Diagnostic Approach to Primary Microcephaly^[*]

Microcephaly (MC) is a frequent sign of many rare neurologic, metabolic, and genetic disorders and is mainly defined as an occipitofrontal head circumference (OFC) below the third centile or more than 2 standard deviations (SD) below the mean for sex, age, and ethnicity. The definition of MC is not uniform worldwide and varies from an OFC more than 2 SD below the mean to more than 3 SD below the mean, or an OFC below the 3rd or 10th centile. According to the World Health Organization (WHO) interim guidelines published in August 2016 for diagnosing primary MC, neonates with an OFC more than 2 SD below the mean are considered to have MC. Neonates with an OFC more than 3 SD below the mean should be considered to have severe MC.

MC affects approximately 2 to 3% of the population and is often associated with intellectual disability and/or motor disability. Due to the nonuniformity in the definition of MC, the different level of ascertainment, and the application of growth curves to populations with different ethnic backgrounds, limited reliable data on the prevalence of MC worldwide are available.[1] [2] [3] [4] MC may be evident at birth (primary MC) or postnatally (secondary MC), although MC classification varies in the international literature. MC can be isolated or syndromal associated with congenital anomalies. The terms do not imply a distinct etiology. The pathogenesis of MC is heterogeneous ranging from genetic causes to acquired MC (environmental etiology).[1] [2]

Due to the Zika virus epidemic, with a significant increase in the prevalence of primary MC at first in north eastern Brazil in the year 2015, the pathogenesis and the classification of MC have come in the focus of neuroscience even more in the last 2 years. In March 2016, the WHO has declared the clustering of MC cases and emerged interim guidelines for diagnosing primary MC.[4] The EUROCAT (European Surveillance of Congenital Anomalies) states that because of the discrepant diagnostic criteria and different levels of ascertainment, smaller increases in MC prevalence in Europe due to Zika virus infection would probably not be detected.[3] The underlying etiologies of MC are complex and multifactorial. The growing number of causative genetic defects and the characterization of their protein expression during brain development opened the door for understanding pathways in impaired neurogenesis. Emerging pathomechanism include abnormal mitotic microtubule spindle structure, abnormalities of the centrosome, altered cilia function, and impaired DNA repair and replication, along with attenuated cell cycle checkpoint proficiency. Many of these processes are interconnected.[5] [6] [7] Furthermore, regarding the mechanism of acquired MC, recent analyses of Zika virus infected human neural progenitor cells (hNPCs) derived from induced pluripotent stem cells revealed that Zika virus infection increases cell death and dysregulates cell-cycle progression in hNPCs.[8] Zika virus infected hNPCs produce infectious ZIKV particles. Onorati et al showed that Zika virus infection causes disrupted mitoses, supernumerary centrosomes, structural disorganization, and cell death.[9]

In this issue, the review article by Zaqout et al describes the rare but actual growing disease group of autosomal recessive primary MCs (MCPH for MicroCephaly Primary Hereditary).[10] The prevalence of MCPH ranges from 1:30,000 to 1:250,000 live births. The manuscript reviews the phenotype, the neuroimaging findings, genetic causes, putative pathomechanisms, diagnostics, and differential diagnoses of MCPH. Seventeen genes have been reported to date and are referred to as MCPH1 to MCPH17. The authors give clinical clues for diagnostics, differential diagnoses, and symptomatic therapies of MCPH for clinicians.

The MCPH types were initially characterized by a predominant isolated primary nonprogressive MC with OFC < 3, a reduced brain volume, mental retardation (intelligence quotient [IQ] between 30 and 70–80) and no further neurologic findings except for mild seizures. Patients have a characteristic head shape with sloping forehead. In the meanwhile, the phenotype spectrum and the genotype-based classification have become much broader.[5] [10] [11] Phenotype–genotype correlations in MCPH are revisited by Zaqout et al. The review expands the phenotype spectrum by describing signs as a short stature, dysmorphic features (low set ears, high arched palate, inverted nipples, etc.), neurobehavioral symptoms, and neuroimaging findings. Intriguingly frequent neuroimaging findings in MCPH include abnormalities of neocortical gyration, for example, periventricular heterotopias, pachygyria, and polymicrogyria. Primary MC caused by mutations in genes at the MCPH loci is seldom an isolated clinical feature and is often accompanied either by additional cortical malformations or primordial dwarfism. The authors point to the phenotypic similarities with Seckel syndrome, which is a major subtype of the highly heterogeneous group of primordial dwarfism disorders. The function of causative genes in Seckel syndrome involves, for example, signaling of DNA damage response, regulation of cell proliferation, and centrosomal integrity.[7] [10]

In their diagnostic algorithm, the authors refer to Sanger sequencing of the two most frequent MCPH genes (ASPM, WDR62) as the initial diagnostic step for confirming the clinical diagnosis. The further genetic work-up inclose the use of disease-specific (MCPH) gene panels for accelerating the time to genetic diagnosis and finally whole-exome sequencing as molecular genetic tests for some MCPH genes are available on research basis only.[10]

Both—genetic primary MC due to mutations in the MCPH genes and Zika virus induced acquired primary MC—may serve as models to deepen our understanding on brain development and pathways of impaired neurogenesis. An exact diagnosis of primary MC is important for (future) (gene) therapy approaches, the development of neuroprotective strategies, and family counseling.

The WHO interim guidelines[4] for primary MC focus on a diagnostic algorithm of Zika virus induced primary MC. The review by Zaqout et al adds profoundly to our knowledge on diagnosing primary putative genetic MC.

^* This article is an editorial comment on “Autosomal recessive primary microcephaly (MCPH): an update” by Zaqout et al (Neuropediatrics 2017;48(3):135–142).

• References

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• 2 von der Hagen M, Pivarcsi M, Liebe J. , et al. Diagnostic approach to microcephaly in childhood: a two-center study and review of the literature. Dev Med Child Neurol 2014; 56 (08) 732-741
• 3 Morris JK, Rankin J, Garne E. , et al. Prevalence of microcephaly in Europe: population based study. BMJ 2016; 354: i4721
• 4 WHO. Screening, assessment and management of neonates and infants with complications associated with Zika virus exposure in utero Interim guidance. Available at http://www.who.int/csr/resources/publications/zika/assessment-infants/en/ Accessed April 28, 2017
• 5 Kaindl AM, Passemard S, Kumar P. , et al. Many roads lead to primary autosomal recessive microcephaly. Prog Neurobiol 2010; 90 (03) 363-383
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• 7 Morris-Rosendahl DJ, Kaindl AM. What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly (MCPH). Mol Cell Probes 2015; 29 (05) 271-281
• 8 Tang H, Hammack C, Ogden SC. , et al. Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 2016; 18 (05) 587-590
• 9 Onorati M, Li Z, Liu F. , et al. Zika virus disrupts phospho-TBK1 localization and mitosis in human neuroepithelial stem cells and radial glia. Cell Reports 2016; 16 (10) 2576-2592
• 10 Zaqout S, Morris-Rosendahl D, Kaindl AM. Autosomal recessive primary microcephaly (MCPH): an update. Neuropediatrics 2017; 48 (03) 135-142
• 11 Kaindl AM. Autosomal recessive primary microcephalies (MCPH). Eur J Paediatr Neurol 2014; 18 (04) 547-548