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

Abstract

Pathogenic variants in polynucleotide kinase 3 0 -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. K E Y W O R D S alpha-fetoprotein, cerebellar atrophy, oculomotor apraxia, seizures

A Novel c.968C > T homozygous Mutation in the Polynucleotide Kinase 3′ − Phosphatase Gene Related to the Syndrome of Microcephaly, Seizures, and Developmental Delay

“…Mutations in this domain have been only described previously in three patients and they all had MCSZ phenotype. 18 In conclusion, we identified a mutation in the PKNP gene which results in a phenotype similar to those described in other reported cases of MCSZ, with evidences of brain anomalies like cerebral atrophy and severe seizures, except for the absence of behavioral changes related to hyperactivity.…”

Mutational Survivorship Bias: The case of PNKP

“…Thus, mutations in the active site of the kinase domain can not only be tolerated but can be found in a homozygous condition. Likewise, Leu399Pro, Cys409Trp and Pro343Leu mutations (all in the kinase domain) usually occur in a compound heterozygous condition, accompanied by a second allele with more serious insults in the kinase domain, usually deletions or frameshifts [22].…”

“…The most severe phenotype is Microcephaly with early-onset Seizures (MCSZ) [20]. In the middle, Ataxia with Oculomotor Apraxia 4 (AOA4) [21] and in the other end the milder Charcot-Marie-Tooth disease type 2B2 (CMT2B2) [22][23][24]. The vast majority of mutations in PNKP are confined to the kinase domain, both in homozygous and compound heterozygous conditions.…”

Mutational Survivorship Bias: The case of PNKP

“…Thus, mutations in the active site of the kinase domain can not only be tolerated but can be found in a homozygous condition. Likewise, p.Leu399Pro, p.Cys409Trp and p.Pro343Leu mutations (all in the kinase domain) usually occur in a compound heterozygous condition, accompanied by a second allele with more serious insults in the kinase domain, usually deletions or frameshifts (Gatti et al, 2019).…”

“…The most severe phenotype is Microcephaly with early-onset Seizures (MCSZ) (Shen et al, 2010). In the middle, Ataxia with Oculomotor Apraxia 4 (AOA4) (Bras et al, 2015) and in the other end the milder Charcot-Marie-Tooth disease type 2B2 (CMT2B2) (Pedroso et al, 2015;Leal et al, 2018;Gatti et al, 2019). The vast majority of mutations in PNKP are confined to the kinase domain, both in homozygous and compound heterozygous conditions.…”