Background

We aimed to expand the number of currently known pathogenic PNKP mutations, to study the phenotypic spectrum, including radiological characteristics and genotype-phenotype correlations, and to assess whether immunodeficiency and increased cancer risk are part of the DNA repair disorder caused by mutations in the PNKP gene.

Methods

We evaluated nine patients with PNKP mutations. A neurological history and examination was obtained. All patients had undergone neuroimaging and genetic testing as part of the prior diagnostic process. Laboratory measurements included potential biomarkers, and, in the context of a DNA repair disorder, we performed a detailed immunologic evaluation, including B cell repertoire analysis.

Results

We identified three new mutations in the PNKP gene and confirm the phenotypic spectrum of PNKP-associated disease, ranging from microcephaly, seizures, and developmental delay to ataxia with oculomotor apraxia type 4. Irrespective of the phenotype, alpha-fetoprotein is a biochemical marker and increases with age and progression of the disease. On neuroimaging, (progressive) cerebellar atrophy was a universal feature. No clinical signs of immunodeficiency were present, and immunologic assessment was unremarkable. One patient developed cancer, but this was attributed to a concurrent von Hippel-Lindau mutation.

Conclusions

Immunodeficiency and cancer predisposition do not appear to be part of PNKP-associated disease, contrasting many other DNA repair disorders. Furthermore, our study illustrates that the previously described syndromes microcephaly, seizures, and developmental delay, and ataxia with oculomotor apraxia type 4, represent the extremes of an overlapping spectrum of disease. Cerebellar atrophy and elevated serum alpha-fetoprotein levels are early diagnostic findings across the entire phenotypical spectrum.

中文翻译：

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荷兰队列中 PNKP 相关疾病的表型谱以及不存在免疫缺陷和癌症倾向

背景

我们旨在扩大目前已知的致病性PNKP突变的数量，研究表型谱，包括放射学特征和基因型-表型相关性，并评估免疫缺陷和癌症风险增加是否是PNKP突变引起的 DNA 修复障碍的一部分基因。

方法

我们评估了 9 名PNKP突变患者。获得了神经病史和检查。作为先前诊断过程的一部分，所有患者都接受了神经影像学和基因检测。实验室测量包括潜在的生物标志物，并且在 DNA 修复障碍的背景下，我们进行了详细的免疫学评估，包括 B 细胞库分析。

结果

我们确定了PNKP基因中的三个新突变，并确认了PNKP相关疾病的表型谱，从小头畸形、癫痫发作和发育迟缓到 4 型动眼神经失用症的共济失调。无论表型如何，甲胎蛋白都是一种生化标志物和随着年龄和疾病的进展而增加。在神经影像学上，（进行性）小脑萎缩是一个普遍特征。不存在免疫缺陷的临床体征，免疫学评估不显着。一名患者患上了癌症，但这归因于同时发生的 von Hippel-Lindau 突变。

结论

与许多其他 DNA 修复障碍相比，免疫缺陷和癌症易感性似乎不是PNKP相关疾病的一部分。此外，我们的研究表明，先前描述的小头畸形、癫痫和发育迟缓以及 4 型动眼神经失用症共济失调代表了疾病谱重叠的极端情况。小脑萎缩和血清甲胎蛋白水平升高是整个表型谱的早期诊断结果。