Paroxysmal tonic upgaze: A heterogeneous clinical condition responsive to carbonic anhydrase inhibition

Background: Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay.

Methods: We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms.

Results: Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them.

Conclusion: Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment.