Dear Sir, Paroxysmal dyskinesias (PxDs) are a group of heterogeneous hyperkinetic disorders characterised by paroxysms of dystonia, chorea, or ballism, with preserved consciousness. PxDs are classified into four types based on the duration and frequency of paroxysms, as well as associated triggers. 1 They often occur in childhood or adolescence. Late-onset occurrences after 20 years of age are rare and typically do not typically fit into the prototypical phenotypic categories mentioned above. PxDs may also be idiopathic (familial or sporadic), but a meticulous workup for secondary and functional causes is mandatory. 2 Various genetic associations with PxDs have been noted since 2004. With advancements in the fields of genetics and genomics, new genotype–phenotype variations are frequently identified and reported. 3, 4 Here, we present a case of late-onset PxDs in whom a novel ANO3 variant of uncertain significance was identified. A 52-year-old male initially presented elsewhere with a 4-year history of low back pain radiating to both lower limbs, associated with tingling and numbness. He was subsequently diagnosed with L5–S1 spondylolisthesis and was treated conservatively. Six months later, he developed an unsteady gait, characterised by intermittent buckling of the knee and a tendency to fall forward after walking a distance. Eight months later, he underwent transforaminal lumbar interbody fusion spine surgery for spondylolisthesis due to increased episodes of falls, which made it difficult for him to walk long distances. Postoperatively, he continued to experience persistent episodes of unsteadiness and falls while walking, with no worsening of symptoms. Later, he also reported involuntary eyelid closure, triggered by exposure to light, suggestive of blepharospasm. Past history revealed that he was hypertensive and had a history of migraine headaches and motor tics since the age of 12. Ten months ago, he developed intermittent episodes of shortness of breath with hyperventilation, which were evaluated. He underwent a left hemithyroidectomy, which showed no evidence of malignancy, and his autoimmune and paraneoplastic panel workup was negative. Family history was strongly positive for similar hyperkinetic disorders Figure 1, Table 1. On clinical examination, general findings were normal. Neurological examination revealed paroxysms of dystonia involving the trunk, bilateral hips, and knees, with adduction of the legs during walking. These episodes could be induced by a provocation manoeuvre. He had bilateral upper limb postural and intentional tremors. He also exhibited motor tics involving the eyebrows and shoulders, along with bilateral blepharospasm Video 1. The rest of the neurological examination was normal. Figure 1: Pedigree of the probandTable 1: Affected family members and their phenotypic characteristics "href": "Single Video Player", "role": "media-player-id", "content-type": "play-in-place", "position": "float", "orientation": "portrait", "label": "Video 1", "caption": "", "object-id": {"pub-id-type": "doi", "id": "", "pub-id-type": "other", "content-type": "media-stream-id", "id": "1₀bl94rew", "pub-id-type": "other", "content-type": "media-source", "id": "Kaltura"} Given the late-onset paroxysmal movements, a comprehensive workup for secondary causes such as Wilson’s disease, hyperparathyroidism, diabetes, and infections was performed and found to be negative. Blood parameters, including electrolytes, liver function tests, thyroid profile, and blood glucose, were all within normal ranges. Given the strong family history and a negative workup for secondary causes, whole exome sequencing was performed, and a novel heterozygous missense variant in exon 21 of ANO3 (ENST00000256737. 8: c. 2459G>A; p. Gly820Asp) was identified. This variant was predicted to be “probably damaging” by PolyPhen-2, “damaging” by Sorting Intolerant From Tolerant (SIFT), and pathogenic according to long terminal repeat analysis. MutationTaster2 classified it as disease-causing, and it had a Combined Annotation Dependent Depletion score of 31, a rare exome variant ensemble learner (REVEL) score of 0. 64, and an Evolutionary Model of Variant Effect score of 0. 81 (PP2). Additionally, individual III-2, who presented with similar symptoms, tested positive for the same ANO3 heterozygous missense variant (PP1). Unfortunately, further testing of other family members was not possible due to personal reasons. Importantly, this variant has not been reported in databases such as gnomAD and has a minor allele frequency of less than 0. 001% (PM2). Genetic testing did not reveal any other variants known to cause dystonia, and while the phenotype has been partially described in patients carrying the ANO3 variant (PP4), 5 the overall classification of this variant remains uncertain (PM2, PP1, PP3, PP4). With a diagnosis of PxD, he was started on carbamazepine, which led to a moderate reduction in the frequency and severity of his episodes of buckling and falls. Later, he was also prescribed baclofen and tetrabenazine. He received botulinum toxin for blepharospasm, which showed a convincing response. PxDs are a group of neurological disorders characterized by episodes of dystonia, chorea, ballism, or a combination of these. Our understanding of the disease has advanced through the proposed classification of PxDs by Erro and colleagues, which consists of Axis 1 (clinical features) and Axis 2 (genetic determinants). 6 PxDs may be isolated or part of complex disorders associated with migraine, epilepsy, episodic ataxias, and periodic paralysis. Although individual reports have shown an association between tics, PxDs and ANO3 variants, we remain uncertain whether the occurrence of tics and PxD in our proband family is related to the identified novel ANO3 variant. 7-9 Hence, in our current report, we classified the condition as a late-onset complex mixed paroxysmal disorder, due to the association of paroxysms with migraine. The underlying pathophysiology of PxDs is attributed to abnormalities in the basal ganglia–thalamocortical circuits. 10 Causative variants lead to neuronal dysfunction through several mechanisms, including synaptopathies (PRRT2, PNKD, TBC1D24), transportopathies (SLC2A1, ATP7B, SLC16A2), channelopathies (ADCY5, PDE10A, PDE2A), second-messenger-related disorders (SCN8A, KCNMA1, ATP1A3, KCNA1, CLCN2, CHRNA4), mitochondrial causes (SACS, POLG, DLAT, PDHA1, PDHX, BCKDHB, ECHS1, HIBCH, PRKN), and miscellaneous causes (DEPDC5, GCH1, SLC20A2, PDGFB, MYORG, XPR1, HTT, ABAT, HPRT1) of PxDs. 3 The literature also describes isolated cases of PxDs caused by novel variants with different phenotypic associations. 3, 11 The ANO3 variant encodes the anoctamin-3 (TMEM16C) protein, which forms phospholipid scramblases and calcium-activated chloride channels. These channels are highly expressed in the striatum, cortex, hippocampus, and dorsal root ganglia. 12ANO3 variants most commonly cause cranio-cervical dystonia in adults. A case series report by Ousingsawat J et al. 5 provided evidence of paroxysmal dystonia associated with ANO3 in one patient. The authors stated that the ANO3 variant altered calcium signalling and the function of calcium-dependent potassium channels, impairing neuronal excitability, which might have contributed to paroxysmal dystonia. We hypothesised that similar pathogenic mechanisms might be associated with the occurrence of PxD in our case. A limitation of this report is the lack of a complete segregation analysis, which might help elucidate the pattern of inheritance. This report highlights a possible association between the novel ANO3: c. 2459G>A variant and late onset PxD in our patient. Further linkage analysis and functional studies would help in dissecting the presence or absence of this association. Acknowledgement We thank the patient and the patient’s family for their cooperation. Author contribution: A. Research project: Conception: Madhavi Karri, Rukmini M. Kandadai, Rupam Borgohain, Sruthi Kola, Rajesh Alugolu, VVSRK Prasad Organization: Madhavi Karri Execution: B. Statistical analysis: Design: Execution: Review and Critique: Rukmini M. Kandadai, Rupam Borgohain, Sruthi Kola, Rajesh Alugolu, VVSRK Prasad C. Manuscript preparation: Writing of the first draft: Madhavi Karri Review and Critique: Madhavi Karri, Rukmini M. Kandadai, Rupam Borgohain, Sruthi Kola, Rajesh Alugolu, VVSRK Prasad Ethical compliance statement The authors confirm that this work did not require ethical approval from the institutional review board. Verbal and written consent was obtained from the patient to publish this case study. 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. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Karri et al. (Thu,) studied this question.