Intellectual disability and global developmental delay are particularly challenging genetic diagnostic challenges because of the presumed myriad of causes.  Microcephaly is a common finding in patients with intellectual disability.  Microcephaly vera is a rare cause of global developmental delay that is characterized by severe microcephaly, MRI with normal structures and without evidence of focal injury or degeneration, developmental delay and no other significant neurological sequelae.  The level of microcephaly involved is generally very severe, with head circumferences typically 6-8 standard deviations below the mean or more as children reach their 2nd decade.  Interestingly, a microcephaly disease has recently been identified with some similarities to microcephaly vera but it also has frequent seizures.

This novel microcephaly autosomal recessive disease has microcephaly, MRI with normal structures, developmental delay and epilepsy.  This condition, named microcephaly with seizures, is caused by mutations in the DNA repair gene, polynucleotide kinase 3’-phosphatase (PNKP) 1.  Seizures have all started within the first year of life and are generally very difficult to control in severely affected patients.  Other DNA repair diseases have been identified previously that also have microcephaly, such as Nijmegen breakage syndrome (NBS1), but seizures are not a prominent feature 2, 3.  In contrast to patients with mutations in NBS1 or ATM, patients with PNKP mutations do not appear to have somatic symptoms often associated with abnormalities in DNA repair such as cancer predisposition or immunological abnormalities.  However, since the age of the patients characterized is fairly young, cancer susceptibility in particular cannot be discounted.  Critically, cells derived from patients with microcephaly and seizures are sensitive to various DNA damaging agents.  Therefore, correct diagnosis can lead to important recommendations to patients such as avoidance of ionizing radiation via X-ray in diagnostic studies. 

In addition to the identification of patients that at first could be mistaken for microcephaly vera with very severe microcephaly, patients with moderate microcephaly have also been identified.   In contrast to the severely affected patients, the moderately affected patients were born with head circumferences within the low but normal range.  They developed seizures within the first year of life with variable severity.  As the children grew older the head circumference dropped below the 3rd percentile.  The family that was identified with moderate microcephaly with seizures was otherwise similar to those patients with severe form of the disease.  A splicing abnormality was identified in the moderately affected patients that produced a small amount of normal transcript and likely protein as well.  These patients’ cells were susceptible to DNA damaging agents.  From clinical experience patients with very severe microcephaly, severe seizures and otherwise normal MRI are quite rare.  However, patients that have head circumferences that are 2-3 standard deviation below the mean, epilepsy and an otherwise normal MRI are not uncommon in clinical practice.  Currently, it is unknown how many of these patients will have PNKP mutations.  Mutation analysis of the PNKP gene is available at the University of Chicago Genetic Services laboratory.  As more patients with PNKP mutations are identified through genetic testing, the clinical spectrum of this disease will likely be further refined.

1.         Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ, Eyaid W, Bodell A, Barry B, Gleason D, Allen K, et al. Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet 2010, 42:245-249.

2.         Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K, Beckmann G, Seemanova E, Cooper PR, Nowak NJ, et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 1998, 93:467-476.

3.         Matsuura S, Tauchi H, Nakamura A, Kondo N, Sakamoto S, Endo S, Smeets D, Solder B, Belohradsky BH, Der Kaloustian VM, et al. Positional cloning of the gene for Nijmegen breakage syndrome. Nat Genet 1998, 19:179-181.