A Novel Homozygous TSPOAP1 Variant in an Indian Patient Causing Childhood‐Onset Generalized Dystonia with Cerebellar Atrophy

Childhood-onset isolated generalized dystonia frequently have a genetic underpinning. While autosomal dominant forms like DYT-TOR1A, DYT-THAP1 are well recognized, several autosomal recessive causes—including DYT-HPCA, and DYT-AOPEP—have increasingly been reported. A 19-year-old Indian female born of a non-consanguineous marriage with a normal birth and perinatal transition presented with progressive posturing of both limbs and trunk since the age of 5 years. She noticed posturing of her left foot while walking at the age of 5 years, followed by progressive twisting of her left upper and lower limbs and opisthotonic posturing during ambulation at 14 years of age, causing recurrent falls. Her speech became dysarthric from the age of 14 and has progressively worsened, leading to complete anarthria by the age of 18 years. She also noted dysphagia to solids and liquids since 17 years age. She noticed episodic (1–2 episodes per year), intense, painful dystonic spasms in both her legs lasting a few days, leading to increased difficulty in walking from the age of 14 years. These episodes were triggered by bouts of fever or stress. She required assisted ambulation since 17 years of age and currently she is partially dependent for her daily activities, requiring wall support or one-person support to walk. Neither the patient nor the family reports any sleep benefit. She does not have any history of vision or hearing abnormality, seizure or any other movement disorders. There is no history of learning difficulty or cognitive decline. No family history of similar complaints. Clinical examination showed facial dysmorphism, hypodontia, severe dysarthria, retrocollis, tongue dystonia and generalized dystonia with dystonic “dromedary” gait (Video 1). Her extraocular movements and tendon jerks were normal. Her BFMDRS (Burke-Fahn Marsden dystonia rating scale) score (Motor) was 98 out of 120. Initial workup, including copper studies, plasma lactate, ammonia, and routine biochemical parameters, was normal. MRI Brain showed subtle iron deposition in both globus pallidus and mild cerebellar atrophy (Fig. 1). Her whole exome sequencing revealed a homozygous single base pair deletion in exon 5 of the TSPOAP1 gene (c.887del; Depth: 79x) that was classified as likely pathogenic (PVS1, PM2) as per ACMG criteria. This variant results in a frameshift mutation and premature truncation of the protein 31 amino acids downstream to codon 296 (p.Pro296ArgfsTer31), and the reference region is conserved across mammals. She was treated with antidystonia medications like trihexyphenidyl (8 mg/day), baclofen (30 mg/day) and Inj Botulinum Toxin (BonT-A) was given in bilateral splenius capitis (120 units each) and bilateral trapezius (40 units each) for retrocollis. Deep Brain Stimulation could not be done due to financial constraints. This is the third case reported from India1 and fewer than 10 patients have been reported worldwide. Abnormal neuronal synaptic transmission (synaptopathy), causing dysfunctional motor circuitry, is one of the proposed pathophysiology of dystonia.2TSPOAP1 has recently been identified as a causative gene for autosomal recessive isolated dystonia (DYT22). The TSPOAP1 gene encodes RIM-binding protein 1 (RIMBP1), which plays a crucial role in organizing and anchoring voltage-gated calcium channels (VGCC) at the presynaptic membrane, thereby facilitating precise temporal coupling between incoming action potentials, calcium influx, and synaptic vesicle exocytosis. Loss-of-function variants of TSPOAP1 reduce VGCC density at the active zone, decreasing presynaptic action potential amplitude, and missense variants increase VGCC synaptic density, leading to increased presynaptic Ca2+ spikes, both of which are detrimental and contribute to the pathophysiology of dystonia. Mencacci et al reported seven patients from three families: two families (Families A and B) carried truncating variants (c.538delG; p.Ala180Profs*8 and c.2449_2450delinsTG; p.Gln817Ter), while the third family (Family C) harbored a missense variant (c.5422G>A; p.Gly1808Ser).3 Furthermore, Hasani et al described one patient4 and Holla et al described two patients with truncating variants (c.1783C > T (p.Arg595Ter)), c.3172dup(p.Arg1058Profs*119).1 Clinically, homozygous truncating variants cause childhood onset isolated severe progressive generalized dystonia with prominent dysphonia, dysarthria, laryngeal dystonia, along with upper limb dystonia, truncal dystonia and foot dystonia with dystonic gait. They can occasionally demonstrate cerebellar signs like square wave jerks, pendular horizontal nystagmus, and intention tremor, with MRI showing cerebellar atrophy. They often have learning disability in childhood with progressive cognitive decline and seizure.3 Dental abnormalities have not been reported yet in this genotype. Dystonia with hypodontia is commonly seen in POLR3A, POLR3B and POLR1C gene variants.5 Interestingly, episodic dystonic spasms involving limbs or trunk precipitated by walking or stressful activities were noted in three patients.1, 3 In contrast, the patients with homozygous missense variants usually show a milder phenotype with adult-onset isolated focal/segmental dystonia, mainly upper limb or cervical dystonia with dystonic tremor. They usually do not have lower limb dystonia, dystonic gait or cerebellar signs. MRI is normal in these patients.3 One patient had a remarkable response to deep brain stimulation.4 Cerebellar atrophy was reported in most patients (6/9) with or without clinical cerebellar signs.3 Dystonia with cerebellar atrophy can also be seen in mutations in a few other genes, such as PLA2G6, ATM and NPC1.6 Our case broadens the expanding genetic landscape of dystonia and reinforces DYT-TSPOAP1 as an important, yet under-recognized cause of childhood-onset generalized dystonia. The presence of hypodontia, paroxysmal painful dystonic spasms, and mild cerebellar atrophy on MRI represents novel phenotypic clues that may aid earlier genotype suspicion. These observations underscore the need to retrospectively re-evaluate patients with a matching phenotype who were deemed “idiopathic” at the time of their diagnosis. Moreover, we need to test for the missense variants of TSPOAP1 in adult-onset isolated focal dystonia, a group in whom genetic testing is traditionally of low yield. (1)Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. D.D.: 1B, 1C, 2B, 3A J.G.: 1B, 2A, 2C, 3B R.K.: 1C, 2B G.S.: 1C, 2B P.B.: 1C, 2B H.K.: 1A, 1B, 2C, 3B Ethical Compliance Statement: Institutional review board approval was not required for this work. Written informed patient consent was taken for this work and documented. 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. Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest for this study. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. Author disclosures are available in the Supporting Information. 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