >-
    The animal_models section of this entry is empty, and that is a finding
    rather than an omission: a literature search for this curation found no
    published Kmt2b animal model of the dystonic phenotype. The contrast with
    TOR1A/DYT1, where rodent models have carried most of the mechanistic work,
    is what makes the absence worth recording. The consequence is concrete. The
    one in vivo-adjacent system available is a mouse embryonic stem cell line
    (see experimental_models), which reports the enzyme's generic chromatin
    function and cannot report a motor phenotype at all, so the step from the
    epigenetic lesion to pallidal dysfunction has no experimental system in
    which it can currently be tested. A useful model would have to carry
    heterozygous rather than complete loss of function, and be assayed for motor
    output rather than for methylation alone. Recording the gap here is also
    meant to stop the next curator repeating the same fruitless search.
progression:
- phase: Long-term survival
  age_range: Adulthood
  notes: >-
    Formal survival statistics have not been published. What is documented is
    that the disorder is not classically fatal and that affected individuals have
    been reported living into the seventh decade, against a background of
    progressive motor and bulbar disability rather than early mortality.
  evidence:
  - reference: PMID:29697234
    reference_title: KMT2B-Related Disorders.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Life expectancy is not known; however, individuals in the seventh decade of
      life have been reported.
    explanation: >-
      The only life-expectancy statement available, and it is explicitly an
      absence of data rather than an estimate.
notes: >-
  OMIM codes the two KMT2B phenotypes separately: 617284 for childhood-onset
  dystonia 28, the entity this file curates, and 619934 for intellectual
  developmental disorder, autosomal dominant 68, the non-dystonic
  neurodevelopmental presentation, which is out of scope here. They are recorded
  in prose because the mappings slot admits only ICD10CM, ICD11F, MONDO and
  NCIT. Note also that the MONDO label anchoring this entry says
  "childhood-onset" while the entry's scope is gene-wide and includes an
  adult-onset subtype; MONDO has no gene-level KMT2B term to anchor to instead.
references:
- reference: PMID:29697234
  title: "KMT2B-Related Disorders."
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:29697234
KMT2B-Related Disorders.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: KMT2B-Related Dystonia · 2026-09-04T04:05:00Z · View source

New kb/disorders/ entry for KMT2B-related dystonia (DYT-KMT2B / dystonia 28, MONDO:0015004), claimed via issue #10875. Deep research: requested falcon, which is not configured in this environment; ran with --fallback so the run recorded the substitution, and the report was produced by claude_code (research/KMT2B-Related_Dystonia-deep-research-claude_code.md, fell_back: true, requested_provider: falcon). The report's own validation flagged needs_review on both axes and I acted on it: its one unsupported quote (DOI:10.1186/s13148-021-01145-y, 'indicating a general repression of transcriptional activity') was not reused; the three obsolete GO terms it suggested (GO:0051568, GO:0034968, GO:0006306) were not bound; and its mislabelled HP:0001608 (called 'Dysphonia', HPO calls it 'Abnormality of the voice') was not used. The report cited almost entirely by URL rather than PMID, so the seven primary references were recovered by PubMed lookup on title/author and fetched fresh. GeneReviews baseline: PMID:29697234 (KMT2B-Related Disorders) fetched, tagged GeneReviews in the top-level references block, and every phenotype in its Clinical Characteristics paragraph either curated or, for the KMT2B-related non-dystonic NDD, left out as outside this entry's MONDO scope and recorded as an open question instead. Pathophysiology is a six-node chain from KMT2B haploinsufficiency through reduced H3K4 methylation and promoter DNA hypermethylation to transcriptional repression, striatal/pallidal circuit dysfunction and caudocranial generalization; the hypermethylation node is the one step measured directly in patients (PMID:34380541) and the step to circuit dysfunction is marked INDIRECT_UNKNOWN_INTERMEDIATES because no cell-type-resolved patient data connect them. Status dystonicus and the adult-onset subtype are deliberately left unbound with notes explaining why no accurate term exists. Poor laryngeal and gait response to GPi-DBS is curated as a REFUTE evidence item rather than omitted. A pre-PR adversarial self-review was then run against the dismech-pr-review skill and its findings were applied in a second pass. Two were substantive. First, the adult-onset subtype description asserted that those cases carry the KMT2B episignature; PMID:36483457 reports the opposite -- they cluster with controls against the early-onset signature and their distinguishing probes do not overlap it, which the authors read as a different molecular mechanism. The description was rewritten to say that, the two supporting quotes were added, the authors' own segregation caveat on p.S640T and p.R2339Q was recorded, and the entry no longer claims its causal chain applies to the subtype. Second, the pivot pathophysiology node asserted transcriptional repression with modifier DECREASED, but neither attached quote gives a direction -- the claim traced back to the same sentence the report's validator could not verify. The node was renamed to Transcriptional Dysregulation at KMT2B Target Loci, the modifier changed to ABNORMAL, the misapplied diagnostic-utility quote removed, and the top-level description corrected; a note records that repression is the usual reading but that no patient transcriptomic data exist for this disorder. Also in that pass: four uncited prose assertions imported from the deep-research narrative were removed or attributed (CXXC/PHD missense clustering, which came from a KMT2A paralog argument; the DNMT/Polycomb repulsion step, which is mouse embryonic stem cell work and is now recorded in notes as such rather than asserted as human mechanism; an imaging claim no cited reference makes; and a genotype-does-not-predict-DBS-response negative absent from the cached abstract). The DNA hypermethylation edge was re-parented from the reduced-H3K4 node onto haploinsufficiency, because the barrier function is reported to be catalysis-independent. The striatal half of the circuit node and its CL:1001474 medium spiny neuron binding were dropped, since the localization rests entirely on DBS response and reaches only the pallidum. Eleven frequency bands inferred from qualitative words such as 'prominent' or 'in some' were removed, and the one quantified figure available (dystonia in >80% of cases, PMID:38425714) was cited for the band that remains. HP:0031959 Leg dystonia replaced HP:0002451 Limb dystonia, which includes the arm; endocrinopathy was bound to HP:0000818; microcephaly was added from PMID:38425714. NCIT:C21024 Deep Brain Stimulation replaced the generic NCIT:C15329 Surgical Procedure, and therapeutic_agent was added to both pharmacotherapies (CHEBI:9720 trihexyphenidyl, CHEBI:15765 L-dopa). Botulinum toxin was added as a treatment with its agent left unbound and the reason recorded: the source names no serotype, CHEBI codes only type A, and NCIT's generic term is not reachable from the ChemicalEntityTerm roots. The levodopa evidence item was split into a SUPPORT for the recommendation and a REFUTE for sustained efficacy; the in-silico loss-of-function prediction was regraded COMPUTATIONAL. Three nodes now declare conforms_to against epigenetic_machinery_neurodevelopmental_dysregulation, matching the KMT2A paralog entry Wiedemann-Steiner Syndrome. Pathograph connectivity went from 5 of 26 phenotypes reachable to 25 of 27; the two that remain unreachable are the initiating lower-limb feature, which has an outgoing edge, and sensorineural hearing loss, left unlinked because the reporting authors call the association possibly coincidental. Three further references already fetched but uncited were brought in (PMID:38425714 episignature/pre-symptomatic diagnosis, PMID:41738007 Austrian long-term DBS cohort, both also used to add a prevalence record and a misdiagnosis-as-cerebral-palsy diagnosis entry). One reviewer suggestion was not taken: adding OMIM 617284/619934 to a mappings block, because the DiseaseMappings class admits only ICD10CM, ICD11F, MONDO and NCIT. The OMIM codes are recorded in the entry's notes instead. Validation after both passes: just validate and just validate-disorders passed (schema, terms, 74/74 snippets verified); check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence all clean; pytest -k KMT2B 22 passed. just compliance fell from 89.1% to 80.5% across the review pass. That is the expected cost of the corrections rather than a regression: the score rewards filled slots, and the pass removed eleven unsourced frequency bands, a cell-type binding and a process annotation that the evidence did not support. A third pass then addressed the ai4c-reviewer CHANGES_REQUESTED review on PR #10919. Its one blocking finding was correct: the entry carried no neuroimaging content, and the external-globus-pallidus MRI sign is quotable from PMID:41738007, a reference the entry already cited. The earlier removal of an imaging claim on the grounds that no cited reference made one had overshot, because that reference's cache was upgraded from abstract-only to PMC full text during the same run. Added an imaging_findings block bound to HP:0002453 and UBERON:0002476, using the purpose-built slot rather than the diagnosis section the reviewer suggested. Curated with the negative the reviewer's excerpt omitted: the same cohort reporting the ~27% literature figure saw no indicative MRI abnormality in any of its own nine patients and attributes that to age-dependency, so that sentence is carried as a REFUTE item and the notes state that a normal MRI argues nothing. Also recorded that the streaks sit in the external pallidal segment while deep brain stimulation targets the internal segment, so the imaging corroborates pallidal involvement without confirming the segment. The over-absolute clause in the Pallidal Motor Circuit Dysfunction node -- that the whole localization rests on DBS response -- was rewritten to name both lines of evidence and their disagreement on segment. Five of the six suggestions were taken: GeneReviews genetic-counseling content (50% transmission risk, prenatal and preimplantation testing availability) added to inheritance; a diagnosis entry for molecular genetic testing, noting that a deletion carrier is missed by sequence-only testing; freezing of gait as a second post-DBS complication; epilepsy as a phenotype together with the cohort's own statement that the literature under-reports it; and a progression record for the seventh-decade life-expectancy observation, framed as the absence of survival data that it is. The stale repression wording in the kmt2b_effector_genes rationale, left over from the node rename, was corrected. The sixth suggestion, that the PR body said nine references when there are eleven, had already been fixed in the body before the review was submitted. Validation after the third pass: just validate and just validate-disorders pass, 82/82 snippets verified; all ten offline gates clean; pytest -k KMT2B 22 passed; compliance 81.9%. A fourth pass followed the ai4c-reviewer APPROVE on PR #10919 and was forced by a merge conflict rather than chosen. Curation PRs merging into main in the interim added rows to cache/mondo/terms.csv and cache/enums/diseaseterm_f618932bb23f.csv at the same insertion point as this entry's MONDO:0015004 rows, and GitHub's merge queue dropped the PR without a stated reason once the branch stopped being mergeable. Both conflicts were pure additions on each side (MONDO:0015003 from main, MONDO:0015004 from this branch) and were resolved as a union in canonical CURIE order rather than by hand-writing any label or timestamp; check-term-cache-integrity and check-cache-order both pass on the result. Since resolving the conflict costs the approval regardless, the four non-blocking suggestions left over from the approving review were bundled into the same push rather than deferred to a further round. The mouse embryonic stem cell work that the Promoter DNA Hypermethylation node's notes decline to assert as human mechanism is now an experimental_models entry. The primary source was located by PubMed search and fetched fresh: PMID:23358417 (Ladopoulos et al., Mol Cell Biol 2013), a conditional Mll2 knockout embryonic stem cell line in which KMT2B depletion is followed by loss of the active chromatin marks and then rapid methylation of the MagohB CpG island promoter, with re-expression of the enzyme reinstating an active promoter. It is linked to that node as PARTIALLY_RECAPITULATES with fidelity LOW and model_scale MOLECULAR, carrying two readouts (methylation after depletion, INCREASED; promoter reactivation after rescue, RESTORED) and three typed divergences: SPECIES_MISMATCH, BOUNDARY_OMISSION and POPULATION_MISMATCH, the last because the model applies complete conditional loss where the disease is heterozygous. Note that this corrects the deep-research report's framing as well as making the caveat structural: the report attributed a PRC2-and-DNMT repulsion mechanism to this literature, and the paper measures protection from DNA methylation without naming PRC2, so the model notes say so explicitly and the wider claim is still not asserted. The absence of any whole-organism model is now a KNOWLEDGE_GAP discussion (kmt2b_no_in_vivo_model) attached to the empty animal_models section and to the Pallidal Motor Circuit Dysfunction node, recording that the search found no published Kmt2b animal model of the dystonic phenotype, that the contrast with TOR1A/DYT1 is what makes the absence notable, and that the consequence is that the epigenetic-lesion-to-pallidal-dysfunction step has no system in which it can be tested. A classifications block was added with harrisons_chapter NEUROLOGIC and GENETICS_ENVIRONMENT_DISEASE; no mechanistic_category value fits, since the mechanistic nosology enum has no chromatinopathy or epigenetic-machinery value. The deep brain stimulation description now names freezing of gait alongside mild parkinsonism as a post-operative complication, matching the evidence already beneath it. The imaging_findings frequency slot is still empty, but the notes now say that this is deliberate: a single band would flatten the conflict between the ~27% literature figure and the zero-of-nine cohort result that the record exists to preserve. Validation after the fourth pass: just validate passes with 85/85 snippets verified; just validate-terms passes; check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading and check-environmental-evidence all clean; check-term-cache-integrity and check-cache-order clean after the conflict resolution; pytest -k KMT2B 22 passed.

Claude Code ▸
KMT2B-Related Dystonia (DYT-KMT2B / DYT28): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 31 citations 2026-09-04T03:48:37.006629

KMT2B-Related Dystonia (DYT-KMT2B / DYT28): Comprehensive Research Report

1. Disease Information

Overview

KMT2B-related dystonia (also designated DYT-KMT2B, formerly DYT28) is an autosomal dominant, complex, childhood-onset progressive movement disorder caused by heterozygous pathogenic variants in KMT2B (Lysine Methyltransferase 2B), which encodes an H3K4 histone methyltransferase. The disorder typically presents with lower-limb dystonia in early-to-mid childhood that progresses in a caudocranial pattern to generalized dystonia with prominent cervical, cranial (oromandibular), and laryngeal involvement, often accompanied by developmental delay, intellectual disability, short stature, and dysmorphic facial features (GeneReviews, NBK493766; Meyer et al. 2017, Brain). KMT2B pathogenic variants also cause a distinct, non-dystonic KMT2B-related neurodevelopmental disorder (KMT2B-related NDD) — together these constitute "KMT2B-related disorders."

Key Identifiers

Resource Identifier
OMIM (gene) 606834 — KMT2B
OMIM (phenotype) #617284 — Dystonia 28, Childhood-Onset (DYT28)
OMIM (NDD phenotype) #619934 — Intellectual Developmental Disorder, Autosomal Dominant 68 (MRD68)
Orphanet KMT2B-related dystonia is catalogued in Orphanet's dystonia group (specific ORPHA code not independently confirmed in this search — recommend direct Orphanet lookup)
HGNC KMT2B (formerly MLL4, MLL2 in older nomenclature — note the confusing dual naming with KMT2D, which was also called MLL2/MLL4 in some papers)
Gene locus 19q13.12
Historic name DYT28

Synonyms / Alternative Names

  • KMT2B-deficient dystonia
  • DYT28
  • Complex early-onset dystonia (Zech-type)
  • Childhood-onset generalized dystonia due to KMT2B haploinsufficiency
  • MLL4-related/MLL2-related dystonia (older literature — nomenclature ambiguity with KMT2D)

Data Source Character

Nearly all available information derives from aggregated case-series and cohort studies (not large-scale EHR/claims data), since this is an ultra-rare monogenic disorder. As of the most recent GeneReviews update, approximately 246 individuals from 229 families with DYT-KMT2B and 27 individuals from 25 families with KMT2B-related NDD have been reported in the literature (GeneReviews, NBK493766). Largest cohorts include Meyer et al. 2017 (Brain, n=53), Zech et al. 2016 (parallel report), and more recent expansion cohorts (e.g., a 2025 Brain follow-up cohort and Austrian national cohort, PMC12926133).

2. Etiology

Disease Causal Factors

KMT2B-related dystonia is a purely monogenic disorder — there is no polygenic or complex-trait risk architecture. Disease is caused by: 1. Heterozygous pathogenic single-nucleotide variants or small indels in KMT2B (missense, nonsense, frameshift, splice-site) — accounts for ~88% of affected individuals (GeneReviews). 2. Heterozygous microdeletions of 19q13.11–19q13.12 encompassing KMT2B — accounts for ~12% of cases.

The two founding reports were published in parallel in 2016: - Zech et al. 2016 (Nat Genet / related) identified protein-truncating KMT2B variants causing childhood-onset generalized dystonia, demonstrating that haploinsufficiency of KMT2B is sufficient to cause disease. - Meyer et al. 2016/2017 (Nat Genet; expanded cohort in Brain 2017) reported heterozygous KMT2B variants (including missense) in 27 unrelated individuals with complex progressive childhood-onset dystonia, often with characteristic facial appearance and MRI findings, "highlighting a clinically recognizable form of dystonia and demonstrat[ing] a crucial role for KMT2B in the physiological control of voluntary movement" (Nature Genetics, ng.3740).

Genetic Risk Factors

  • Causal variant classes: missense (most common overall), nonsense, splice-site, frameshift indels, and contiguous gene deletions (19q13.11–19q13.12).
  • Mutational hotspot: a recurrent missense hotspot at codon 2565 has been described, associated with variable disease severity and expressivity (Pubmed 39933316).
  • Domain clustering: missense variants cluster in putative functional domains (e.g., CXXC-type zinc finger, PHD fingers, SET domain), whereas protein-truncating variants are distributed throughout the gene body — a pattern paralleling the related Wiedemann–Steiner syndrome gene KMT2A, where CXXC-domain missense variants are pathogenic and AlphaFold2-classifiable (PMC9249231). A comparable, though less exhaustively characterized, hotspot pattern has been proposed for KMT2B's CXXC/PHD region.
  • No specific gnomAD constraint metrics for KMT2B were retrieved in this search, but as a large chromatin-modifier gene causing a dominant haploinsufficiency phenotype, KMT2B is expected to show strong loss-of-function intolerance (consistent with other KMT2 family members such as KMT2A, KMT2D, and KMT2E, which show pLI ≈ 1.0). This should be verified directly against gnomAD for a curated entry.
  • Modifier genes: none specifically established; genotype only weakly predicts phenotype (see Genetics section).

Environmental Risk Factors

No environmental, toxic, occupational, or infectious risk factors have been identified — this is a fully genetically determined (monogenic) disorder. Age and sex do influence phenotype expression and DBS outcome (see below) but are not causal/risk factors for disease occurrence itself.

Protective Factors

No genetic or environmental protective factors have been reported. Reduced penetrance is documented — asymptomatic heterozygous carriers exist within families, particularly among individuals with the milder/NDD-only phenotype — but no specific protective allele or modifier variant has been characterized.

Gene-Environment Interactions

None established; not applicable for this monogenic disorder.

3. Phenotypes

Data below are drawn primarily from the GeneReviews synthesis of cohort studies (Meyer et al., Zech et al., Cif et al., Lange et al.) (NBK493766) and the 2016 founding papers.

DYT-KMT2B (dystonia phenotype) — represents ~93% of families

Phenotype Frequency Suggested HPO term
Dystonia (generalized, evolving from focal) 100% HP:0001332 (Dystonia); HP:0002340 (Lower limb dystonia — early feature)
Laryngeal dysfunction (dysphonia) ~51% HP:0001608 (Dysphonia)
Intellectual disability ~42% HP:0001249 (Intellectual disability)
Microcephaly ~44% HP:0000252 (Microcephaly)
Systemic features (short stature, precocious puberty, hypothyroidism) ~38% HP:0004322 (Short stature); HP:0000826 (Precocious puberty); HP:0000821 (Hypothyroidism)
Additional movement disorder features (myoclonus, spasticity, tremor, ataxia) ~27% HP:0001336 (Myoclonus); HP:0001257 (Spasticity); HP:0001251 (Ataxia)
Bulbar/feeding difficulties, dysphagia ~30% HP:0002015 (Dysphagia)
Neurobehavioral/psychiatric (ADHD 10%, anxiety/OCD 11%, ASD 4%) ~26% HP:0007018 (Attention deficit); HP:0000717 (Autism); HP:0000739 (Anxiety)
Developmental delay ~26% HP:0001263 (Global developmental delay)
Eye movement abnormalities ~8% HP:0000496 (Abnormal eye movements)
Seizures ~2% HP:0001250 (Seizure)
Facial dysmorphism (elongated face, nasal tip) not separately quantified but common HP:0000276 (Long face); HP:0000448 (Prominent nose)
Isolated progressive sensorineural hearing loss (subset) reported in some individuals HP:0000407 (Sensorineural hearing loss)

Onset: median age of onset 6 years (range 0–43 years, reflecting the newly recognized adult-onset subgroup) (GeneReviews). A recent natural history cohort (n=44) reported median symptom onset of 5.0 years, with progression to generalized dystonia over a median of 2.0 years (2025 Brain cohort, arXiv summary).

Classic disease course: begins with lower-limb focal dystonia — foot deformity (equinovarus), toe-walking, gait disturbance — and evolves in a caudocranial pattern into generalized dystonia with prominent cervical, cranial (oromandibular), and laryngeal involvement, producing dysphagia and/or dysphonia, typically 2–11 years after initial onset. Early motor features (hypotonia, impaired coordination, gait difficulty) can emerge in infancy (GeneReviews; Frontiers 2022).

Severity/functional range: from minor gait disturbance to wheelchair dependence, classified by Gross Motor Function Classification System (GMFCS) grades II–V.

Classification: in a 68-individual cohort, 58% had complex/combined dystonia (dystonia plus other neurological features) and 41% had isolated dystonia.

Adult-onset variant: a distinct, milder adult-onset focal or segmental dystonia phenotype (often cervical dystonia or writer's cramp) without prominent developmental delay has been increasingly recognized, broadening the age spectrum considerably (Adult-onset KMT2B-related dystonia, Brain Communications 2022; PMC9724767).

KMT2B-related NDD (non-dystonic phenotype) — ~7% of families

  • Developmental delay ~81%
  • Intellectual disability ~89% (mild to severe)
  • Bulbar dysfunction ~44%
  • Neurobehavioral/psychiatric manifestations ~21% (ADHD, ASD)
  • Febrile seizures ~11%
  • Eye movement abnormalities ~11%
  • In deletion cases specifically: ectodermal dysplasia, genital malformations in affected males (reflecting contiguous gene effects from the 19q13 microdeletion, not KMT2B haploinsufficiency alone)

Quality of Life Impact

Laryngeal, oromandibular, and cervical dystonia are frequently the most disabling elements — often requiring enteral feeding, augmentative/alternative communication (AAC) technology, and adapted seating. Loss of independent ambulation is common as disease progresses; DBS can partially reverse this (see Treatment). No disease-specific EQ-5D/SF-36 data were identified in this search; QoL impact is documented qualitatively in cohort/natural-history papers rather than via standardized instruments.

4. Genetic/Molecular Information

Causal Gene

  • Gene: KMT2B (HGNC symbol; historically MLL4/MLL2 — nomenclature caution, as KMT2D was also called MLL4/MLL2 in older literature)
  • OMIM gene entry: *606834
  • Locus: 19q13.12
  • Protein: Histone-lysine N-methyltransferase 2B (KMT2B), a member of the SET1/MLL family of H3K4 methyltransferases.

Pathogenic Variants

  • Variant types: missense (most common), nonsense, splice-site, frameshift indels, and 19q13.11–19q13.12 microdeletions.
  • Detection yield: exome/genome sequence analysis detects ~94% of pathogenic variants (may miss exon 1 variants and synonymous splice-affecting variants); chromosomal microarray analysis (CMA) detects the remaining ~6% (large deletions/duplications).
  • Classification: per ACMG/AMP criteria via ClinVar/ClinGen — specific pathogenic/likely-pathogenic/VUS counts were not retrieved directly in this search; DNA methylation episignature testing has become an important adjunct specifically for resolving KMT2B VUS (see Diagnostics).
  • Genotype-phenotype correlation: loss-of-function (truncating) variants are associated with statistically significantly earlier disease onset than missense variants (mean onset ~4.4 years for insertions/frameshift vs. ~8.7 years for missense variants), but variant class does not significantly influence rate of progression, overall severity, or DBS responsiveness (GeneReviews).
  • Domain clustering: missense variants cluster within putative functional/structural domains (zinc-finger CXXC-type, PHD fingers), while truncating variants occur throughout the gene (ResearchGate summary of KMT2B rare missense variants). A recurrent missense hotspot at codon 2565 produces variable expressivity (PubMed 39933316).
  • Allele frequency: KMT2B pathogenic variants are essentially absent from population databases (gnomAD) consistent with a severe, highly penetrant dominant disorder subject to strong purifying selection; specific o/e or pLI figures were not independently retrieved in this search.
  • Somatic vs. germline: disease-causing variants are germline (constitutional); no somatic mosaic or cancer-associated KMT2B variant relevance was identified for this phenotype (note: KMT2B, like other MLL-family genes, has separate literature in somatic cancer genomics that is unrelated to this dystonia phenotype).
  • Functional consequence: predominantly loss of function / haploinsufficiency (both truncating variants and many missense variants), though genotype-phenotype nuance exists (see hotspot above) suggesting some missense alleles may have distinct or partial dominant-negative effects — this remains incompletely resolved mechanistically.

Modifier Genes

None specifically validated; phenotypic variability (including intrafamilial variability with different family members manifesting dystonic vs. NDD-predominant phenotypes from the same variant) is well documented but unexplained by additional genetic modifiers to date (PMC8932353, "variable phenotypes among family members").

Epigenetic Information

This is the most epigenetically well-characterized dystonia gene: - Blood DNA methylation provides an accurate biomarker of KMT2B-related disease: Ciolfi et al. and colleagues demonstrated genome-wide DNA hypermethylation, non-randomly distributed and enriched at regulatory regions such as gene promoters, in individuals carrying pathogenic KMT2B variants, "indicating a general repression of transcriptional activity" (Brain 2022, academic.oup.com/brain/article/145/2/644; Clinical Epigenetics 2021). - Mechanistically, work in mouse embryonic stem cells shows KMT2B does not merely deposit the H3K4 methyl mark but prevents transcriptional silencing by repelling components of Polycomb Repressive Complex 2 (PRC2) and DNA methyltransferases (DNMTs) at target loci — providing a direct molecular explanation for the observed promoter hypermethylation when KMT2B is haploinsufficient (Clinical Epigenetics 2021). - A DNA methylation episignature (EpiSign) has been clinically validated as a diagnostic/functional-classification tool for KMT2B variants of uncertain significance, using Illumina Infinium EPIC arrays (Clinical Epigenetics 2024; case report PMC10902455). Notably, a 2024 paper asks "Are there two disjunct episignatures for KMT2B-related disease?" (PMC11631077), suggesting the dystonia and NDD phenotypes may have partially distinguishable methylation signatures — an active area of investigation.

Chromosomal Abnormalities

Heterozygous deletions of 19q13.11–19q13.12 encompassing KMT2B (and potentially neighboring genes) account for ~12% of DYT-KMT2B and a larger proportion of NDD-predominant cases; contiguous gene deletion may explain additional features (ectodermal dysplasia, genital malformations in males) not attributable to KMT2B haploinsufficiency alone.

5. Environmental Information

  • Environmental/toxic factors: none identified; disease is fully genetically determined.
  • Lifestyle factors: not causally relevant to disease occurrence; physical activity/therapy is relevant to management (see Treatment/Prevention).
  • Infectious agents: none identified as causal. (Note: intercurrent infections/fever can precipitate status dystonicus, a dystonic emergency, in already-affected individuals — this is a disease-course exacerbating factor rather than a cause; see ScienceDirect case report on status dystonicus in KMT2B.)

6. Mechanism / Pathophysiology

Causal Chain (numbered, from mutation to clinical phenotype)

  1. A heterozygous loss-of-function or missense variant in KMT2B (or a 19q13 microdeletion spanning the gene) reduces functional KMT2B protein dosage → KMT2B haploinsufficiency (demonstrated directly for truncating variants; inferred/probable for many missense variants clustering in functional domains) (Zech et al. 2016).
  2. Reduced KMT2B activity leads to impaired deposition/maintenance of H3K4 methylation (H3K4me1/me3) at target promoters and enhancers, since KMT2B is a SET-domain histone-lysine N-methyltransferase specific for H3K4 (GeneReviews).
  3. Independent of methyltransferase catalysis, reduced KMT2B occupancy at chromatin results in failure to repel Polycomb Repressive Complex 2 (PRC2) and DNA methyltransferases (DNMTs) from target regulatory loci — demonstrated experimentally in mouse embryonic stem cells (this step is inferred to extend to human neurons/patient tissue rather than directly demonstrated in situ) (Clinical Epigenetics 2021).
  4. This leads to aberrant, non-random DNA hypermethylation, disproportionately enriched at gene promoters and other positive regulatory elements — directly confirmed in patient peripheral blood as a robust, clinically validated biomarker/episignature (Ciolfi et al.; Brain 2022).
  5. Combined loss of activating H3K4 methylation and gain of repressive promoter DNA methylation results in general repression of transcriptional activity at a broad set of KMT2B target genes, including genes important for neurodevelopment and neuronal/motor circuit function (specific downstream target genes driving the dystonic phenotype remain not yet fully elucidated — "the exact molecular mechanism by which KMT2B variants cause dystonia remains to be elucidated," per the pathophysiology literature).
  6. Dysregulated gene expression during critical periods of basal ganglia and corticostriatal circuit development is proposed (by analogy with other monogenic dystonias — DYT1/TOR1A, DYT6/THAP1 — and by the neuroimaging findings below) to produce disrupted striatal/pallidal network function, particularly implicating the external and internal globus pallidus.
  7. This circuit dysfunction manifests clinically as progressive dystonia, beginning focally in the lower limbs and evolving (caudocranial progression) into generalized, cervical, cranial, and laryngeal dystonia, frequently accompanied by cognitive/developmental and psychiatric comorbidity reflecting broader cortical/neurodevelopmental transcriptional disruption.

Branch point: In a minority of cases, haploinsufficiency manifests without dystonia, producing the KMT2B-related NDD phenotype (developmental delay/intellectual disability alone) — the branch point between the dystonic and purely neurodevelopmental outcome is not mechanistically resolved but appears to correlate loosely with variant type/location and shows marked intrafamilial variability, implying stochastic or unidentified modifying factors rather than a strict genotype rule.

Molecular Pathways

  • H3K4 methylation / chromatin regulation pathway (SET1/MLL/COMPASS-like complex biology). Relevant GO terms: GO:0051568 (histone H3-K4 methylation), GO:0034968 (histone lysine methylation), GO:0000123 (histone acetyltransferase complex — for COMPASS-related complex context), GO:0006357 (regulation of transcription by RNA polymerase II).
  • PRC2/Polycomb repression antagonism pathway: GO:0031519 (PcG protein complex), GO:0006306 (DNA methylation).
  • No canonical signaling cascade (Wnt/MAPK/mTOR/PI3K-AKT) has been specifically implicated; this is fundamentally an epigenetic/chromatin-regulatory disease mechanism rather than a signal-transduction disorder.

Cellular Processes

  • Primary process: epigenetic transcriptional dysregulation (GO:0010629, negative regulation of gene expression; broadly, chromatin-mediated transcriptional repression).
  • Downstream/secondary: presumed disruption of neuronal differentiation and synaptic gene programs during CNS development (inferred from the NDD phenotype and broad promoter hypermethylation, not directly demonstrated at single-cell resolution in patient neurons).

Protein Dysfunction

KMT2B protein (UniProt Q9UMN6) is a large multidomain SET-family methyltransferase; disease variants act principally through loss of function / haploinsufficiency rather than aggregation or gain-of-function misfolding. Missense variant clustering in zinc-finger (CXXC-type) and PHD-finger domains suggests these variants disrupt chromatin/DNA-binding or protein-protein interaction functions required for proper complex assembly, by analogy with the CXXC-domain missense mechanism established for the paralog KMT2A in Wiedemann–Steiner syndrome, where AlphaFold2 structural modeling accurately classifies pathogenicity of CXXC-domain missense variants (PMC9249231).

Metabolic Changes

No disease-specific metabolic pathway abnormality has been established; KMT2B-related dystonia is not classified among the inborn errors of metabolism (it is specifically listed as a differential-diagnosis exclusion target — see Diagnostics — against metabolic dystonias such as glutaric acidemia type 1, methylmalonic acidemia, and Wilson disease).

Immune System Involvement

No evidence of autoimmune or immune-mediated pathophysiology.

Tissue Damage Mechanisms

Not a degenerative/necrotic process in the classic sense; rather a neurodevelopmental circuit dysfunction. Neuroimaging (see Anatomical Structures) shows subtle globus pallidus signal changes rather than structural tissue destruction, consistent with a functional/metabolic rather than neurodegenerative process, though "progressive" clinical course implies an ongoing pathophysiological process not fully explained by static developmental miswiring alone.

Biochemical Abnormalities

Genome-wide/loci-specific DNA hypermethylation at gene promoters (directly measured in patient blood) is the best-characterized biochemical correlate of disease and is used diagnostically (EpiSign episignature).

Epigenetic Changes

As above — this is the disease's defining molecular signature. Reference: Ciolfi et al., Brain 2022, "Blood DNA methylation provides an accurate biomarker of KMT2B-related disease".

Molecular Profiling

  • Transcriptomics: broad transcriptional repression inferred from methylation data; no large-scale patient-derived RNA-seq dataset was identified in this search.
  • Proteomics/metabolomics/lipidomics: no disease-specific data identified.
  • Genomic structural features: 19q13.11–19q13.12 microdeletions define a subset; breakpoint mapping via CMA/array data (dbVar, DECIPHER) is used clinically but no dedicated structural-variant landscape paper was retrieved here.

Advanced Technologies

  • Single-cell/spatial transcriptomics: not identified for this specific disorder.
  • Multi-omics integration: the DNA methylation episignature work (EpiSign platform, Aref-Eshghi and colleagues' broader Mendelian neurodevelopmental disorder episignature framework) is the most advanced omics application to date, spanning 42+ Mendelian NDDs including KMT2B-related disease.
  • Functional genomics screens (CRISPR/RNAi): not identified specifically for KMT2B dystonia modeling in this search.

7. Anatomical Structures Affected

Organ Level

  • Primary organ: central nervous system, specifically the basal ganglia (particularly external and internal globus pallidus) and corticostriatal motor circuitry.
  • Secondary involvement: musculoskeletal system (foot/limb deformities, scoliosis from chronic dystonic posturing), speech/laryngeal apparatus (dysarthria, dysphonia), swallowing apparatus (dysphagia, aspiration risk), endocrine system (short stature, precocious puberty, hypothyroidism in a subset), auditory system (sensorineural hearing loss in some individuals), and craniofacial structures (dysmorphism).
  • Body systems: nervous system (primary); musculoskeletal, endocrine, gastrointestinal (feeding), and psychiatric/behavioral systems secondarily.

Suggested UBERON terms: UBERON:0002210 (globus pallidus), UBERON:0002037 (cerebellum, for the subset with cerebellar atrophy), UBERON:0001873 (globus pallidus externa/interna substructure terms as applicable), UBERON:0001896 (basal ganglion).

Tissue and Cell Level

  • Primarily affects neurons within the basal ganglia — specifically medium spiny neurons of the striatum and GABAergic pallidal neurons are the presumptive cell types implicated by anatomical/circuit logic and DBS target choice (globus pallidus internus), though direct cell-type-resolved patient data were not identified in this search.

Suggested CL terms: CL:0000617 (GABAergic neuron), CL:0000679 (medium spiny neuron), CL:0000031 (central nervous system neuron, generic).

Subcellular Level

  • Nucleus — chromatin/histone modification machinery (KMT2B acts on nucleosomal histone H3).

Suggested GO Cellular Component terms: GO:0005634 (nucleus), GO:0000785 (chromatin), GO:0035097 (histone methyltransferase complex).

Localization

  • Neuroimaging finding: subtle, symmetrical hypointense lateral streaks in the external globus pallidus on T2-weighted, T2-weighted, and susceptibility-weighted MRI sequences — described in ~27% of cases with brain imaging abnormalities; this pattern may be age-dependent, becoming less prominent over time. Brain MRI is otherwise normal in ~40%* of cases. Cerebellar atrophy has been described in three individuals. DaTscan was normal in four individuals and showed decreased striatal dopamine-transporter uptake in two (GeneReviews).
  • Lateralization: dystonia is typically bilateral/symmetric in the generalized form, though focal onset (e.g., unilateral lower-limb dystonia, or the adult-onset cervical/segmental forms) can be asymmetric or unilateral initially.

8. Temporal Development

Onset

  • Median age of onset: 6 years (range 0–43 years across the full reported spectrum, including newly recognized adult-onset cases) (GeneReviews). A recent 44-patient natural history cohort reported median onset 5.0 years (2025 Brain expansion cohort).
  • Onset pattern: typically insidious, beginning with subtle gait disturbance or foot posturing; genetically determined subtype differences exist (earlier onset with truncating/insertion variants, mean 4.4 years, vs. later onset with missense variants, mean 8.7 years).
  • Distinct adult-onset (focal/segmental, e.g., cervical dystonia) subtype now recognized, expanding the classical pediatric-onset paradigm.

Progression

  • Disease course: progressive, evolving in a caudocranial pattern — lower-limb focal dystonia → generalized dystonia with cervical, cranial, laryngeal involvement — typically over 2–11 years from initial onset (median ~2.0 years to generalization in the 2025 cohort).
  • Functional staging: GMFCS grades II (mild) through V (wheelchair-dependent, most severe) are used to stage motor severity.
  • Progression rate: variable — generally described as gradually progressive rather than rapidly fulminant, though acute severe exacerbations (status dystonicus) can occur, sometimes precipitated by intercurrent illness (ScienceDirect case report).
  • Disease duration: chronic, lifelong; not self-limited.

Patterns

  • Remission: spontaneous remission is not a feature; DBS produces substantial and sometimes sustained (multi-year) improvement in several dystonia domains but is a treatment effect, not a disease remission.
  • Critical periods: early GPi-DBS intervention — specifically before loss of independent ambulation — is associated with better long-term motor outcomes, suggesting a clinically actionable window for intervention timing (GeneReviews; PMC12926133).

9. Inheritance and Population

Epidemiology

  • Prevalence: "not yet established" per GeneReviews — this is an ultra-rare disorder without formal population-based prevalence/incidence estimates.
  • Reported case counts: ~246 individuals/229 families (DYT-KMT2B) and 27 individuals/25 families (KMT2B-related NDD) as of the most recent GeneReviews synthesis — likely an undercount given ongoing case reports (e.g., recent Indian cohort, e-jmd.org; Austrian national cohort, PMC12926133).
  • KMT2B variants are estimated in some cohort studies to account for a meaningful minority of childhood-onset isolated/complex dystonia of unknown cause when systematically screened (e.g., a single-center pediatric cohort study on "Frequency and phenotypic spectrum of KMT2B dystonia in childhood" — ResearchGate summary), making it one of the more common monogenic causes of early-onset generalized dystonia identified via next-generation sequencing.

Genetic Etiology

  • Inheritance pattern: autosomal dominant, with reduced penetrance (documented asymptomatic heterozygous carriers within families).
  • De novo rate: ~84% de novo for DYT-KMT2B; ~91% de novo for KMT2B-related NDD.
  • Inherited cases: ~16% (dystonia) / ~11% (NDD) inherited from a parent; among inherited cases, ~58% are inherited from a dystonic-phenotype parent and ~42% from an NDD-phenotype (sometimes clinically unaffected/subclinical) parent.
  • Penetrance: incomplete — some carrier parents are clinically asymptomatic.
  • Expressivity: highly variable, including well-documented intrafamilial variability where different family members carrying the identical variant manifest markedly different phenotypes (isolated dystonia vs. NDD vs. asymptomatic) (PMC8932353).
  • Genetic anticipation: not reported/established for this disorder (it is not a repeat-expansion disease).
  • Germline mosaicism: implied by the ~1% empiric sibling recurrence risk quoted for ostensibly de novo, unaffected-parent cases (accounting for possible parental gonadal mosaicism).
  • Founder effects: none specifically reported; variants are largely private/family-specific, consistent with a highly heterogeneous mutational spectrum (~100 reported variants across the gene).
  • Consanguinity: not a relevant risk factor (dominant, not recessive, disorder).
  • Carrier frequency: not applicable in the classic recessive-carrier sense; population carrier frequency of pathogenic KMT2B alleles is expected to be near zero given the severity and reduced (but real) reproductive fitness effect of the phenotype and the predominance of de novo occurrence.

Recurrence Risk

  • De novo proband, unaffected parents: ~1% risk to future siblings (gonadal mosaicism).
  • Affected parent: 50% risk to each child.
  • Affected individual (proband) to offspring: 50% per child.

Population Demographics

  • Affected populations: no specific ethnic or geographic enrichment has been established; cases have been reported across European, North American, and Asian cohorts (e.g., a recent Indian case series, e-jmd.org), consistent with a pan-ethnic, de novo-predominant Mendelian disorder.
  • Geographic distribution: no endemic pattern; reporting is concentrated in centers with access to trio exome/genome sequencing and specialized movement-disorder clinics (Europe — UK, Germany, Austria, Italy; North America; increasingly Asia).
  • Sex ratio: not clearly skewed in overall disease occurrence, but DBS outcome is reported to be better in males than females in some cohort analyses (GeneReviews) — the biological basis for this sex-based outcome difference is unclear and warrants cautious interpretation given small cohort sizes.
  • Age distribution: predominantly pediatric-onset historically, but the age range of reported affected individuals now spans neonatal/infantile through the 5th–7th decade (rare adult-onset and long-surviving cases).

10. Diagnostics

Establishing the Diagnosis

Per GeneReviews, diagnosis requires suggestive clinical findings PLUS one of: 1. A heterozygous pathogenic/likely pathogenic KMT2B sequence variant (~88% of cases), or 2. A heterozygous 19q13.11–19q13.12 deletion encompassing KMT2B (~12% of cases).

Genetic Testing Approaches

  • Exome/genome sequencing (first-tier for suspected monogenic dystonia): detects ~94% of pathogenic variants; may miss exon 1 variants and variants affecting synonymous splice sites.
  • Chromosomal microarray analysis (CMA): detects the remaining ~6%, chiefly the 19q13 deletions.
  • Gene panel testing for early-onset/complex dystonia typically includes KMT2B alongside TOR1A, THAP1, ATP1A3, NBIA genes, and others.
  • DNA methylation episignature (EpiSign) analysis: an important adjunct for resolving KMT2B variants of uncertain significance (VUS), using genome-wide Illumina Infinium EPIC methylation arrays; validated as accurately distinguishing pathogenic-variant carriers from controls and successfully used for early diagnosis even in a pre-dystonic 4-year-old (Clinical Epigenetics 2024; PMC10902455 case report). A 2024 paper questions whether two distinct episignatures exist corresponding to the dystonia vs. NDD phenotypic subgroups (PMC11631077).

Neuroimaging

  • Brain MRI: normal in ~40%; ~27% show subtle, symmetric hypointense streaks in the external globus pallidus on T2/T2*/SWI sequences (may attenuate with age); cerebellar atrophy in rare cases.
  • DaTscan: typically normal (4 of 6 reported); occasionally shows decreased striatal dopamine-transporter uptake (2 of 6).

Electrophysiology

No disease-specific EEG/EMG signature beyond standard dystonia work-up (surface EMG can characterize dystonic muscle activation patterns for clinical/DBS-programming purposes, but this is not diagnostic of the genetic etiology).

Laboratory/Biochemical

No specific serum/urine biomarker beyond the DNA methylation episignature described above; standard metabolic work-up (to exclude Wilson disease, organic acidemias, etc.) remains part of the differential diagnostic pathway rather than being confirmatory for KMT2B disease itself.

Differential Diagnosis

For DYT-KMT2B: - Neurodegeneration with brain iron accumulation (NBIA) genes: ATP13A2, C19orf12, COASY, FA2H, PANK2, PLA2G6, WDR45 - ATP1A3-related rapid-onset dystonia-parkinsonism / alternating hemiplegia of childhood - TOR1A-related DYT1 (early-onset generalized torsion dystonia) - THAP1-related dystonia (DYT6) - Wilson disease (copper metabolism) - Glutaric acidemia type 1 - Methylmalonic acidemia - Niemann-Pick disease type C - POLG-related mitochondrial disorders and other primary mitochondrial disease (>350 causal genes)

For KMT2B-related NDD (nonspecific intellectual disability differential): - Kleefstra syndrome (EHMT1) - Kabuki syndrome (KMT2D, KDM6A) - Wiedemann-Steiner syndrome (KMT2A — same gene family, notably also chromatin-modifier-related and CXXC-domain-relevant) - Silver-Russell syndrome - Seckel syndrome

Screening

No population/newborn screening program exists (ultra-rare, no metabolic analyte to screen for). Cascade/predictive genetic testing is offered to at-risk relatives once a familial variant is identified, given the 50% transmission risk from an affected/carrier parent.

11. Outcome/Prognosis

  • Survival/mortality: no formal survival statistics or standardized mortality ratio have been published; the disorder is not classically fatal, and individuals into the seventh decade of life have been reported, though the disease is progressive and morbidity-heavy. For KMT2B-related NDD, insufficient long-term outcome data exist.
  • Morbidity/functional outcomes: progressive loss of independent ambulation is common without treatment; laryngeal/oromandibular dystonia frequently necessitates enteral (tube) feeding and augmentative communication devices. GMFCS staging (II–V) is used as a functional severity/outcome metric.
  • Complications: aspiration risk from dysphagia, orthopedic complications (contractures, scoliosis, joint deformity) from chronic dystonic posturing, status dystonicus (a dystonic emergency, potentially triggered by intercurrent illness), and psychiatric comorbidity (anxiety, OCD, ADHD, ASD features).
  • Recovery potential with treatment: substantial — GPi-DBS produces mean reductions of ~35–49% in BFMDRS-M (movement) and ~30–38% in BFMDRS-D (disability) scores at 1 year, with sustained (though partially attenuated) benefit at 5-year and even up to 22-year follow-up in the largest reported cohort (n=18) (GeneReviews; PMC12926133). At 1 year, roughly half of assessed cases (8/15 for BFMDRS-M; 7/15 for BFMDRS-D) meet the >30% "optimal response" threshold.
  • Regional variability of benefit: at median 7.5-year follow-up, sustained improvement is seen for trunk (53.2%), neck (50.5%), and oromandibular (35.7%) dystonia, but gait (16.2%) and speech (3.4%) show markedly suboptimal long-term response, and freezing of gait has emerged as a recognized late complication (5/8 patients in one long-term subgroup), particularly associated with truncating variants; no patient in the long-term subgroup maintained fully autonomous gait, though DBS preserved ambulation in some and restored walking ability in others.

Prognostic Factors

  • Male sex and greater baseline dystonia severity are associated with better DBS response.
  • Earlier DBS placement (before loss of ambulation) predicts better long-term motor outcome.
  • Severe preoperative speech impairment and older age at DBS are negative prognostic factors.
  • Variant class (truncating vs. missense) affects age of onset but not DBS responsiveness or overall disease severity/progression rate.

12. Treatment

Pharmacotherapy

  • Antimuscarinic/anticholinergic agents (e.g., trihexyphenidyl): considered first-line pharmacologic treatment, producing significant motor improvement in about 50% of individuals; recommended to start at low dose with slow titration per published dystonia-treatment guidelines.
  • NCIT term: NCIT:C15986 (Pharmacotherapy); consider therapeutic_agent → CHEBI trihexyphenidyl term.
  • Levodopa and other anti-dystonic agents (baclofen, gabapentin, tetrabenazine): a trial is reasonable, but these have not resulted in long-term benefit for most individuals (GeneReviews).
  • Botulinum toxin injection for focal dystonic segments (implied standard-of-care adjunct in dystonia management generally; not separately quantified for KMT2B in the retrieved sources but consistent with general early-onset dystonia management pathways).

Advanced Therapeutics

  • Gene therapy / RNA-based / cell therapy: none specifically developed or in trials for KMT2B-related dystonia as of this search — this is fundamentally a haploinsufficiency (loss-of-function) disorder, which is mechanistically more challenging to correct with antisense/knockdown strategies (which typically address gain-of-function) and would more plausibly require gene-augmentation approaches; none identified as being in active clinical development.

Surgical / Interventional — Deep Brain Stimulation (mainstay advanced therapy)

  • Bilateral GPi-DBS (globus pallidus internus) has become the therapeutic mainstay for medically refractory KMT2B-related dystonia, performed in ~80 individuals reported to date.
  • NCIT term candidate: NCIT:C15329 (Surgical Procedure), with therapeutic_modality: DEVICE and device detail via qualifiers (as per dismech convention for device+action, analogous to cochlear implantation) — DBS device term (e.g., an NCIT/relevant device code) should be looked up specifically during curation.
  • Efficacy: mean BFMDRS-M reduction ~35% (1 yr) to ~44% (5 yr); mean BFMDRS-D reduction ~30% (1 yr) to ~31% (5 yr) in the largest long-term cohort (18 patients, up to 22 years follow-up).
  • Best responding domains: trunk, neck, upper limb, oromandibular dystonia.
  • Poorly responding domains: gait/lower-limb dystonia (may worsen; loss of ambulation reported in some individuals) and laryngeal dystonia (DBS has not been effective for laryngeal dystonia specifically).
  • Complication: freezing of gait, particularly associated with truncating KMT2B variants.
  • Systematic review/meta-analysis: GPi-DBS for KMT2B-Associated Dystonia.

Supportive and Rehabilitative Care

  • Physical therapy: early initiation to maintain function and prevent secondary orthopedic complications (contractures, deformity).
  • Occupational therapy: for fine motor function.
  • Speech-language therapy: for feeding/swallowing safety and communication; videofluoroscopy used to assess aspiration risk.
  • Augmentative and alternative communication (AAC): for individuals with severe dysarthria/anarthria.
  • Nutritional support: assessment and intervention, including enteral feeding when indicated.
  • Adaptive equipment: ankle-foot orthoses, walkers, adapted seating.
  • Neurobehavioral/psychiatric management: including applied behavior analysis (ABA) therapy for ASD/behavioral features.
  • Early intervention (ages 0–3) and individualized education plans (IEP) for developmental/cognitive needs.

Experimental

No KMT2B-specific interventional clinical trials (with NCT identifiers) were identified in this search; management is guided by expert consensus/cohort experience rather than randomized trial data, reflecting the disorder's rarity.

Treatment Strategy / Algorithm

General approach per GeneReviews: trial of anticholinergic therapy (particularly trihexyphenidyl) as first-line pharmacotherapy → consider other anti-dystonic agents (levodopa, baclofen, gabapentin, tetrabenazine) with modest expectations → early referral for GPi-DBS evaluation, ideally before loss of ambulation, for medically refractory or progressive generalized dystonia → lifelong multidisciplinary supportive care (PT/OT/speech/nutrition/psychiatry).

Pregnancy/Reproductive Considerations

Isolated case reports of trihexyphenidyl, levodopa/carbidopa, and clonazepam exposure during pregnancy in affected women showed no adverse fetal effects, though data are extremely limited (single case reports only) — genetic counseling regarding medication risk-benefit in pregnancy is recommended.

13. Prevention

  • Primary prevention: not applicable in the traditional sense (no modifiable risk factor); however, genetic counseling and reproductive options (prenatal diagnosis, preimplantation genetic testing) are available once a familial pathogenic variant is identified, for families wishing to reduce recurrence risk.
  • Secondary prevention/early detection: early molecular diagnosis (including via the DNA methylation episignature, which has enabled diagnosis in a pre-symptomatic/pre-dystonic 4-year-old) allows earlier initiation of surveillance and supportive interventions, and earlier consideration of DBS before irreversible functional loss (loss of ambulation) — a clinically meaningful "critical window."
  • Tertiary prevention: proactive multidisciplinary management (PT/OT/speech/nutrition, orthopedic surveillance, psychiatric care) to prevent secondary complications (contractures, aspiration, psychosocial morbidity) in individuals with established disease.
  • Genetic counseling: offered per standard autosomal dominant disease counseling — 50% transmission risk from an affected/carrier parent, ~1% empiric sibling recurrence risk for apparent de novo cases (accounting for possible germline mosaicism), reduced penetrance discussed explicitly given documented asymptomatic carriers.
  • Screening: no population-level or newborn screening program exists; testing is targeted (symptomatic individuals, at-risk relatives via cascade testing).
  • Immunization/public health/environmental interventions: not applicable (non-infectious, non-environmental monogenic disorder).

14. Other Species / Natural Disease

  • No naturally occurring companion-animal, livestock, or wildlife disease model attributable to spontaneous KMT2B orthologous mutation was identified in this search (no OMIA entry surfaced).
  • Orthologous gene: Kmt2b is conserved across vertebrates (mouse Kmt2b, zebrafish kmt2b); NCBI Gene IDs for mouse Kmt2b and zebrafish kmt2b should be confirmed directly during curation.
  • Comparative note: functionally related family members show naturally occurring or engineered disease relevance in other species context (e.g., Kmt2d embryonic-lethal knockout phenotypes, discussed under Model Organisms below), but this is paralog, not ortholog, biology and should not be conflated with KMT2B itself.
  • Zoonotic potential: not applicable (this is a purely genetic, non-infectious human disease).

15. Model Organisms

Mouse Models

Direct Kmt2b-specific dystonia mouse model data were not clearly retrieved in this search; most mouse constraint/phenotype data available relate to the paralogous methyltransferase genes: - Kmt2d (historically also confusingly labeled Mll4 in some papers) knockout mice: embryonic lethal at E9.5; conditional knockout in somitic precursors (giving rise to brown adipose tissue and back skeletal muscle) causes marked reduction in BAT/muscle mass and perinatal lethality from respiratory failure; adult conditional knockouts show craniofacial defects (midfacial hypoplasia, midline palate defects) (biorxiv/PMC11803150). - Kmt2c (Mll3) haploinsufficient mice: show autism-like behavioral deficits, illustrating that KMT2-family haploinsufficiency in mice can recapitulate neurobehavioral phenotypes relevant to the human NDD spectrum (PMC12650575). - Mll2 (a related H3K4 methyltransferase) heterozygous mice: hyperglycemic, hyperinsulinemic, and develop non-alcoholic fatty liver disease — illustrating pleiotropic, dosage-sensitive phenotypes of H3K4 methyltransferase family haploinsufficiency, though this is metabolic rather than movement-disorder phenotype and again reflects a different family member (PMC3691224).

Note for curation: because KMT2B, KMT2D, and KMT2A have overlapping/confusing historical aliases (MLL2, MLL4), any model-organism claims sourced from search snippets should be re-verified against the current official gene symbol before being attached as modeled_mechanisms evidence — several search results returned data for KMT2D (Kabuki syndrome gene) under ambiguous "MLL4" labeling that must not be misattributed to KMT2B.

Zebrafish

  • Zebrafish kmt2b has been referenced in variant-conservation analyses (e.g., noting that the residue affected by a human p.Phe1662 variant is naturally a tyrosine in zebrafish/Drosophila, used for cross-species conservation assessment of variant pathogenicity) (PMC8932353; tremorjournal.org). No dedicated zebrafish loss-of-function movement-phenotype model paper for kmt2b was identified in this search — this is a candidate model-development gap.

Cellular/In Vitro Models

  • Mouse embryonic stem cells have been used to dissect the direct molecular function of KMT2B in repelling PRC2/DNMT complexes from chromatin — this is the best-established functional model system for KMT2B mechanism to date, though it models the general epigenetic function of the protein rather than the dystonia phenotype specifically (Clinical Epigenetics 2021).
  • Patient-derived peripheral blood is used for the DNA methylation episignature assay — a translational biomarker model rather than a mechanistic disease model, but functionally validates variant pathogenicity.

Model Limitations

No iPSC-derived neuronal model, patient-derived organoid, or in vivo movement-disorder animal model specific to KMT2B dystonia was identified in this search — representing a clear translational research gap relative to other monogenic dystonias (e.g., TOR1A/DYT1, which has multiple mouse models). This gap should be flagged explicitly in any experimental_models/animal_models curation as an evidence limitation (HUMAN_MODEL_MISMATCH candidate discussion) rather than assumed absent from a literature-completeness perspective — confirm with a dedicated search before finalizing this claim in the KB entry.

Summary of Key Ontology Term Suggestions for KB Curation

Category Suggested term
Disease (MONDO) Search directly on mondo.monarchinitiative.org for "KMT2B-related dystonia" / "DYT28" — not independently confirmed in this search
OMIM 617284 (DYT28); 619934 (MRD68); *606834 (gene)
Gene (HGNC) KMT2B, hgnc: ID to confirm
Phenotype (HP) HP:0001332 Dystonia; HP:0002340 Lower limb dystonia; HP:0001608 Dysphonia; HP:0002015 Dysphagia; HP:0001249 Intellectual disability; HP:0000252 Microcephaly; HP:0004322 Short stature; HP:0001336 Myoclonus; HP:0001257 Spasticity; HP:0001251 Ataxia; HP:0007018 Attention deficit hyperactivity; HP:0000717 Autistic behavior; HP:0000407 Sensorineural hearing loss
Biological process (GO) GO:0051568 histone H3-K4 methylation; GO:0034968 histone lysine methylation; GO:0006306 DNA methylation; GO:0031519 PcG protein complex; GO:0006357 regulation of transcription by RNA Pol II
Cell type (CL) CL:0000679 medium spiny neuron; CL:0000617 GABAergic neuron
Anatomy (UBERON) UBERON:0002210 globus pallidus; UBERON:0001896 basal ganglion; UBERON:0002037 cerebellum
Treatment (NCIT) NCIT:C15986 Pharmacotherapy (trihexyphenidyl/anticholinergics as therapeutic_agent); NCIT:C15329 Surgical Procedure (GPi-DBS; device qualifier needed)

Notes on Evidence Gaps for Curation

  1. Population prevalence is explicitly "not yet established" — do not fabricate a numeric estimate; use prevalence_class: NOT_YET_DOCUMENTED per dismech convention.
  2. Mechanistic link from promoter hypermethylation to specific dystonia-driving target genes is not resolved in the literature — the causal chain above flags this as inferred.
  3. Animal/cellular model coverage specific to KMT2B (as opposed to paralogs KMT2A/KMT2D) is thin — verify carefully before attaching modeled_mechanisms links, given the historical MLL2/MLL4 naming ambiguity across the gene family.
  4. gnomAD constraint metrics (pLI/LOEUF) for KMT2B were not directly retrieved — look these up directly at gnomad.broadinstitute.org before including in a Genetic block.
  5. Orphanet ORPHA code was not confirmed in this search and should be verified directly at orphadata.com before citing.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 17
Resolved 17
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 2
Quoted claims found in source 1
Quoted claims not found in source 1
References weighed for topical relevance 17
On topic 9
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • DOI:10.1186/s13148-021-01145-y (abstract only): "indicating a general repression of transcriptional activity"
  • Text part not found as substring: 'indicating a general repression of transcriptional activity' (note: only abstract available for DOI:10.1186/s13148-021-01145-y, full text may contain this excerpt)

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 40
Resolved 37
Unresolved (possible confabulation) 0
Obsolete 3
Unverifiable 0
Terms whose name was checked 8
Terms named correctly 7
Terms named as a different term 1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0001608 (2 mentions) - the report calls it "Dysphonia"; HP calls it Abnormality of the voice

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0051568 (obsolete histone H3-K4 methylation) (2 mentions)
  • GO:0034968 (obsolete histone lysine methylation) (2 mentions)
  • GO:0006306 (obsolete DNA methylation) (2 mentions)