Microcephaly, seizures and developmental delay caused by two novel mutations in the PNKP gene: a case report

Microcephaly, seizures and developmental delay, known as MCSZ, is an uncommon autosomal recessive neurodevelopmental disorder linked to a bifunctional enzyme named polynucleotide-kinase-3'-phosphatase (PNKP). Prompt identification and management of the disorder are crucial, as delayed diagnosis or intervention may lead to severe complications or mortality.

We describe a patient with small anterior fontanelle and head circumference, refractory epilepsy and global developmental delay. He was a baby conceived via in vitro fertilization (IVF). Microcephaly and oligohydramnios were detected at 32 weeks. At 4 months, the patient had recurrent convulsions without fever, presenting with tonic-clonic seizures. He was treated with four anti-seizure medications (ASMs), but did not achieve satisfactory control. At the age of 5 years old, he had not learned to speak and was unable to stand unaided. The patient harbored two novel mutations, c. 1299-1G>A and c.1283_1287dup (p.S430Pfs*39), in the PNKP gene. We confirmed, through RNA-seq, that c. 1299-1G>A results in exon 15 skipping and intron 14 retention. Both variants led to a truncated protein and may affect protein stability and enzyme activity.

This is the third report of MCSZ in a non-consanguineous Chinese mainland family. Our results offer additional evidence for clinical variability associated with disorders stemming from mutations in the PNKP gene, which complicates disease diagnosis. This underscores the significance of genetic testing to identify the underlying causes of these conditions. Furthermore, these findings expand the mutation spectrum of the PNKP gene and establish a solid foundation for both clinical and prenatal diagnoses within this family.