Clinical characteristics.

KMT2B-related dystonia (DYT-KMT2B) is a complex childhood-onset (mean age 7 years) movement disorder described to date in 39 individuals. It is characterized by a progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties, secondary to articulation difficulties and low speech volume, are common. Bulbar dysfunction leads to impaired swallowing. Intellectual disability (ID) / developmental delay (DD) are commonly reported.

Additional findings can include eye movement abnormalities, skin changes, psychiatric comorbidities (attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder), myoclonus, seizures, spasticity, and sensorineural hearing loss. Many affected individuals follow a similar disease course, though milder and atypical findings have been described.

Diagnosis/testing.

The diagnosis of DYT-KMT2B is established in a proband with either a heterozygous pathogenic variant in KMT2B or a heterozygous interstitial deletion of 19q13.12 that includes a KMTB2 whole-gene deletion.

Management.

Treatment of manifestations:

• Dystonia: Although pharmacologic treatment with levodopa and other commonly used anti-dystonic agents generally does not result in long-term benefit for the majority of affected individuals, a trial of these agents is considered reasonable. One group observed a significant improvement of motor manifestations with an antimuscarinic (anticholinergic) agent. Bilateral globus pallidus interna deep brain stimulation results in substantial clinical improvement, particularly in younger individuals.
• Other: Early initiation of physiotherapy and a tailored exercise program is advised as well as use of adaptive aids (e.g., ankle-foot orthoses, walkers) as necessary to support and maintain ambulation. Speech-language therapy is crucial to assist in feeding skills and communication. Nutrition specialists / dieticians are needed to assess calorie needs and reduce the risk of malnutrition. Address DD/ID issues through appropriate specialists/agencies.

Surveillance: Regular monitoring of weight and height in children, nutritional status, swallowing function, speech and language, adaptive functioning (ability to perform activities of daily living), orthopedic complications (hip dislocation and kyphoscoliosis), hearing, eye movements, skin, and psychiatric status.

Genetic counseling.

DYT-KMT2B is inherited in an autosomal dominant manner. To date, ~84% of individuals have the disorder as the result of a de novo KMT2B pathogenic variant and ~16% have inherited the KMT2B variant (10% from an affected parent; 6% from a clinically asymptomatic parent). Each child of an individual with DYT-KMT2B has a 50% chance of inheriting the KMT2B pathogenic variant; reduced penetrance and intrafamilial clinical variability have been reported. Once the KMT2B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

DYT-KMT2B should be suspected in individuals with the following findings.

Neuroimaging

Brain MRI abnormalities frequently reported in younger affected individuals (age range: 3-18 years) include subtle and symmetric hypointense lateral streaks in the external globus pallidus (Figure 1) on T₂-weighted, T₂*-weighted, susceptibility-weighted, and echo-planar b0-diffusion imaging data sets [Meyer et al 2017].

Figure 1.

Radiologic MRI features of patients with KMT2B variants a-l. T₂*-weighted (a, d) and T₂-weighted (b, c) images; echo-planar technique diffusion imaging data set images with b value of zero (e-h); susceptibility-weighted sequences (i-l)

Note: This pattern may represent an age-dependent phenomenon as these features were often not evident in adults and may become less prominent over time. Indeed, in one individual such MR changes were less evident on MRI performed at age 17 years compared to neuroimaging performed at age 13 years.

DaTSCAN and FDG-PET-CT scan were normal in the three individuals evaluated with these methods.

Establishing the Diagnosis

The diagnosis of DYT-KMT2B is established in a proband with one of the following [Zech et al 2016, Lange et al 2017, Meyer et al 2017, Zech et al 2017a, Zech et al 2017b] (see Table 1):

• A heterozygous pathogenic (or likely pathogenic) variant in KMT2B (26/36 probands reported to date)
• A heterozygous interstitial deletion of 19q13.12 that encompasses the entirety of KMTB2 (10/36 probands reported to date)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of a heterozygous KMT2B variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, genomic sequencing, exome array) depending on the phenotype.

Persons with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using comprehensive genomic testing (see Option 2).

Clinical Description

KMT2B-related dystonia (DYT-KMT2B) is a complex childhood-onset movement disorder. It typically presents with a progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Additional neurologic, psychiatric, and systemic features are commonly reported. Many affected individuals follow a similar disease course, though milder and atypical cases have been described.

DYT-KMT2B has been recently described in 36 probands. Of these, one proband had an affected mother and another had a similarly affected father and grandfather (total 39 individuals reported).

Disease onset typically occurs between ages one and 10 years (33/39 individuals); however, onset in the second decade was reported in five individuals for whom data were available. Mean age of onset was 7.05 years in 38 individuals for whom data were available.

Presenting manifestations (documented for 37/39 individuals) include the following:

• Lower-limb dystonia characterized by foot posturing, toe walking, and gait disturbance (in 28 individuals)
• Upper-limb dystonia leading to abnormal hand/arm posturing, dystonic tremor, and difficulties in handwriting and hand dexterity (6)
• Cervical dystonia (1)
• Truncal/axial dystonia (1)
• Dystonic tremor and (action) myoclonus (1)

Over time, the majority of individuals developed progressive cranial, cervical, and laryngeal dystonia with features of retrocollis, torticollis, dysarthria/anarthria, dysphonia, and difficulties in swallowing and chewing.

Affected individuals often have communication difficulties, secondary to articulation difficulties and low speech volume.

Bulbar dysfunction leads to impaired swallowing, which can cause substantial morbidity because of the risk of aspiration pneumonia. A few individuals with DYT-KMT2B have required gastrostomy insertion for feeding difficulties.

Generalized dystonia becomes evident in most individuals (34/39) within two to 11 years of initial presentation. The level of gross motor disability comprises a broad spectrum ranging from minor gait disturbance to wheelchair dependence (GMFCS II-V).

Developmental delay, described in 16 of 39 affected individuals, usually precedes the onset of dystonia and is thought to be non-progressive. Eight presented with neurodevelopmental delay, seven had isolated speech delay, and one had only delay in attainment of fine motor skills.

Mild cognitive impairment was reported in 21 of 39 affected individuals, most of whom developed variable degrees of functional independence in adolescence and adulthood.

Life expectancy is not known, but individuals in the seventh decade of life with DYT-KMT2B have been reported [Zech et al 2016].

Additional clinical features of DYT-KMT2B included the following (note that 9 individuals had >1 additional clinical feature):

• Eye movement abnormalities including strabismus, astigmatism, delay in saccade initiation, hypometric vertical saccades, oculomotor apraxia (in 8 individuals)
• Dermatologic features of ectodermal dysplasia including cutis aplasia, sparse hair, sparse to absent eyelashes or brows, hypertrichosis, and ichthyotic skin with criss-cross pattern under the feet and at the knees (5). Although broad postsurgical scarring and "phimosis" have been reported, it is not currently known if these features are incidental or truly disease related. Future identification of further individuals with molecularly confirmed DYT-KMT2B may better clarify these associations.
• Psychiatric comorbidities including attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, and obsessive-compulsive disorder (3)
• Myoclonus (3)
• Microcephaly (3)
• Seizures (2), including one with absence seizures
• Spasticity (1)
• Sensorineural hearing loss (1)
• Subtle dysmorphic features that may include an elongated face and bulbous nasal tip [Zech et al 2016, Meyer et al 2017, Zech et al 2017a, Zech et al 2017b]

The following atypical DYT-KMT2B disease manifestations [Meyer et al 2017] are rarely reported:

• Paroxysmal cervical dystonia, reported in one individual. Notably, the mother of this proband, who was found to harbor this KMT2B variant, had onset of symptoms in early adulthood. She developed gait abnormalities, a progressive inability to run, and periodic paroxysmal upper-limb and neck dystonia.
• Solely oromandibular features without clinical evidence of limb dystonia

Genotype-Phenotype Correlations

Meyer and colleagues [2017] reported statistically significant earlier disease onset in individuals with DYT-KMT2B with loss-of-function variants (e.g., interstitial deletions; frameshift, splice site, and stop-gain variants) compared to those with missense variants. However, genotype does not appear to influence the rate of disease progression, disease severity, or clinical response to deep brain stimulation.

Early neurodevelopmental delay was reported in 5/10 individuals with a heterozygous 19q13.12 contiguous gene deletion, compared to 11/29 with intragenic KMT2B pathogenic variant. Likewise, the majority of individuals (8/10) with a heterozygous 19q13.12 contiguous gene deletion had mild cognitive impairment, compared to 13/29 with an intragenic KMT2B pathogenic variant. Identification of additional individuals with DYT-KMT2B will determine if this is a true genotype-phenotype correlation.

Penetrance

DYT-KMT2B is postulated to show reduced penetrance as asymptomatic heterozygotes have been identified. Although parental status is not always known, to date two (6%) of 32 reported pathogenic variants have been inherited from a seemingly unaffected parent [Meyer et al 2017].

Male-female differences in penetrance have not been observed to date.

Prevalence

Disease prevalence is not yet established. To date, 39 individuals (from 36 families) with DYT-KMT2B have been described.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DYT-KMT2B, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Complete detailed neurologic examination to delineate movement disorder phenotype (dystonia, myoclonus, spasticity)
• Consider early assessment for possible effectiveness of deep brain stimulation
• Physiotherapy, occupational therapy, and speech and language therapy assessment
• Evaluation of swallowing safety (videofluoroscopy may be needed)
• Nutritional evaluation to ensure adequate calorie intake
• Developmental assessment / IQ testing
• Orthopedic examination for secondary complications including fixed contractures, joint dislocation, and/or kyphoscoliosis
• Ophthalmologic examination including assessment of vision and eye movements
• Assessment of hearing
• Formal neuropsychiatric testing
• Dermatologic examination
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Dystonia. Although pharmacologic treatment with levodopa and other commonly used anti-dystonic agents (e.g., trihexiphenidyl, baclofen, gabapentin, tetrabenazine, benzodiazepines) has not proven to result in long-term benefit for the majority of individuals with DYT-KMT2B [Zech et al 2016, Meyer et al 2017, Zech et al 2017a], a trial of these anti-dystonia agents would be considered reasonable. Lange and colleagues [2017] observed a significant improvement of motor manifestations on treatment with an antimuscarinic (anticholinergic) agent.

Bilateral globus pallidus interna deep brain stimulation (DBS) results in substantial clinical improvement, particularly in younger individuals, and should be considered as a possible therapeutic route for patients with DYT-KMT2B based on the following results [Zech et al 2016, Meyer et al 2017, Zech et al 2017a, Zech et al 2017b]:

• Three patients regained independent ambulation.
• Five patients demonstrated sustained clinical effect at eight years following implantation.

Early initiation of physiotherapy and a tailored exercise program is essential to maintain function and prevent secondary orthopedic complications such as joint contractures, hip dislocation, and/or kyphoscoliosis.

Adaptive aids (e.g., ankle-foot orthoses, walkers) should be supplied to support and maintain ambulation.

Speech and language therapy is crucial to assist in feeding skills and communication. Some affected individuals may need communication devices.

Nutrition specialists / dieticians are of utmost importance to assess calorie needs and reduce the risk of malnutrition.

Videofluoroscopy can be used to evaluate the risk of aspiration and assess the need for alternative means of feeding.

For individuals with respiratory compromise from chest deformities related to scoliosis, prophylactic antibiotics during the winter months, regular physiotherapy, and influenza immunizations should be considered because of the increased risk of pulmonary infections.

Surveillance

Surveillance includes regular monitoring of the following:

• Weight and height using age-appropriate and sex-matched growth charts in children
• Nutritional status to evaluate dietary requirements
• Swallowing to evaluate risk for aspiration
• Speech and language regarding needs for augmentative communication
• Adaptive functioning (ability to perform activities of daily living)
• Potential orthopedic complications (e.g., hip dislocation and kyphoscoliosis with hip and spine x-rays every 6 to 12 months)
• Hearing
• Strabismus and refractive errors
• Skin examination for changes requiring appropriate management
• Psychiatric status

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Before conception, counseling on the potential effects of antidystonic medications on the pregnancy and developing fetus should be discussed and an appropriate plan on managing medications during pregnancy should be established. Pregnant women with DYT-KMT2B should also be advised about the induction of dystonic side effects of antiemetics [Nageshwaran et al 2011].

Data on the use of antidystonic agents in pregnancy are scarce. Although single case reports of medical treatment with trixhexyphenidyl, levodopa/carbidopa, and clonazepam during pregnancy have not observed adverse effects on the affected mother or the fetus [Watanabe et al 2009, Mendhekar & Andrade 2011, Nageshwaran et al 2011, Robottom & Reich 2011, Serikawa et al 2011, Watanabe & Matsubara 2012, Dostal et al 2013], oral medications may be preferably tapered to the lowest effective dose.

Treatment with DBS has been reported in a series of cases with implantation prior to conception [Scelzo et al 2015, Ziman et al 2016, Park et al 2017]. No adverse effects on the affected mother and the fetus have been reported to date.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

KMT2B-related dystonia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• When parental DNA was available (32/39), ~84% of individuals diagnosed with DYT-KMT2B had the disorder as the result of a de novo KMT2B pathogenic variant [Zech et al 2016, Lange et al 2017, Meyer et al 2017, Zech et al 2017a, Zech et al 2017b].
• Approximately 16% of individuals diagnosed with DYT-KMT2B inherited a KMT2B variant: 10% from an affected parent and 6% from a clinically asymptomatic parent (see Penetrance) [Zech et al 2016, Meyer et al 2017]. Clinical variability within families is reported.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the KMT2B pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
• The family history of some individuals diagnosed with DYT-KMT2B may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• Note: If the parent is the individual in whom the KMT2B pathogenic variant first occurred, the parent may have somatic (and germline) mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected and/or is known to be heterozygous for the KMT2B pathogenic variant, the risk to sibs of inheriting the pathogenic variant is 50%, intrafamilial clinical variability and reduced penetrance have been observed in DYT-KMT2B.
• If the KMT2B pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the estimated recurrence risk to sibs is 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If both parents are clinically unaffected but have not been tested for the KMT2B pathogenic variant, the sibs of a proband are still at increased risk for DYT-KMT2B because of the possibility of reduced penetrance in a heterozygous parent or germline mosaicism in a parent.

Offspring of a proband. Each child of an individual with DYT-KMT2B has a 50% chance of inheriting the KMT2B pathogenic variant; reduced penetrance and intrafamilial clinical variability have been reported [Meyer et al 2017, Zech et al 2016].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the KMT2B pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the KMT2B pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

KMT2B encodes a ubiquitously expressed lysine-specific histone methyl-transferase. Histone methylation represents a post-translational epigenetic mechanism to either repress or activate gene transcription in a residue-specific manner [Shi & Whetstine 2007, Shilatifard 2008]. KMT2B is a member of the SET/MLL protein family that is specifically involved in histone 3 lysine 4 (H3K4) methylation. H3K4 is enriched at promoter, enhancer, and other regulatory sequences and associated with active transcription [Barski et al 2007, Zhou et al 2011]. Besides gene activation, H3K4 is also thought to be essential for transcriptional stability and enhanced transcriptional consistency [Muramoto et al 2010, Benayoun et al 2014].

The exact pathogenic mechanisms in DYT-KMT2B still remain to be fully elucidated. Given that dysregulated H3K4 methylation has an effect on the transcriptional activation and stability of a variety of genes, it is likely that additional genes or other genetic mechanisms contribute to DYT-KMT2B.

Several patients harbor small deletions on chromosome 19q.13.12, a region that encompasses KMT2B. It is possible that other genes within these genomic deletions could additionally contribute to the affected individual's phenotype.

Gene structure. The protein coding transcript NM_014727.2 encompasses 37 exons.

Pathogenic variants. KMT2B variants have been identified in 39 individuals with early-onset complex dystonia [Zech et al 2016, Meyer et al 2017]. In addition to frameshift, nonsense, splice site, and missense variants, small overlapping interstitial deletions of chromosome 19q13.12 have also been detected. For the ten individuals with reported small deletions, the smallest region of overlap spanned from 36,191,000 bp to 36,229,548 bp, encompassing two genes, ZBTB32 and KMT2B (MLL4). Given that a number of loss-of-function pathogenic variants are reported in DYT-KMT2B, it is likely that pathogenic variants result in KMT2B haploinsufficiency.

Novel missense variants have been reported recently in another four unrelated individuals [Zech et al 2017a, Zech et al 2017b]:

• Two variants are of uncertain significance because of unknown parental inheritance.
• Two variants showed strong conservation and were predicted to be likely protein damaging [Zech et al 2017a]:
  • p.Ala1541Val was transmitted to two unaffected adult offspring.
  • p.Arg1779Gln was present in an individual in the ExAC population database.

Lange et al [2017] identified a proband with early-onset dystonia with a novel three-bp in-frame deletion that affects a highly conserved amino acid located within the PHD-like domain that is important for DNA-protein and protein-protein interaction. Protein modeling revealed altered loop formation and impaired coordination of a zinc ion.

Normal gene product. KMT2B has a single protein-coding transcript of 8,469 bp. The protein encompasses 2,715 amino acids and consists of multiple functional domains including a CXXC zinc finger, three PHD/PHD-like zinc fingers domains, two FY-rich domains, and a C-terminal SET (suppressor of variegation, enhancer of zeste, and trithorax) domain (RefSeq, Jul 2008). The KMT2B protein belongs to the MLL (mixed-lineage leukemia) protein family, which is characterized by a conserved C-terminal catalytic SET domain. KMT2B is ubiquitously expressed in the brain with highest expression in the cerebellum [Meyer et al 2017].

Abnormal gene product. Loss-of-function KMT2B pathogenic variants are predicted to alter gene dosage, leading to KMT2B haploinsufficiency. The effect of missense variants remains to be fully elucidated, but they may affect normal protein stability and function. Abnormal KMT2B protein function may lead to dysregulated gene expression.

The role of KMT2B has been investigated using a mouse model [Kerimoglu et al 2013]. A conditional knockdown of KMT2B in forebrain excitatory neurons resulted in downregulation of a specific subset of genes. The mouse model had evidence of impaired memory formation but no dystonia.

Author Notes

Dr Lucia Abela

Developmental Neurosciences

UCL-Great Ormond Street Institute of Child Health, London

Dr Abela is a senior resident in pediatric neurology and currently a research fellow in Dr Kurian's research group with a special interest in childhood movement disorders.

Dr Manju Kurian

Developmental Neurosciences

UCL-Great Ormond Street Institute of Child Health, London

Dr Kurian is a pediatric neurologist and clinician-scientist with a clinical and research interest in childhood movement disorders.

Dr Kurian's web page

Acknowledgments

Dr Kurian is funded by an NIHR Research Professorship and the Wellcome Trust. Dr Abela is funded by a Swiss National Foundation Advanced Postdoc Mobility fellowship.

Revision History

• 29 September 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis, Option 2)
• 26 April 2018 (bp) Review posted live
• 19 October 2017 (la/mak) Original submission

Literature Cited

• Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129:823-37. [PubMed: 17512414]
• Benayoun BA, Pollina EA, Ucar D, Mahmoudi S, Karra K, Wong ED, Devarajan K, Daugherty AC, Kundaje AB, Mancini E, Hitz BC, Gupta R, Rando TA, Baker JC, Snyder MP, Cherry JM, Brunet A. H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell. 2014;158:673-88. [PMC free article: PMC4137894] [PubMed: 25083876]
• Camargos S, Scholz S, Simón-Sánchez J, Paisán-Ruiz C, Lewis P, Hernandez D, Ding J, Gibbs JR, Cookson MR, Bras J, Guerreiro R, Oliveira CR, Lees A, Hardy J, Cardoso F, Singleton AB. DYT16, a novel young-onset dystonia-parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol. 2008;7:207-15. [PubMed: 18243799]
• Dale RC, Grattan-Smith P, Nicholson M, Peters GB. Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: a single-centre study. Dev Med Child Neurol. 2012;54:618-23 [PubMed: 22515636]
• Dostal M, Weber-Schoendorfer C, Sobesky J, Schaefer C. Pregnancy outcome following use of levodopa, pramipexole, ropinirole, and rotigotine for restless legs syndrome during pregnancy: a case series. Eur J Neurol. 2013;20:1241-6. [PubMed: 23083216]
• Gorman KM, Meyer E, Kurian MA. Review of the phenotype of early-onset generalised progressive dystonia due to mutations in KMT2B. Eur J Paediatr Neurol. 2018;22:245-56 [PubMed: 29289525]
• Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling R, Bahari-Javan S, Benito-Garagorri E, Halder R, Burkhardt S, Stewart AF, Fischer A. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci. 2013;33:3452-64. [PMC free article: PMC6619533] [PubMed: 23426673]
• Lange LM, Tunc S, Tennstedt S, Münchau A, Klein C, Assmann B, Lohmann K. A novel, in-frame KMT2B deletion in a patient with apparently isolated, generalized dystonia. Mov Disord. 2017;32:1495-7. [PubMed: 28921672]
• Lee S, Ochoa E, Barwick K, Cif L, Rodger F, Docquier F, Pérez-Dueñas B, Clark G, Martin E, Banka S, Kurian MA, Maher ER. Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders. Epigenomics. 2022;14:537-47. [PubMed: 35506254]
• Levy MA, McConkey H, Kerkhof J, Barat-Houari M, Bargiacchi S, Biamino E, Bralo MP, Cappuccio G, Ciolfi A, Clarke A, DuPont BR, Elting MW, Faivre L, Fee T, Fletcher RS, Cherik F, Foroutan A, Friez MJ, Gervasini C, Haghshenas S, Hilton BA, Jenkins Z, Kaur S, Lewis S, Louie RJ, Maitz S, Milani D, Morgan AT, Oegema R, Østergaard E, Pallares NR, Piccione M, Pizzi S, Plomp AS, Poulton C, Reilly J, Relator R, Rius R, Robertson S, Rooney K, Rousseau J, Santen GWE, Santos-Simarro F, Schijns J, Squeo GM, St John M, Thauvin-Robinet C, Traficante G, van der Sluijs PJ, Vergano SA, Vos N, Walden KK, Azmanov D, Balci T, Banka S, Gecz J, Henneman P, Lee JA, Mannens MMAM, Roscioli T, Siu V, Amor DJ, Baynam G, Bend EG, Boycott K, Brunetti-Pierri N, Campeau PM, Christodoulou J, Dyment D, Esber N, Fahrner JA, Fleming MD, Genevieve D, Kerrnohan KD, McNeill A, Menke LA, Merla G, Prontera P, Rockman-Greenberg C, Schwartz C, Skinner SA, Stevenson RE, Vitobello A, Tartaglia M, Alders M, Tedder ML, Sadikovic B. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders. HGG Adv. 2021;3:100075. [PMC free article: PMC8756545] [PubMed: 35047860]
• Mendhekar DN, Andrade C. Uneventful use of haloperidol and trihehexyphenidyl during three consecutive pregnancies. Arch Womens Ment Health. 2011;14:83-4. [PubMed: 21116668]
• Meyer E, Carss KJ, Rankin J, Nichols JME, Grozeva D, Joseph AP, Mencacci NE, Papandreou A, Ng J, Barral S, Ngoh A, Ben-Pazi H, Willemsen MA, Arkadir D, Barnicoat A, Bergman H, Bhate S, Boys A, Darin N, Foulds N, Gutowski N, Hills A, Houlden H, Hurst JA, Israel Z, Kaminska M, Limousin P, Lumsden D, McKee S, Misra S, Mohammed SS, Nakou V, Nicolai J, Nilsson M, Pall H, Peall KJ, Peters GB, Prabhakar P, Reuter MS, Rump P, Segel R, Sinnema M, Smith M, Turnpenny P, White SM, Wieczorek D, Wiethoff S, Wilson BT, Winter G, Wragg C, Pope S, Heales SJH, Morrogh D, UK10K Consortium, Deciphering Developmental Disorders Study, NIHR BioResource Rare Diseases Consortium, Pittman A, Carr LJ, Perez-Dueñas B, Lin JP, Reis A, Gahl WA, Toro C, Bhatia KP, Wood NW, Kamsteeg EJ, Chong WK, Gissen P, Topf M, Dale RC, Chubb JR, Raymond FL, Kurian MA. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia. Nat Genet 2017;49:223-37.
• Mirza-Schreiber N, Zech M, Wilson R, Brunet T, Wagner M, Jech R, Boesch S, Škorvánek M, Necpál J, Weise D, Weber S, Mollenhauer B, Trenkwalder C, Maier EM, Borggraefe I, Vill K, Hackenberg A, Pilshofer V, Kotzaeridou U, Schwaibold EMC, Hoefele J, Waldenberger M, Gieger C, Peters A, Meitinger T, Schormair B, Winkelmann J, Oexle K. Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset. Brain. 2022;145:644-54. [PubMed: 34590685]
• Muramoto T, Müller I, Thomas G, Melvin A, Chubb JR. Methylation of H3K4 is required for inheritance of active transcriptional states. Curr Biol. 2010;20:397-406. [PubMed: 20188556]
• Nageshwaran S, Nageshwaran S, Edwards MJ, Morcos M. Management of DYT1 dystonia throughout pregnancy. BMJ Case Rep. 2011;2011. [PMC free article: PMC3176356] [PubMed: 22679185]
• Park HR, Lee JM, Park H, Shin CW, Kim HJ, Park HP, Kim DG, Jeon BS, Paek SH. Pregnancy and delivery in a generalized dystonia patient treated with internal globus pallidal deep brain stimulation: a case report. J Korean Med Sci. 2017;32:155-9. [PMC free article: PMC5143289] [PubMed: 27914146]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126-33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Rilstone JJ, Alkhater RA, Minassian BA. Brain dopamine-serotonin vesicular transport disease and its treatment. N Engl J Med. 2013;368:543-50. [PubMed: 23363473]
• Robottom BJ, Reich SG. Exposure to high dosage trihexyphenidyl during pregnancy for treatment of generalized dystonia: case report and literature review. Neurologist. 2011;17:340-1. [PubMed: 22045287]
• Scelzo E, Mehrkens JH, Bötzel K, Krack P, Mendes A, Chabardès S, Polosan M, Seigneuret E, Moro E, Fraix V. Deep brain stimulation during pregnancy and delivery: experience from a series of "DBS Babies". Front Neurol. 2015;6:191 [PMC free article: PMC4556026] [PubMed: 26388833]
• Serikawa T, Shimohata T, Akashi M, Yokoseki A, Tsuchiya M, Hasegawa A, Haino K, Koike R, Takakuwa K, Tanaka K, Tanaka K, Nishizawa M. Successful twin pregnancy in a patient with parkin-associated autosomal recessive juvenile parkinsonism. BMC Neurol. 2011;11:72. [PMC free article: PMC3135525] [PubMed: 21682904]
• Shi Y, Whetstine JR. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell. 2007;25:1-14. [PubMed: 17218267]
• Shilatifard A. Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr Opin Cell Biol. 2008;20:341-8. [PMC free article: PMC2504688] [PubMed: 18508253]
• Watanabe T, Matsubara S. Good obstetric outcome in a patient with Segawa disease. Arq Neuropsiquiatr. 2012;70:559-60. [PubMed: 22836471]
• Watanabe T, Matsubara S, Baba Y, Tanaka H, Suzuki T, Suzuki M. Successful management of pregnancy in a patient with Segawa disease: case report and literature review. J Obstet Gynaecol Res. 2009;35:562-4. [PubMed: 19527400]
• Zech M, Boesch S, Maier EM, Borggraefe I, Vill K, Laccone F, Pilshofer V, Ceballos-Baumann A, Alhaddad B, Berutti R, Poewe W, Haack TB, Haslinger B, Strom TM, Winkelmann J. Haploinsufficiency of KMT2B, encoding the lysine-specific histone methyltransferase 2B, results in early-onset generalized dystonia. Am J Hum Genet 2016;99:1377-87. [PMC free article: PMC5142117] [PubMed: 27839873]
• Zech M, Jech R, Havránková P, Fečíková A, Berutti R, Urgošík D, Kemlink D, Strom TM, Roth J, Růžička E, Winkelmann J. KMT2B rare missense variants in generalized dystonia. Mov Disord. 2017a; 32:1087-91. [PubMed: 28520167]
• Zech M, Jech R, Wagner M, Mantel T, Boesch S, Nocker M, Jochim A, Berutti R, Havránková P, Fečíková A, Kemlink D, Roth J, Strom TM, Poewe W, Růžička E, Haslinger B, Winkelmann J. Molecular diversity of combined and complex dystonia: insights from diagnostic exome sequencing. Neurogenetics. 2017b; 18:195-205. [PubMed: 28849312]
• Zhou VW, Goren A, Bernstein BE. Charting histone modifications and the functional organization of mammalian genomes. Nat Rev Genet. 2011;12:7-18. [PubMed: 21116306]
• Ziman N, Coleman RR, Starr PA, Volz M, Marks WJ Jr, Walker HC, Guthrie SL, Ostrem JL. Pregnancy in a series of dystonia patients treated with deep brain stimulation: outcomes and management recommendations. Stereotact Funct Neurosurg. 2016;94:60-5 [PubMed: 26977859]