Microcephaly, seizures, and developmental delay (MCSZ) is a condition characterized by an abnormally small head size (microcephaly) and neurological problems related to impaired brain development before birth. Affected individuals typically have recurrent seizures (epilepsy) beginning in infancy and delayed development of motor skills, such as sitting and walking. Speech is also delayed, and some affected individuals are never able to speak. Intellectual disability and behavior problems, primarily hyperactivity, are also common features of MCSZ. Rarely, individuals with MCSZ also have poor balance and coordination (ataxia).

MCSZ is caused by mutations in the PNKP gene. This gene provides instructions for making an enzyme that is critical for repairing broken DNA strands. DNA breaks may be caused by potentially harmful molecules (such as reactive oxygen species) produced during normal cellular functions, natural and medical radiation, or other environmental exposures. They may also occur when chromosomes exchange genetic material in preparation for cell division. At the site of damage, the PNKP enzyme modifies the broken ends of the DNA strands so that they can be joined back together.

PNKP gene mutations lead to production of an unstable enzyme that is quickly broken down in the cell. Shortage of the PNKP enzyme prevents efficient repair of damaged DNA. Nerve cells seem especially susceptible to such damage. It is thought that DNA damage that accumulates during development before birth leads to the death of nerve cell precursors, impairing normal brain growth and causing microcephaly and the other neurological features of MCSZ.

Accumulated DNA damage in nerve cells in the brain after birth, particularly the part that coordinates movement (the cerebellum), likely underlies ataxia. It is unclear why some people have cerebellar nerve degeneration after birth in addition to impaired brain development before birth and others do not. Researchers suspect that additional genetic factors play a role.

Normal Function

The PNKP gene provides instructions for making the polynucleotide kinase-phosphatase (PNKP) enzyme. This enzyme is critical for repairing broken strands of DNA molecules. It can help fix damage that affects one DNA strand (single-strand breaks) or both strands (double-strand breaks). At the site of the damage, the PNKP enzyme modifies the broken ends of the DNA strands so that they can be joined back together.

Health Conditions Related to Genetic Changes

Ataxia with oculomotor apraxia

At least nine PNKP gene mutations have been found to cause ataxia with oculomotor apraxia type 4. This condition is characterized by poor coordination and balance (ataxia) and problems with side-to-side movement of the eyes (oculomotor apraxia). These problems are due to the breakdown (degeneration) of nerve cells in the part of the brain that coordinates movement (the cerebellum).

PNKP gene mutations that cause ataxia with oculomotor apraxia type 4 lead to production of an unstable enzyme that is quickly broken down in the cell. Shortage of the PNKP enzyme prevents efficient repair of damaged DNA. Researchers suggest that the repair of single-strand breaks is particularly impaired in ataxia with oculomotor apraxia type 4. It is thought that single-strand DNA damage increases after birth as the brain grows. Without repair, the accumulating damage leads to a loss of nerve cell in the brain, resulting in the movement problems characteristic of ataxia with oculomotor apraxia type 4.

Microcephaly, seizures, and developmental delay

At least six mutations in the PNKP gene have been found to cause microcephaly, seizures, and developmental delay (MCSZ). This condition is characterized by problems with brain development before birth that result in an unusually small head size (microcephaly), recurrent seizures (epilepsy), and delayed development of speech and motor skills. Rarely, affected individuals also have difficulty coordinating movements (ataxia) due to degeneration of nerve cells in the cerebellum.

PNKP gene mutations that cause MCSZ lead to production of an unstable enzyme that is quickly broken down in the cell. Shortage of the PNKP enzyme prevents efficient repair of damaged DNA. Researchers suggest that, in contrast to ataxia with oculomotor apraxia type 4 (described above), the repair of double-strand breaks is particularly impaired in MCSZ. The accumulating damage is especially harmful to nerve cells. It is thought that excessive DNA damage before birth leads to the death of nerve cell precursors, impairing normal brain development and causing microcephaly and the other neurological features of MCSZ.

It is unclear why mutations in the same gene, even the same mutation in some cases, can have different effects on single-strand or double-strand DNA damage repair and cause either ataxia with oculomotor apraxia type 4 or MCSZ.

Other Names for This Gene

• AOA4
• bifunctional polynucleotide phosphatase/kinase
• DNA 5'-kinase/3'-phosphatase
• EIEE10
• Homo sapiens polynucleotide kinase 3'-phosphatase (PNKP)
• MCSZ
• PNK

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

MCSZ is a rare disorder. Its prevalence is unknown.