{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T03:08:10Z","timestamp":1774062490989,"version":"3.50.1"},"reference-count":23,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2019,8,22]],"date-time":"2019-08-22T00:00:00Z","timestamp":1566432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Italian Ministry of Health","award":["GR-2016-02363337"],"award-info":[{"award-number":["GR-2016-02363337"]}]},{"name":"Italian Ministry of Health","award":["RF-2011-02351165"],"award-info":[{"award-number":["RF-2011-02351165"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pathogenic variants in polynucleotide kinase 3\u2032\u2010phosphatase (<jats:italic>PNKP<\/jats:italic>) 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\u2010onset intractable seizures, to adult onset slowly progressive sensory\u2010motor neuropathy and cerebellar ataxia. We describe three unrelated Italian patients with different phenotypes and novel or recurrent pathogenic variants in <jats:italic>PNKP<\/jats:italic> gene. Patient 1, homozygous for the recurrent frameshift variant (p.Thr424Glyfs*49), had an early\u2010onset 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\u2010fetoprotein plasma levels. The clinical presentation of our patients encompassed early\u2010to\u2010adult\u2010onset manifestations. For these cases, the long clinical follow\u2010up allowed an in\u2010depth phenotypic characterization and a better delineation of the natural history of patients carrying <jats:italic>PNKP<\/jats:italic> pathogenic variants.<\/jats:p>","DOI":"10.1002\/ajmg.a.61339","type":"journal-article","created":{"date-parts":[[2019,8,22]],"date-time":"2019-08-22T15:17:28Z","timestamp":1566487048000},"page":"2277-2283","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with <i>PNKP<\/i> gene mutations"],"prefix":"10.1002","volume":"179","author":[{"given":"Marta","family":"Gatti","sequence":"first","affiliation":[{"name":"Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta  Milan 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