Marco Percetti1, Michela Zini2, Paola Soliveri2, Filippo Cogiamanian3, Mariarosa Ferrara4, Eva Orunesu5, Alessandra Ranghetti2, Carlo Ferrarese6, Gianni Pezzoli2, Barbara Garavaglia7, Ioannis Isaias8, Giorgio Sacilotto2
1School of Medicine and Surgery and Milan Center for Neuroscience, University of Milan-Bicocca, 2Parkinson Institute, ASST Gaetano Pini - CTO, 3Neurophysiopathology Unit, 4Medical Genetics, 5Nuclear Medicine, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 6Department of Neuroscience, University of Milano-Bicocca, 7Medical genetics and Neurogenetics Unit, IRCCS Istituto Neurologico Carlo Besta, 8University of Wurzburg
Objective:
To describe the clinical and genetic findings of a new ANO3 family, and to attempt a genotype-phenotype correlation reviewing all previous published cases of ANO3.
Background:
Mutations in ANO3 are a rare cause of autosomal dominant isolated or combined dystonia, mainly presenting in adulthood.
Design/Methods:
Written informed consent was obtained from all patients. Demographic and clinical data were collected from medical records. A NGS panel including genes associated with dystonia was performed. The terms “ANO3”, “TMEM16C”, “anoctamin 3”, “anoctamin-3”, “DYT-24”, and “DYT-ANO3” were searched in the online database PubMed.
Results:
We extensively characterize a new, large ANO3 family with six affected carriers. The proband is a young girl who had suffered from tremor and painful dystonic movements in her right arm since the age of 11 years. She later developed a diffuse dystonic tremor and mild extrapyramidal signs (i.e., rigidity and hypodiadochokinesis) in her right arm. She also suffered from psychomotor delay and learning difficulties. Repeated structural and functional neuroimaging were unremarkable. A dystonic tremor was also present in her two sisters. Her paternal aunt, father, and a third older sister presented episodic postural tremor in the arms. The father and one sister also presented learning difficulties. The heterozygous p.G6V variant in ANO3 was identified in all affected subjects. By reviewing the previous literature on ANO3, we were able to divide ANO3 cases into two major groups, where younger patients displayed a more severe phenotype, probably due to variants near the scrambling domain.
Conclusions:
We describe the phenotype of a new ANO3 family and highlight the need for functional studies to explore the impact of ANO3 variants on its phospholipid scrambling activity.