Microcephaly, seizures, and developmental delay

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.

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.

  • EIEE10
  • epileptic encephalopathy, early infantile, 10
  • MCSZ