Failure to thrive - an overlooked manifestation of KMT2B-related dystonia: a case presentation

Abstract

Background: KMT2B-related dystonia is a recently described form of childhood onset dystonia that may improve with deep brain stimulation. Prior reports have focused on neurologic features including prominent bulbar involvement without detailing general health consequences that may result from orolingual dysfunction. We describe a family with novel KMT2B mutation with several members with failure to thrive to highlight this nonneurologic, but consequential impact of mutation in this gene. Case presentation: We present a case of a 15-year old female who was admitted and evaluated for failure to thrive. On exam, she had severe speech dysfluency, limited ability to protrude the tongue, and generalized dystonia involving the oromandibular region, right upper and left lower extremity with left foot inversion contracture. The proband and her parents underwent whole genome sequencing. A previously undescribed variant, c.4960 T > C (p.Cys1654Arg), was identified in the KMT2B gene in the proband and mother, and this variant was subsequently confirmed in two maternal cousins, one with failure to thrive. Literature review identified frequent reports of prominent bulbar involvement but failure to thrive is rarely mentioned. Conclusion: Failure to thrive is a common pediatric clinical condition that has consequences for growth and development. In the presence of an abnormal neurologic exam, a search for a specific underlying genetic etiology should be pursued. With this case series, we highlight an unusual potentially treatable cause of failure to thrive, reinforce the importance of precise molecular diagnosis for patients with failure to thrive and an abnormal neurologic exam, and underscore the importance of cascade screening of family members.

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

“…In fact, Cif et al, 2020 identified nine patients harboring pathogenic KMT2B variants, in whom no dystonic features developed at time of assessment (median age 11.8 years with a range from 2.2–57.0 years). Additional features related to KMT2B variants have been documented such as failure to thrive, renal involvement, retinal dystrophy, oculomotor abnormalities like impaired saccades and strabismus, skin changes like cutis aplasia, and additional psychiatric comorbidities such as ADHD, anxiety, depression, and obsessive-compulsive disorder ( Abela and Kurian, 2018 ; Ng et al, 2020 ). There have also been reports of myoclonus, seizures, spasticity, and sensorineural hearing loss ( Meyer et al, 2017 ; Abela and Kurian, 2018 ; Zech et al, 2019 ; Owczarzak et al, 2022 ).…”

KMT2B-Related Dystonia in Indian Patients With Literature Review and Emphasis on Asian Cohort

“…Since that publication, there has been a further expansion of the literature with 18 scientific papers, comprising 60 additional patients with pathogenic, likely pathogenic or VUSs. 5,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] A single report of a synonymous variant leading to the generation of a premature stop codon resulting in early-onset dystonia has also been published. 8 In contrast to the world literature, the most common mutations www.e-jmd.org 291 in the KMT2B gene in our study cohort were missense mutations (n = 5), followed by two PTVs (Table 2, Supplementary Tables 3 and 4 in the online-only Data Supplement).…”

Adult‐Onset KMT2B‐Related Dystonia Responsive to Deep Brain Stimulation

“…Only one other family has been described with KMT2Brelated dystonia due to this exact mutation. 4 PolyPhen and SIFT analysis predict this variant's pathogenicity. This allele is not found in the gnomAD database.…”