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Letter to the editor
TBC1D2B-Related Neurodevelopmental Disorder With Gingival Overgrowth and Movement Disorders: A Case Series and Literature Review -
Farsana Mustafa1
, Jacky Ganguly2, Ayush Agarwal1
, Sayoni Roy Chowdhury2, Surojit Ruidas3, Ajay Garg3, Debayan Dutta2, Divya M Radhakrishnan1, Hrishikesh Kumar2, Achal Kumar Srivastava1, Divyani Garg1 -
Journal of Movement Disorders 2026;19(3):356-359.
DOI: https://doi.org/10.14802/jmd.26091
Published online: June 30, 2026
1Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
2Department of Neurology, Institute of Neurosciences, Kolkata, India
3Department of Neuroimaging and Interventional Neuroradiology, All India Institute of Medical Sciences, New Delhi, India
- Corresponding author: Divyani Garg, DM, FRCP Department of Neurology, All India Institute of Medical Sciences, Room 705, Cardio Neuro Centre, Ansari Nagar, New Delhi 110029, India / Tel: +91-1126594317 / E-mail: divyanig@gmail.com
- Corresponding author: Ayush Agarwal, DM Department of Neurology, All India Institute of Medical Sciences, Room 705, Cardio Neuro Centre, Ansari Nagar, New Delhi 110029, India / Tel: +91-1126594317 / E-mail: ayushthetaurian@gmail.com
• Received: March 31, 2026 • Revised: June 28, 2026 • Accepted: June 30, 2026
Copyright © 2026 The Korean Movement Disorder Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Dear Editor,
Recent studies have identified that biallelic loss-of-function variants in the TBC1D2B gene [1-3] result in a combination of neurodevelopmental and neurodegenerative traits associated with a distinctive facial appearance and gingival overgrowth [4]. Herein, we report three new patients with TBC1D2B variants, expanding the phenotypic spectrum.
A 22-year-old female, first-born of nonconsanguineous parents, was delivered vaginally and achieved normal early developmental milestones. At the age of 5 years, she underwent surgery for a posterior subcapsular cataract in the left eye. At age 12, she developed progressive imbalance while walking. At age 14, she developed progressive dysarthria and facial freckling. At age 17, she developed progressive hand tremors. On examination, she had facial freckling, coarse facies with a broad nasal bridge, pigmentary retinopathy and gingival overgrowth (Figure 1). Neurological examination revealed scanning speech, macrosaccadic oscillations, gaze-evoked nystagmus, brisk reflexes, an impaired finger-to-nose test, dysdiadochokinesia, impairment on the heel-to-shin test, bilateral upper limb dystonic tremors and an ataxic gait (Supplementary Video 1).
The younger brother of patient 1 was born at term by vaginal delivery and achieved normal developmental milestones. He developed generalized seizures at the age of 5 years, for which he was started on valproic acid. He remained seizure-free for 2 years, after which the drug was tapered and discontinued, without further seizure recurrence. Starting at 10 years of age, he developed mild gait instability. Physical examination at 20 years of age revealed coarse facies and gingival overgrowth (Figure 1). Neurological examination revealed hypometric saccades, saccadic pursuits, mild gait ataxia and brisk reflexes (Supplementary Video 2).
Routine evaluations, including serum alpha fetoprotein levels, lipid profiles, anti-thyroid peroxidase levels, and thyroid profiles, were normal. Spinocerebellar ataxia (SCA) panels, including those for SCAs 1, 2, 3, 6, 7, and 12, and Friedreich’s ataxia testing were negative. The chromosomal microarray (CMA) was normal. Brain MRI revealed bilateral cerebellar atrophy in both siblings as well as subcortical white matter changes in the posterior frontal and parietal regions and a mega-cisterna magna in Patient 1 (Supplementary Figure 1). Whole-exome sequencing (WES) of Patient 1 revealed a homozygous variant (c.8_14 dup, p.Ala6fs*140, NM_144572.2) in exon 1 of TBC1D2B, which was classified as likely pathogenic by American College of Medical Genetics (ACMG) criteria (PVS1, PM2). Sanger sequencing confirmed this variant in a homozygous state in Patient 2 and in a heterozygous state in their mother. The father could not be tested due to his accidental death.
A 17-year-old male patient—born to second-degree consanguineous parents following an uneventful perinatal period—presented with global developmental delay, a 3-year history of progressive gait imbalance and limb posturing, irritability and emotional lability. He experienced recurrent seizures (alternating hemiclonic with postictal limb weakness) at 9 months of age, which were controlled with antiseizure medications (levetiracetam, clobazam). On examination, coarse facial features, strabismus and bilateral horizontal gaze-evoked nystagmus were noted along with scanning speech and dysmetria on the finger-to-nose and heel-to-shin tests (Supplementary Video 3). Dystonic posturing was present in both the upper and lower limbs. Myoclonus was noted in the perioral and lingual regions and upper limb regions. He also demonstrated lower limb spasticity and broad-based and crouched gait. Gingival overgrowth was prominent; notably, an elder sibling, who died with a similar history at 15 years of age, also had gingival overgrowth (Figure 1). Brain MRI revealed prominent Virchow–Robin spaces, cerebellar atrophy and posterior fossa arachnoid cysts (Supplementary Table 1). CMA was normal. WES revealed a homozygous 23-base pair deletion in exon 1 of TBC1D2B (chr15:g.78077549_78077571del; depth: 82x), resulting in a frameshift and premature truncation of the protein 107 amino acids downstream of codon 29 (p.Gly29AlafsTer107; NM_144572.2). The variant was classified as pathogenic according to ACMG criteria (PVS1, PM2, and PP4).
Tre2-Bub2-Cdc16 (TBC) domain-containing Rab-specific GTPase-activating proteins (TBC/RABGAPs) act as key regulators of small Rab GTPases (Rab5, Rab31, Rab22, and Rab7), which collectively play important roles in endosomal trafficking (Supplementary Figure 1) [1]. Pathogenic variants in members of the TBC/RABGAP family have been identified in various neurodevelopmental disorders [3]. TBC1D2B regulates the activities of the small GTPases Rab5, Rab7, and Rab22, which are involved in epithelial-to-mesenchymal transition and E-cadherin internalization. This mechanism may contribute to gingival overgrowth [4]. Establishing a genotype–phenotype correlation in TBC1D2B-related disorders remains challenging because of the pleiotropic effects of pathogenic variants in this gene [4].
We have summarized all reported families to date (Supplementary Table 1), including our patients. Affected individuals may present with either normal or delayed cognitive and motor development. Most individuals develop seizures, as observed in 11/14 reported cases. Gingival overgrowth is another diagnostic clue, noted in 12/14 reported cases, which typically commences during early childhood. Coarse facial features, including mandibular prognathism, mandibular or maxillary fibrous dysplasia and hypertelorism, have been described.
Fundus abnormalities in TBC1D2B-related disorders include optic atrophy, retinal cavitation, and rarely, a retinitis pigmentosa (RP)-like phenotype, which was observed in one of our patients and by Harms et al. [1]. RP has also been linked to pathogenic TBC1D32 variants, which disrupt retinal ciliogenesis [5].
Among the movement abnormalities, gait ataxia and ataxic dysarthria were the most common findings. Other movement features included upper limb dystonia in Patients 1 and 3 as well as action-induced myoclonus, notably involving the lingual and perioral regions, triggered by tasks such as tongue protrusion and speech in Patient 3. Harms et al. [3] reported dystonia and myoclonus in TBC1D2B-related disorders, although detailed movement phenotyping was not available. Perioral and lingual myoclonus has also been described in other neurodevelopmental disorders associated with variants in nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) and dehydrodolichol diphosphate synthetase (DHDDS), which are similarly characterized by prominent epilepsy and ataxia [6]. Although dysmorphic features may be present in these disorders, the absence of gingival overgrowth and cherubism may help distinguish them from TBC1D2B-associated disorders. Interestingly, pathogenic variants in a related group of disorders due to variants in the TBC1D24 gene are linked to a spectrum of disorders ranging from benign infantile and progressive myoclonic epilepsies and epileptic encephalopathies to deafness, onychodystrophy, osteodystrophy, mental retardation and seizures syndrome [7], suggesting shared underlying disease mechanisms.
Our report adds three new cases to the limited body of literature on TBC1D2B-related disorders, reinforcing its role in a distinctive syndromic constellation uniting neurodevelopmental delay, movement disorders, and characteristic craniofacial and gingival features. Recognition of the clinical hallmark of gingival overgrowth in association with ataxia and other movement disorders should prompt consideration of TBC1D2B variants and facilitate early genetic diagnosis, counseling, and multidisciplinary care.
Supplementary Materials
The Data Supplement is available with this article at https://doi.org/10.14802/jmd.26091.
Supplementary Figure 1.
Flowchart showing hypothetical pathogenesis mechanisms leading to gingival fibromatosis, seizure, and epithelial dysplasia due to TBC1D2B mutations.
Supplementary Video 1.
Video of case 1. Segment 1. Scanning speech. Segment 2. Gaze evoked nystagmus, macrosaccadic oscillations. Segment 3. Brisk reflexes. Segment 4. Impaired finger-nose test. Segment 5. Gait ataxia. Segment 6. Dystonia with dystonic tremors in upper limbs.
Supplementary Video 2.
Video of case 2. Segment 1. Hypometric saccades. Segment 2. Mild
impairment in straight-line walking test.
Supplementary Video 3.
Video of case 3. Segment 1 shows cerebellar dysarthria. Segment 2 shows upper limb dysmetria. Segment 3 shows broad-based crouch gait. Segment 4 shows dystonia involving all.
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Ethics Statement
Institutional ethical clearance of All India Institute of Medical Sciences, New Delhi was obtained for this study (IEC #273/16.05.2023, RP-10/23, OP-20/12.01.2024); informed consent was obtained from the participants. We confirm that we have read the journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
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Conflicts of Interest
The authors have no financial conflicts of interest.
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Funding Statement
The study was partially supported by an institutional intramural grant awarded to D.G. (Project code A-977). All other authors report no financial disclosures.
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Acknowledgments
We thank the patients and their families for their kind cooperation.
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Author Contributions
Conceptualization: Divyani Garg. Data curation: Farsana Mustafa, Ayush Agarwal, Jacky Ganguly. Formal analysis: Farsana Mustafa, Divyani Garg. Funding acquisition: Divyani Garg. Investigation: Divyani Garg, Surohit Ruidas, Ajay Garg. Project administration: Divyani Garg. Resources: Achal Kumar Srivastava, Hrishikesh Kumar. Supervision: Divyani Garg, Ayush Agarwal. Validation: Divyani Garg, Ayush Agarwal. Visualization: Farsana Mustafa. Writing—original draft: Farsana Mustafa. Writing—review & editing: Ayush Agarwal, Jacky Ganguly, Sayoni Roy Chowdhury, Surojit Ruidas, Ajay Garg, Debayan Dutta, Divya M Radhakrishnan, Hrishikesh Kumar, Achal Kumar Srivastava, Divyani Garg.
Notes
Figure 1.
Facial (A-G) and MRI features (H-K) of cases. A: Case 1 with coarse facial features, broad nasal bridge and freckles over face. B: Fundus photograph of case 1 showing retinal pigment dystrophy. C: Gingival overgrowth in case 1 (arrows). D: Coarse facial features with a rounded heavy face, prominent brow and broad nasal bridge in case 2. E: Gingival overgrowth in case 2 (arrows). F: Gingival overgrowth in case 3. G: Gum hypertrophy in the elder sibling of case 3, who died with similar history. MRI brain of showing. H: T2/FLAIR axial images with mega cisterna magna in case 1. I: T2/FLAIR axial images with subcortical white matter changes in frontal and parietal white matter in case 1. J: Cerebellar atrophy in case 1. K: MRI brain T2-weighted images of case 3 showing prominent Virchow-Robin spaces, cerebellar atrophy and an arachnoid cyst in the posterior fossa.
- 1. Harms FL, Parthasarathy P, Zorndt D, Alawi M, Fuchs S, Halliday BJ, et al. Biallelic loss-of-function variants in TBC1D2B cause a neurodevelopmental disorder with seizures and gingival overgrowth. Hum Mutat 2020;41:1645–1661.ArticlePubMedPDF
- 2. Correia-Costa GR, de Leeuw N, Pfundt R, Sgardioli IC, Dos Santos AP, de Lima Santos M, et al. Biallelic frameshift variant in the TBC1D2B gene in two siblings with progressive gingival overgrowth, fibrous dysplasia of face, and mental deterioration. Clin Genet 2022;102:537–542.PubMed
- 3. Harms FL, Rexach JE, Efthymiou S, Aynekin B, Per H, Güleç A, et al. Loss of TBC1D2B causes a progressive neurological disorder with gingival overgrowth. Eur J Hum Genet 2024;32:558–566.ArticlePubMedPMCPDF
- 4. Kularbkaew T, Thongmak T, Sandeth P, Daroontum T, Durward CS, Vittayakittipong P, et al. Genetic variants in the TBC1D2B gene are associated with ramon syndrome and hereditary gingival fibromatosis. Int J Mol Sci 2024;25:8867.ArticlePubMedPMC
- 5. Bocquet B, Borday C, Erkilic N, Mamaeva D, Donval A, Masson C, et al. TBC1D32 variants disrupt retinal ciliogenesis and cause retinitis pigmentosa. JCI Insight 2023;8:e169426. ArticlePubMedPMC
- 6. Williams LJ, Waller S, Qiu J, Innes E, Elserafy N, Procopis P, et al. DHDDS and NUS1: a converging pathway and common phenotype. Mov Disord Clin Pract 2024;11:76–85.PubMed
- 7. Balestrini S, Milh M, Castiglioni C, Lüthy K, Finelli MJ, Verstreken P, et al. TBC1D24 genotype-phenotype correlation: epilepsies and other neurologic features. Neurology 2016;87:77–85.ArticlePubMedPMC
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Figure 1. Facial (A-G) and MRI features (H-K) of cases. A: Case 1 with coarse facial features, broad nasal bridge and freckles over face. B: Fundus photograph of case 1 showing retinal pigment dystrophy. C: Gingival overgrowth in case 1 (arrows). D: Coarse facial features with a rounded heavy face, prominent brow and broad nasal bridge in case 2. E: Gingival overgrowth in case 2 (arrows). F: Gingival overgrowth in case 3. G: Gum hypertrophy in the elder sibling of case 3, who died with similar history. MRI brain of showing. H: T2/FLAIR axial images with mega cisterna magna in case 1. I: T2/FLAIR axial images with subcortical white matter changes in frontal and parietal white matter in case 1. J: Cerebellar atrophy in case 1. K: MRI brain T2-weighted images of case 3 showing prominent Virchow-Robin spaces, cerebellar atrophy and an arachnoid cyst in the posterior fossa.
Figure 1.
TBC1D2B-Related Neurodevelopmental Disorder With Gingival Overgrowth and Movement Disorders: A Case Series and Literature Review
