Autosomal recessive primary microcephalies (MCPH) are very rare disorders. In the Central European population, the frequency is about 1:1 million, and in Pakistan it is about 1:10,000. The disorders are characterized by a head circumference at birth or in the last trimester of pregnancy that is at least two standard deviations (SD) below the median value. At the age of 6 months the deviation can be -3 standard deviations or more.
It is a heterogeneous group of diseases whose genes are partially known.
The diagnostic criteria are:
- head circumference of -2 SD at birth and under -3 SD within the 1st year of life;
- impaired cognitive development, minimally impaired motor development with language development delay and attention deficit;
- no serious neurological symptoms other than seizures in about 10%;
- no serious malformations, only discrete signs of dysmorphia due to microcephaly, such as a narrow receding forehead and occasional dwarfism with body measurements also between the 2nd and 3rd SD below the median;
- reduction of the brain volume, which affects both the white and grey matter, whereby the cerebral cortex can present a simplified gyration. In addition, signs of neuronal migration disturbances, such as periventricular heterotopias, cortical dyplasia or polymicrogyria, can also be found. This is especially true for MCPH2 (pathogenic variants in WDR2), in which schizencephaly and lissencephaly can also occur.
The proteins encoded by the microcephaly genes are centrosomal proteins whose alterations cause an imbalance between the cell proliferation of neuronal progenitor cells and cell death, ultimately leading to a reduced number of neurons and a smaller brain volume. There is an allele of MCPH6 for Seckel syndrome type 4 and MCPH9 for Seckel syndrome type 5, since loss-of-function variants in CENPJ and CEP152, respectively cause these forms of Seckel syndrome. Clinical overlaps exist with microcephalic osteodysplastic primordial dwarfism (MOPD2), which differs from Seckel syndrome through its more pronounced short stature, less pronounced developmental delay and radiological abnormalities. MOPD2 is caused by loss-of-function variants in the pericentrin gene. Pericentrin is also a centrosomal protein that plays an essential role in the organization of the mitotic spindles and thus in cell division.
Since there is little difference clinically between the individual forms of autosomal recessive primary microcephalies, molecular genetic diagnostics using NGS (gene panel diagnostics) can be used to identify a causative pathogenic variant and facilitate diagnosis.
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