Objective: To report the case of a young boy suffering from a severe hyperkinetic movement disorder caused by mutations in the recently described TSFM gene.

Background: Very few genes have been identified to cause childhood-onset choreatic movement disorders so far: ADCY5, PDE10a, PDE2a, NKX2.1 and the GNAO1 gene.

Method: We report on the first patient with a complex childhood-onset choreatic movement disorder without structural brain abnormalities caused by compound heterozygous mutations in the TSFM gene.

Results: The patient is the third child of non-consanguineous healthy parents of Crimean descent, was born at term after uneventful gestation and delivery. He showed generalized muscular hypotonia, feeding problems and a global developmental delay. From the age of 2.5 years a progressive generalized hyperkinetic movement disorder developed. Laboratory findings were inconclusive except for elevations of serum lactate (60.7 mg/dl) and pyruvate levels (2.5 mg/dl). MRIs of the brain at the age of five and thirteen years were normal except for signs of progressive bilateral optic atrophy. The additional diagnostic workup showed no signs of a neuropathy, a cardiomyopathy or a sensorineuronal hearing loss. Whole exome sequence analysis demonstrated compound heterozygous mutations in the TSFM gene encoding the mitochondrial translation elongation factor Ts, which was confirmed through Sanger sequencing. While the maternally inherited nonsense mutation (c.919C>T) was published before in 3 patients, the paternal missense mutation (c.161G>A) has not been described before. Pathogenicity of the latter mutation is predicted by various in silico analysis.

Conclusion: Disorders caused by mutations in the TSFM gene have only rarely been described so far with a wide phenotypic spectrum. The most common symptoms were cardiomyopathy and slowly progressive optic atrophy. A movement disorder was found in three of the published twelve patients, however hyperkinesia did not start until late puberty or early adulthood. Notably, the dominating symptom in our patient was a severe chorea since early childhood. In contrast to the other two individuals our patient showed no lesions in the basal ganglia and cerebellum in repeated MRI examinations.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-compound-heterozygous-mutations-in-the-tsfm-gene-causes-childhood-onset-chorea/