Overview
Autosomal recessive primary microcephaly (MCPH) is a rare disorder in which the head circumference at birth is significantly below the median value. It involves a heterogeneous group of diseases with known genetic causes and leads to a reduction in brain volume, impaired cognitive development, and specific dysmorphic features. The proteins encoded by MCPH genes are centrosomal proteins that influence cell proliferation; molecular genetic diagnostics can help to distinguish between the different forms of MCPH.
Frequency
MCPH are very rare disorders. In Central Europe, the frequency is about 1:1 million, and in Pakistan it is about 1:10,000.
Symptoms
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 SD or more.
Diagnosis
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 brain volume, which affects both the white and grey matter, with the cerebral cortex showing simplified gyration. Signs of neuronal migration disturbances, such as periventricular heterotopias, cortical dysplasia or polymicrogyria, can also be found. This is especially true for MCPH2 (pathogenic variants in WDR2), in which schizencephaly and lissencephaly can also occur.
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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Cause
It is a heterogeneous group of diseases whose genes are partially known.
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.
Differential Diagnosis
There is an allele of MCPH6 associated with Seckel syndrome type 4 and MCPH9 associated with Seckel syndrome type 5, as 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.
References
Zaqout et al. 2017, Neuroped 48:135 / Passemard et al. 2013, Handb Clin Neurol III:129 / Hussain et al. 2012, Am J Hum Genet 90:871 / Genin et al. 2012, Hum Mol Genet 21, 24:5306 / Mahmood et al. 2011, Orphanet J Rare Dis 6:39 / Kaindl et al. 2010, Prog Neurobiol 90:363 / Kousar et al. 2010, J Child Neurol 25:715 / Willems et al. 2010, J Med Genet 47:797 / Rauch et al. 2008, Science 319:816 / Woods et al. 2005, Am J Hum Genet 76:717 / Neitzel et al. 2002, Am J Hum Genet 70:1015
