From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations

: Pathogenic variants in polynucleotide kinase 3'-phosphatase (PNKP) gene have been associated with two distinct clinical presentations: autosomal recessive microcephaly, seizures, and developmental delay (MCSZ; MIM 613402) and ataxia with oculomotor apraxia type 4 (AOA4; MIM 616267). More than 40 patients have been reported so far, and their clinical presentations revealed a continuum phenotypic spectrum ranging from congenital microcephaly and early-onset intractable seizures, to adult onset slowly progressive sensory-motor neuropathy and cerebellar ataxia. We describe three unrelated Italian patients with different phenotypes and novel or recurrent pathogenic variants in PNKP gene. Patient 1, homozygous for the recurrent frameshift variant (p.Thr424Glyfs*49), had an early-onset MCSZ phenotype. Late in the disease progression, cerebellar ataxia and peripheral neuropathy were recognized. Patient 2, homozygous for a frameshift variant (p.Ala429Thrfs*42), presented a phenotype partially consistent with MCSZ including microcephaly and developmental delay, but without seizures. Patient 3 is one of the oldest patients described to date and presented polyneuropathy, and cerebellar signs. Biochemical tests showed abnormalities of cholesterol, albumin, or alpha-fetoprotein plasma levels. The clinical presentation of our patients encompassed early-to-adult-onset manifestations. For these cases, the long clinical follow-up allowed an in-depth phenotypic characterization and a better delineation of the natural history of patients carrying PNKP pathogenic variants.