Reviewing the Clinical Spectrum Related to KMT2B Gene Mutations: an Unusual Clinical Presentation and a Possible New Pathogenic Mutation: a Case Report

Toro-Pérez, Cristina del; Romero, Jesús Olivares

doi:10.1007/s42399-022-01209-x

Cited by 1 publication

(3 citation statements)

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“…Approximately one hundred KMT2B variants have been reported to date with a wide spectrum of phenotypes, including dystonic and non-dystonic symptoms ( Zech et al, 2016 ; Zech et al, 2019 ; del Toro-Pérez and Romero, 2022 ; Cif et al, 2020 ). KMT2B-related disorders are associated with variable, complex, and often non-specific clinical features that overlap with other neurodevelopmental diseases, making a definitive and early diagnosis challenging ( Sadikovic et al, 2021 ; Smit et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…KMT2B-related dystonia (also known as DYT28, DYT-KMT2B, Dystonia 28) is an autosomal dominant complex childhood-onset movement disorder and is emerging as an important and frequent cause of progressive generalized dystonia ( Gorman et al, 2018 ). With a median age at symptom onset of 7.0 years, the disease course commonly evolves from lower-limb focal dystonia resulting in foot deformity, toe walking, or gait disturbances, into generalized dystonia with prominent cervical, cranial, and laryngeal involvement, resulting in dysphagia and/or dysphonia ( del Toro-Pérez and Romero, 2022 ; Abela and Kurian, 2018 ). Unlike other dystonias, pathogenic variants in KMT2B have also been associated with additional features such as facial dysmorphia (e.g., elongated face with nasal tip) as well as intellectual disability and preceding developmental delay in more than 50% of reported cases ( del Toro-Pérez and Romero, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…Since the first description of KMT2B-related dystonia in 2016, novel disease presentations and heterogeneous phenotypes are being described such as atypical patterns of dystonia evolution and non-dystonic neurodevelopmental phenotypes, as well as varying age of symptom onset ( Zech et al, 2016 ; Zech et al, 2019 ; del Toro-Pérez and Romero, 2022 ; Cif et al, 2020 ). The growing phenotypic variability and broad clinical spectrum have not only presented a diagnostic challenge but have added an additional difficulty for physicians in assuring an early diagnosis of this rare disease ( Cif et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Diagnostic utility of DNA methylation episignature analysis for early diagnosis of KMT2B-related disorders: case report

Bouhamdani,

McConkey,

Leblanc

et al. 2024

Front. Genet.

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The lysine methyltransferase 2B (KMT2B) gene product is important for epigenetic modifications associated with active gene transcription in normal development and in maintaining proper neural function. Pathogenic variants in KMT2B have been associated with childhood-onset Dystonia-28 and Intellectual developmental disorder, autosomal dominant 68 (MRD 68) for cases of neurodevelopmental impairment without dystonia (DYT28; OMIM 617284 and MRD68; OMIM 619934, respectively). Since its first description in 2016, approximately one hundred KMT2B genetic variants have been reported with heterogeneous phenotypes, including atypical patterns of dystonia evolution and non-dystonic neurodevelopmental phenotypes. KMT2B-related disorders share many overlapping phenotypic characteristics with other neurodevelopmental disorders and delayed dystonia, that can appear later in childhood, often delaying clinical diagnosis. Furthermore, conventional genetic testing may not always provide actionable information (e.g., gene panel selection based on early clinical presentation or variants of uncertain significance), which prevents patients and families from obtaining early access to treatments and support. Herein, we describe the early diagnosis of KMT2B-related neurodevelopmental disorder by DNA methylation episignature testing in a 4-year-old patient without features of dystonia at diagnosis, which is reported to develop in more than 80% of KMT2B-related disorder cases. 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. 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.

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