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.

中文翻译：

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阵发性强直升级：对碳酸酐酶抑制反应的异质临床病症

背景 阵发性强直向上凝视 (PTU)，定义为眼睛的无意识向上运动，被认为是一种良性现象，但也可能与共济失调和发育迟缓有关。方法 我们报告了 8 名患有 PTU 的儿童；其中六人还表现出共济失调和/或发育迟缓的症状。为持续和/或严重形式的儿童提供碳酸酐酶抑制治疗。结果 全外显子组测序和全基因组阵列分析（n = 7）没有揭示与 PTU 相关的三个已知基因（CACNA1A、GRID2、SEPSECS）的突变，而通过 MLPA，CACNA1A 基因的外显子 31 杂合缺失可能在一名患者、她的母亲和另外两名家庭成员身上检测到。进一步的外显子组和阵列分析显示，在一名以上患者中，潜在的新型 PTU 相关基因没有复发变异。在一名患者中检测到 SIM1 基因中高度保守位置的 de novo 变异，可以推测其致病作用。碳酸酐酶抑制作用在 5 名儿童中开始实施，并证明对所有儿童至少部分有效。结论 无论 PTU 的临床背景和分子基础机制如何，治疗性碳酸酐酶抑制对接受这种治疗的所有 5 名儿童（乙酰唑胺，n = 3；舒噻美，n = 2）均有效。碳酸酐酶抑制作用在 5 名儿童中开始实施，并证明对所有儿童至少部分有效。结论 无论 PTU 的临床背景和分子基础机制如何，治疗性碳酸酐酶抑制对接受这种治疗的所有 5 名儿童（乙酰唑胺，n = 3；舒噻美，n = 2）均有效。碳酸酐酶抑制作用在 5 名儿童中开始实施，并证明对所有儿童至少部分有效。结论 无论 PTU 的临床背景和分子基础机制如何，治疗性碳酸酐酶抑制对接受这种治疗的所有 5 名儿童（乙酰唑胺，n = 3；舒噻美，n = 2）均有效。