Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Scientific Background

Primary autosomal recessive microcephalies are highly rare disorders. In Central Europe the frequency is approx. 1 in 1 million, in Pakistan approximately 1 in 10,000. At birth, or even during the third trimester of pregnancy, the head circumference is typically two standard deviations below the mean. At the age of one year, the head may be 3 or more deviations below the average.

MCPHs form a heterogenous group of currently 10 diseases, whose genes are known.

The diagnostic criteria are:

  • Head circumference -2 SD at birth and below -3 SD within the 1st year of life
  • Impaired cognitive development; however, hardly any impairment in motor development with delayed speech development and attention deficit
  • No severe neurological signs and symptoms, except seizures in approx. 10% of all cases
  • No severe malformations, only minor signs of dysmorphia due to microcephaly, such as small, receding forehead, sometimes short stature with the body size also being between the 2nd and 3rd SD below the mean
  • Reduction of the brain volume affecting both the white and grey matter with simplified cortical gyration in some cases. In addition, periventricular heterotopies, cortical dysplasia or a polymicrogyria may be found as signs of neuronal migration disorder, especially in MCPH2 (mutations in WDR2), which may be accompanied by schizencephaly and lissencephaly.

The proteins which are encoded by microcephaly genes are centrosomal proteins. Their mutations cause an imbalance between the cell proliferation of neural progenitor cells and the cell death. Thus, they eventually cause a reduction in neurons and the brain volume. MCPH6 is allelic with the Seckel syndrome type 4, MCPH9 with the Seckel syndrome type 5, since loss-of-function mutations in CENPJ or CEP152 are causing these forms of the Seckel syndrome. The signs and symptoms overlap with microcephalic osteodysplastic primordial dwarfism (MOPD2), which can be distinguished from the Seckel syndrome by severe hyposomia, less severe developmental delay and radiologic abnormalities. MOPD2 is caused by loss-of-function mutations in the pericentrin gene. Pericentrin is a centrosomal protein as well, and plays a major role in the organization of mitotic spindles and therefore in the cell division.

Since the primary autosomal recessive microcephalies are clinically hard to distinguish, molecular genetic detection of a mutation may enable identification. Stepwise diagnostics are recommended. Analysis of the ASPM gene (MCPH5) is recommended as the first step, since mutations in this gene are responsible for approx. 50% of all MCPH cases reported so far. MCPH1 is characterized by an increase in prophase cells (> 2%) in chromosome preparation. In this case, MCPH1 is tested for mutations. If a mutation cannot be found, the other 8 genes associated with microcephalies can be analyzed in the next step using next generation sequencing.