KMDS
E-submission
Articles
- Page Path
- HOME > J Mov Disord > Volume 19(2); 2026 > Article
-
Letter to the editor
Congenital Ataxic Phenotype of ITPR1-Related Disorders Due to Novel Missense Variants: A Video Case Series -
Vikram V. Holla
, Nitish Kamble, Ravi Yadav, Pramod Kumar Pal
-
Journal of Movement Disorders 2026;19(2):217-220.
DOI: https://doi.org/10.14802/jmd.25216
Published online: November 14, 2025
Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India
- Corresponding author: Pramod Kumar Pal, MD, DNB, DM, FRCP Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bengaluru-560029, Karnataka, India / Tel: +91-80-26995147 / E-mail: palpramod@hotmail.com
• Received: August 14, 2025 • Revised: September 22, 2025 • Accepted: November 7, 2025
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.
- 715 Views
- 43 Download
Dear Editor,
Inositol 1,4,5-triphosphate receptor type 1 (ITPR1) genetic abnormalities are known to cause various ataxia phenotypes, such as congenital ataxia with global developmental delay, hypotonia and mild cognitive impairment or spinocerebellar ataxia type-29 (SCA29); adult-onset, slowly progressive, predominantly isolated ataxia or spinocerebellar type 15/16 (SCA15/16); and ataxia with iris hypoplasia, also known as Gillespie syndrome [1-5]. All three phenotypes are relatively rare, and no reports from India exist. We report three cases from two families who were diagnosed with congenital ataxia due to novel heterozygous missense variants in the ITPR1 gene. All three had congenital ataxia with a relatively slow or nonprogressive course.
Case 1 is a 3-year-old girl (Figure 1A) born to nonconsanguineous parents with a normal perinatal history, presenting with motor-predominant global developmental delay from infancy. As the child slowly reached milestones (neck control: 8 months, sitting: 1 year, standing: 24 months, and walking with support: 30 months), the parents noted walking-related imbalance and clumsiness in the hands. The child could speak only a few bisyllables. Otherwise, there was no significant history. On examination, the child was alert and playful and had normal anthropometry, normal pupils and fundi, and gaze-evoked horizontal nystagmus. Hypotonia was noted in all four limbs; however, power, deep-tendon reflexes, and plantar responses were normal. In addition, upper limb incoordination and gait ataxia were noted (Supplementary Video 1). There were no other significant neurological or systemic abnormalities. On evaluation, routine blood investigations, ammonia levels, lactate levels, and blood screening for abnormal metabolites, electroencephalograms, and nerve conduction studies (NCSs) were normal. Magnetic resonance imaging (MRI) of the brain revealed mild isolated cerebellar atrophy (Figure 1B). A novel heterozygous missense variant (NM_001378452.1:c.5063T>G; p.Leu1688Arg) in exon 39 of the ITPR1 gene was identified by whole-exome sequencing (WES). No progression was noted during the last follow-up after 6 months. However, long-term follow-up is warranted to confirm the progression.
Case 2, the mother of the proband (Case 1), had a similar history of motor-predominant global developmental delay noted since infancy. Over time, she reached her milestones but persisted in having mild incoordination in her upper limbs and difficulty walking that was first noted in early childhood. She could perform household activities without support but had difficulty running errands outside. On examination, she had cognitive impairment (Montreal Cognitive Assessment [MoCA] score 23), normal pupils and fundus, horizontal gaze-evoked nystagmus with a downbeating component, mild ataxic dysarthria, and appendicular and gait ataxia (Supplementary Video 2). The results of the remaining neurological and systemic examinations were normal. Blood investigations, electroencephalograms, and NCSs were normal, whereas MRI revealed mild cerebellar atrophy (Figure 1C). WES of the mother revealed the same novel variant (NM_001378452.1:c.5063T>G; p. Leu1688Arg) in a heterozygous state. The pathogenicity of the variant was classified according to the American College of Medical Genetics (ACMG) guidelines. The variant has not been reported in the general population (PM2). A different amino acid at the same locus has been reported in ClinVar (Variant ID: 1204039; p.Leu1688Pro) to be pathogenic (PM5). In silico prediction tools predict that the variant is deleterious (PP3) and that the gene has a low percentage of missense benign variants (PP2). The variant is segregated with disease (PP1). No other genetic variants that could explain the phenotype were identified in either patient. On the basis of this evidence, the variant was classified as likely pathogenic, confirming the diagnosis of congenital ataxic presentation of an ITPR1-related disorder. The family was counseled regarding the illness and the patients were managed with physiotherapy and supportive care.
Case 3 is a 5-year-old boy (Figure 1D) born to nonconsanguineous parents with a normal perinatal and family history who presented with two episodes of seizures at 7 days and 4 years of age. In addition, the child had motor-predominant global developmental delay and was noted to have gait imbalance when the child started walking at 4 years of age. There was no other significant history. On examination, the child was active and playful and had normal anthropometry, pupils and fundus, and horizontal gaze-evoked nystagmus. Hypotonia was noted in all four limbs; however, power, deep tendon reflexes, and plantar responses were normal. In addition, there was appendicular and gait ataxia (Supplementary Video 3). Blood investigations, electroencephalograms, and NCSs were normal upon evaluation. MRI of the brain revealed mild isolated cerebellar atrophy (Figure 1E and F). WES revealed a novel heterozygous missense variant (NM_001378452.1:c.1203C>A; p.Ser401Arg) in exon 15 of the ITPR1 gene. No other genetic variants that could explain the phenotype were identified in the patient. The variant has not been reported in the general population (PM2); in silico prediction tools predict the variant to be deleterious (PP3), and the gene has a low percentage of missense benign variants (PP2). In addition, the variant was de novo, as neither parent carried the variant (PM6). On the basis of this evidence, the variant was classified as likely pathogenic, confirming the diagnosis of congenital ataxic presentation of an ITPR1-related disorder. No progression was noted during the last follow-up after 6 months. However, long-term follow-up is warranted to confirm the progression.
The ITPR1 gene encodes the 1,4,5-triphosphate receptor type 1 (IP3R1) protein, which regulates calcium release from the endoplasmic reticulum. It is densely expressed in Purkinje cells of the cerebellum; therefore, ITPR1 gene abnormalities result in loss of IP3R1 function and disruption of calcium release, leading to cerebellar degeneration [6]. The SCA29 phenotype presents with congenital, relatively nonprogressive ataxia along with motor and speech predominant global developmental delay, often mild to moderate cognitive impairment, and generalized hypotonia in the majority of patients [7]. In addition, patients may have seizures, strabismus, nystagmus, oculomotor apraxia, and poor visual fixation. In the majority of cases, cerebellar atrophy is noted, preferentially involving the superior cerebellar and vermis with relatively preserved supratentorial brain and cortex [8]. In contrast to relatively static clinical features, cerebellar atrophy can progress. Among our patients, Cases 1 and 2 had the classic phenotype of nonprogressive ataxia with developmental delay, cognitive impairment, and generalized hypotonia. However, Case 3 had additional seizures, which are rarely reported in patients with SCA29 [1,2,9]. In one of these reports, the patient had an additional GRIN2A variant that caused the seizures [1]. No other variants that could explain the seizures were identified in our patient.
Studies reported thus far have suggested that missense variants localized to the IP3 binding domain, the coupling-regulatory domain, and the transmembrane domain are the main underlying factors of the SCA29 phenotype [1]. As a consequence, dominant-negative dysregulated calcium channel function occurs [7]. The variants identified in our cohort are also localized to these domains (p.Leu1688Arg in Cases 1 and 2 to the coupling-regulatory domain, and p.Ser401Arg in Case 3 to the IP3 binding domain). In contrast, heterozygous deletions in the ITPR1 gene resulting in haploinsufficiency of ITPR1 are the main underlying mechanism of the allelic disorder SCA15, an adult-onset, slowly progressive, isolated ataxia [4,5]. However, the missense variants responsible for Gillespie syndrome occur predominantly in the C-terminus of the protein, especially in the transmembrane domain [3]. However, cases with phenotypic heterogeneity have been noted within families or from different families despite having the same variant, indicating the presence of additional contributors to the observed phenotypic evolution.
Both the SCA29 and Gillespie syndrome phenotypes are expected to have a very early onset but a relatively nonprogressive course [1]. In contrast, the onset of the SCA15/16 phenotype occurs in adulthood, and the progression of ataxic symptoms can be very slow. Patients are expected to have a near-normal life expectancy and maintain independent ambulation for a very long time, especially those with the SCA15/16 and SCA29 phenotypes. The severity of Gillespie syndrome can vary. The early-onset presentation and the absence of aniridia in all three of our cases, the nonprogressive course, especially in Case 2, and the heterozygous missense variants in the IP3 binding domain and the coupling regulatory domain are more akin to the SCA29 phenotype.
Genetic causes of congenital nonprogressive cerebellar ataxia are highly heterogeneous and involve several key genes with autosomal dominant (SPTBN2, CANCA1A, KCNC3, etc.), autosomal recessive (CA8, WDR81, VLDLR, GRM1, ATP8A2, CWF19L1, PMPCA, etc.), and X-linked (ATP2B3) inheritance patterns [10,11]. In addition, various other causes, such as Joubert syndrome and other hindbrain–cerebellar malformations, ponto- cerebellar hypoplasia disorders, perinatal infections, and other perinatal acquired causes, can result in static to very-slowly progressive congenital ataxias [11].
To conclude, we describe two families with genetically confirmed SCA29 phenotypes of ITPR1-related disorders. In one patient, additional seizures were present, which are infrequently reported in patients with SCA29. In addition, we expand the genotypic spectrum by reporting two novel variants.
Supplementary Materials
The Data Supplement is available with this article at https://doi.org/10.14802/jmd.25216.
Video 1.
Video of the proband of Family 1. The video demonstrates horizontal gaze-evoked nystagmus, ataxia of upper limbs, generalized appendicular hypotonia, and ataxic gait. The video was taken after written informed consent for online publication and dissemination.
Video 2.
Video of the mother of the proband of Family 1. The video demonstrates mild dysarthria, horizontal gaze-evoked nystagmus with a downbeat component, impaired bilateral finger-nose and knee-heel shin tests, ataxic gait, and impaired tandem walking. The video was taken after written informed consent for online publication and dissemination.
Video 3.
Video of the proband of Family 2. The video demonstrates horizontal gaze-evoked nystagmus, ataxic speech, impaired upper limb coordination, and ataxic gait. The video was taken after written informed consent for online publication and dissemination.
-
Ethics Statement
The study was approved by the National Institute of Mental Health and Neurosciences Institute Ethics Committee (No. NIMHANS/3.05/55th IEC (BS & NS DIV.)/2025, and informed consent was obtained from the patients for video recording and publishing in print and online.
-
Conflicts of Interest
The authors have no financial conflicts of interest.
-
Funding Statement
None
-
Acknowledgments
None
-
Author Contributions
Conceptualization: Vikram V. Holla, Pramod Kumar Pal. Data curation: Vikram V. Holla. Formal analysis: Vikram V. Holla. Resources: all authors. Supervision: Nitish Kamble, Ravi Yadav, Pramod Kumar Pal. Writing—original draft: Vikram V. Holla. Writing—review & editing: all authors.
Notes
Figure 1.
Pedigrees and brain MRI findings of the reported cases. A: Pedigree of Family 1. B and C: Brain MRI of proband (B) and her mother (C) showing isolated cerebellar atrophy. D: Pedigree of Family 2. E and F: Brain MRI of proband of Family 2 showing isolated cerebellar atrophy. MRI, magnetic resonance imaging; wt, wild type; +, variant present.
- 1. Zambonin JL, Bellomo A, Ben-Pazi H, Everman DB, Frazer LM, Geraghty MT, et al. Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia. Orphanet J Rare Dis 2017;12:121.PubMedPMC
- 2. Tolonen JP, Parolin Schnekenberg R, McGowan S, Sims D, McEntagart M, Elmslie F, et al. Detailed analysis of ITPR1 missense variants guides diagnostics and therapeutic design. Mov Disord 2024;39:141–151.PubMed
- 3. Ciaccio C, Taddei M, Pantaleoni C, Grisoli M, Di Bella D, Magri S, et al. Phenotypic spectrum and natural history of gillespie syndrome. An updated literature review with 2 new cases. Cerebellum 2024;23:2655–2670.ArticlePubMedPMCPDF
- 4. van de Leemput J, Chandran J, Knight MA, Holtzclaw LA, Scholz S, Cookson MR, et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet 2007;3:e108.ArticlePubMedPMC
- 5. Iwaki A, Kawano Y, Miura S, Shibata H, Matsuse D, Li W, et al. Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16. J Med Genet 2008;45:32–35.ArticlePubMed
- 6. Tada M, Nishizawa M, Onodera O. Roles of inositol 1,4,5-trisphosphate receptors in spinocerebellar ataxias. Neurochem Int 2016;94:1–8.ArticlePubMedPMC
- 7. Huang L, Chardon JW, Carter MT, Friend KL, Dudding TE, Schwartzentruber J, et al. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet J Rare Dis 2012;7:67.ArticlePubMedPMCPDF
- 8. Romaniello R, Pasca L, Panzeri E, D’Abrusco F, Travaglini L, Serpieri V, et al. Superior cerebellar atrophy: an imaging clue to diagnose ITPR1-related disorders. Int J Mol Sci 2022;23:6723.ArticlePubMedPMC
- 9. In Lee J, Choi JY, Yang SS. Discovery of a de novo ITPR1 missense mutation in a patient with early-onset cerebellar ataxia: a rare case report of spinocerebellar ataxia 29. Mol Genet Genomic Med 2024;12:e2466.PubMedPMC
- 10. Brandsma R, Verschuuren-Bemelmans CC, Amrom D, Barisic N, Baxter P, Bertini E, et al. A clinical diagnostic algorithm for early onset cerebellar ataxia. Eur J Paediatr Neurol 2019;23:692–706.ArticlePubMed
- 11. Bertini E, Zanni G, Boltshauser E. Nonprogressive congenital ataxias. Handb Clin Neurol 2018;155:91–103.PubMed
REFERENCES
Figure & Data
References
Citations
Citations to this article as recorded by 
Comments on this article
PubReader
ePub Link
Cite
XML DownloadCongenital Ataxic Phenotype of ITPR1-Related Disorders Due to Novel Missense Variants: A Video Case Series
Figure 1. Pedigrees and brain MRI findings of the reported cases. A: Pedigree of Family 1. B and C: Brain MRI of proband (B) and her mother (C) showing isolated cerebellar atrophy. D: Pedigree of Family 2. E and F: Brain MRI of proband of Family 2 showing isolated cerebellar atrophy. MRI, magnetic resonance imaging; wt, wild type; +, variant present.
Figure 1.
Congenital Ataxic Phenotype of ITPR1-Related Disorders Due to Novel Missense Variants: A Video Case Series
