4 research outputs found
The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort
Get PDFBackground: 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 HippelLindau 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
