Compound heterozygous mutations in three Chinese patients of Segawa syndrome and their treatment outcomes

Abstract Segawa syndrome is a rare autosomal recessive form of dopa‐responsive dystonia resulting from TH gene dysfunction. Patients typically exhibit symptoms such as generalized dystonia, rigidity, tremors, infantile Parkinsonism, and pseudo‐spastic paraplegia. Levodopa is often an effective treatment. Due to its rarity, high heterogeneity, and poorly understood pathological mutation and phenotype spectrums, as well as genotype–phenotype and genotype‐treatment outcome correlations, Segawa syndrome poses diagnostic and therapeutic challenges. In our study, through clinical and molecular analyses of three Chinese Segawa patients, we re‐evaluated the pathogenicity of a TH mutation (c.880G>C;p.G294R) previously categorized as “Conflicting classifications of pathogenicity” in ClinVar. Also, we summarized the clinical phenotypes of all reported Segawa syndrome cases until 2023 and compared them with our patients. We identified a novel phenotype, “cafe‐au‐lait macules,” not previously observed in Segawa patients. Additionally, we discussed the correlation between specific genotypes and phenotypes, as well as genotypes and treatment outcomes of our three cases. Our findings aim to enhance the understanding of Segawa syndrome, contributing to improved diagnosis and treatment approaches in the future.