Hereditary Truncal Dystonia Associated with ANO3 Gene Variant

Camptocormia is characterized by forward spine flexion of 45 degrees or more in the upright position that reverses when laying down and is not associated with fixed deformities.1 It is more common in males (58%) with a mean age at diagnosis of 68.6 years.1 As for Pisa syndrome, it consists of a postural abnormality characterized by trunk flexion in the coronal plane that improves in supine position.2 A wide array of causes has been linked to camptocormia such as idiopathic Parkinson's disease (22.5% of camptocormia patients), axial myopathy (14.1%) and degenerative joint disease (13.0%).1 It can also be noticed in up to 32% of patients with multiple systems atrophy (MSA).2 Up to 8% of patients have positive family history. In such cases, underlying diseases are usually facioscapulohumeral muscular dystrophy, myotonic dystrophy, idiopathic axial myopathy or calpainopathy.1 With regards to Pisa syndrome, it is associated with Parkinson's disease, MSA, subdural hematoma, and normal pressure hydrocephalus.2 It can be found in 1.9% of Parkinson's disease patients and 42% of those with MSA.2 Here, we describe a novel phenotype of ANO3 variant causing truncal dystonia. A 67-year-old woman presented with flexion of the thoracolumbar spine that started 7 years before consultation. She developed lumbar pain and was diagnosed with fractures of the body of S1 and the left ischiopubic bone 2 years prior. Past medical history was remarkable for primary hyperparathyroidism. The patient's family originated from Hokkaido, Japan and her paternal grandmother and father had a history of late onset camptocormia. Furthermore, her sister was diagnosed with cranial and lower limbs dystonia at age 61 (Fig. 1A). She did not present complaints compatible with bladder dysfunction or orthostatic hypotension. Neurological examination showed camptocormia and Pisa syndrome (Fig. 1B, Video 1). There was no cognitive impairment, bradykinesia, rigidity, tremor or postural instability. Muscle tonus, strength, osteotendinous reflexes, and sensibility were normal. Laboratory tests, including serum creatinine phosphokinase, were unremarkable. Electromyography of the thoracolumbar paraspinal region evidenced co-contraction of antagonist muscles, confirming axial dystonia. Musculoskeletal magnetic resonance imaging showed scoliosis, hypotrophy and fatty replacement of the paravertebral muscles. Whole exome sequencing (WES) identified a likely pathogenic heterozygous variant in the anoctamin 3 gene (ANO3) gene [NM_031418.4: c.1942A > G,p(Asn648Asp)]. Her symptomatic sister was found to carry the same variant by WES and sequencing of her asymptomatic mother was negative. According to The American College of Medical Genetics and Genomics (ACMG) guidelines, the ANO3 variant was classified as "likely pathogenic" (evidence: PM2, PM5, PP1 and PP3) (Table S1).3 The WES filtering strategy included: variant allele frequency above 0.20, allele balance between 0.20 and 0.80, depth above 10 bases, population allele frequency lower than 1% (0.01), and phenotype (dystonia, parkinsonism). Quality parameters were average number of reads of 129x, number of reads above 20x was 99.37%. No other variants of interest were found. The proband and her sister were both sequenced (WES). Dystonia 24 consists of a monogenic autosomal dominant dystonia caused by pathogenic variants of the ANO3 gene.3 Said gene is located on the short arm of chromosome 11 and encodes a Ca2+-gated chloride channel (CaCC).3 It has been demonstrated that ANO3 does not have ion channel activity and interacts with sodium activated potassium channels, which are related to regulation of resting membrane potential.4 Moreover, Charlesworth et al identified that the ANO3 mRNA is highly expressed in the striatum.5 Therefore, it seems reasonable to propose that pathogenic ANO3 variants could change neuronal excitability and neurotransmission in the striatum, hampering proper functionality of the basal ganglia circuitry and promoting the dystonic manifestations associated with camptocormia and Pisa syndrome.5 With regards to clinical manifestation, Charlesworth et al described the association of craniocervical dystonia with ANO3 variants.5, 6 Even though it is still the most commonly observed presentation, distinct phenotypical characteristics have been associated with newly described variants of the ANO3.6, 7 ANO3 variants can also present with limb, laryngeal, and generalized dystonia, as well as myoclonic jerks and tremor.7 The age of onset is also dependent on the genetic variations and ranges from childhood to the sixth decade of life.7 Moreover, Ramito et al reported a patient with childhood-onset chorea that later progressed into a dystonia-dominant phenotype.7 Furthermore, the presentation of choreiform movements with psychiatric symptoms has also been documented.8 Finally, Percetti et al described ANO3-related extrapyramidal signs such as limb rigidity and hypodiadochokinesis, as well as developmental delay and learning disability.9 Concerning the phenotype of carriers of other variants, there is a report of p.Asn648Ser with myoclonus-dystonia.10 On the anoctamin domain, other variants were associated with late-onset craniocervical dystonia (p.Trp490Cys, p.Ser685Gly, p.Lys862Asn), and early-onset generalized dystonia (p.Glu510Lys; p.Ser651Asn).5 Our findings broaden the phenotypic spectrum of ANO3 by adding truncal dystonia. After excluding the most common aetiologies, such as idiopathic Parkinson's disease, axial myopathy and degenerative joint disease, genetic testing should be considered for patients with truncal dystonia and a positive family history. (1) Case report project: A. Conception, B. Organization, C. Execution; (2) Data collection: A. Case Report; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. S.M.G.: 1A, 1B, 1C, 2A, 3A J.V.G.T.: 1A, 1B, 1C, 2A, 3A J.B.O.: 1A, 1B, 2A T.Y.T.S.: 1A, 1B, 1C, 2A, 3B J.L.P.: 1A, 1B, 1C, 2A, 3A, 3B O.G.P.B.: 1A, 1B, 1C, 2A, 3B Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. Informed consent was obtained. 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 Conflict of Interest: No specific funding was received for this work. We declare no conflicts of interest for this work. Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. Data sharing is not applicable to this article as no new data were created or analyzed in this study. Supplemental Table S1. Strategy and quality metrics for the exome data. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.