Objective: Delineation of phenotypic diversity of DYT-ANO3 in a large tribal family of Indian origin.
Background: DYT-ANO3 (DYT24) is a rare cause of autosomal dominant isolated or combined dystonia, age of onset varying from childhood to middle age. It commonly presents with cranio-cervical involvement with or without dystonic tremor. Other reported phenotypes include myoclonus-dystonia, non-dystonic tremor, lower limb dystonia, parkinsonism and chorea [1-3].
Method: We assessed the index patient in the movement disorder clinic at Institute of Neurosciences Kolkata (I-NK). Clinical assessment and blood sample collection of the other affected members [Figure 1] were done by visiting a remote coastal village near Porbandar district, Gujarat, in the westernmost part of India [Figure 2].
Results: Out of these 14 patients with DYT-ANO3 (7 males and 7 females), the mean age of onset was 26.92 ± 11.71 years. Segmental dystonia involving the neck and upper limbs along with dystonic tremor was the commonest phenotype (n=6, 42.85%), followed by isolated cervical dystonia with dystonic tremor (n=5, 35.71%) [Figure 3]. Myoclonus-dystonia phenotype was observed in 3 of them (21.42%) [Figure 4]. Speech was involved in 4, because of laryngeal dystonia (n=2) and voice tremor (n=2). Other associated clinical findings were mild parkinsonism (n=3) and generalized chorea (n=1). Isolated dystonic tremor in the upper limbs was seen in 3 patients (21.42%), while non-dystonic foot tremor was noted in 1 patient. Conjunctival and scleral telangiectasia and vessel tortuosity were present in all of them [Figure 5].
Whole exome sequencing of the index patient revealed a novel heterozygous 3 base pair insertion in exon 17 of the ANO3gene (c.1796_1798dup) on chromosome 11 resulting in an in-frame insertion of amino acid Alanine at codon 599 (p.Ala599dup). Sanger sequencing of the other 13 affected members confirmed the segregation of this same variant in a heterozygous state.
Conclusion: We have documented the largest family of DYT-ANO3 reported so far with a novel variant. The overlapping phenotypic spectrum includes segmental dystonia, isolated cervical dystonia, dystonic tremor in upper limbs, myoclonus-dystonia, non-dystonic tremor, parkinsonism and chorea. Conjunctival and scleral telangiectasia and vessel tortuosity were unique findings in our case series.
References: [1] Percetti M, Zini M, Soliveri P, Cogiamanian F, Ferrara M, Orunesu E, Ranghetti A, Ferrarese C, Pezzoli G, Garavaglia B, Isaias IU, Sacilotto G. The Clinical Spectrum of ANO3-Report of a New Family and Literature Review. Mov Disord Clin Pract. 2024 Jan 29. doi: 10.1002/mdc3.13979
[2] Carvalho V, Martins J, Correia F, Costa M, Massano J, Temudo T. Another Twist in the Tale: Intrafamilial Phenotypic Heterogeneity in ANO3-Related Dystonia. Mov Disord Clin Pract. 2021 Apr 23;8(5):758-762. doi: 10.1002/mdc3.13209
[3] Stamelou M, Charlesworth G, Cordivari C, Schneider SA, Kägi G, Sheerin UM, Rubio-Agusti I, Batla A, Houlden H, Wood NW, Bhatia KP. The phenotypic spectrum of DYT24 due to ANO3 mutations. Mov Disord. 2014 Jun;29(7):928-34. doi: 10.1002/mds.25802
To cite this abstract in AMA style:
J. Ganguly, N. Sarmah, A. Rawool, H. Kumar. Intrafamilial phenotypic variability of DYT-ANO3: Analyzing 14 affected members with a novel variant [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/intrafamilial-phenotypic-variability-of-dyt-ano3-analyzing-14-affected-members-with-a-novel-variant/. Accessed October 15, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/intrafamilial-phenotypic-variability-of-dyt-ano3-analyzing-14-affected-members-with-a-novel-variant/