Microcephaly, seizures and developmental delay
MCSZ

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Description from OMIM

Microcephaly, seizures, and developmental delay is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients have a disease course consistent with early infantile epileptic encephalopathy (EIEE), whereas others have more well-controlled seizures and a protracted course associated with cerebellar atrophy and peripheral neuropathy (Shen et al., 2010 and Poulton et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).



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List of symptoms



Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Microcephaly nervous 100 % 20118933 2014-06-18
Seizures nervous 100 % 20118933 2014-06-18
Hyperactivity nervous 100 % 20118933 2014-06-18
Developmental delay nervous 91 % 20118933 2014-06-18
Cerebellar atrophy nervous 83 % 20118933 2014-06-18
Hypotonia nervous 9 % 20118933 2014-06-18



List of references:


Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.
Jun Shen, Edward C Gilmore, Christine A Marshall, Mary Haddadin, John J Reynolds, Wafaa Eyaid, Adria Bodell, Brenda Barry, Danielle Gleason, Kathryn Allen, Vijay S Ganesh, Bernard S Chang, Arthur Grix, R Sean Hill, Meral Topcu, Keith W Caldecott, A James Barkovich, Christopher A Walsh,

Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration. We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.

Nature genetics - Mar 2010