Clinical Diagnosis

The primary autosomal recessive microcephalies are a group of nonsyndromic disorders characterized by a small-sized brain not associated with gross anomalies of brain architecture or malformations in other organ systems. The seven types of primary autosomal recessive primary microcephaly, recognized by the gene involved, are designated MCPH(microcephaly primary hereditary)1 - MCPH7.

Diagnosis of MCPH is based on the following clinical and neuroimaging criteria:

• Microcephaly. Occipito-frontal head circumference (OFC) less than 2 SD below the mean for sex, age, and ethnicity at birth and at least -3 SD after age six months. Note: The term “mild microcephaly” can be used for an OFC between -2 SD and -3 SD.

• Onset of microcephaly during the second trimester of gestation

• Mild to moderate cognitive impairment without major motor delay in the majority of cases; however, more severe cognitive impairment has been observed in a small number of affected individuals.

• Normal height and weight. Mild shortness of stature (up to -3 SD) may be observed, but the height of most individuals is usually between -1 SD and -2 SD.

• No neurologic signs except mild seizures and mild pyramidal syndrome [Aicardi 1998; Passemard et al 2009; Verloes, personal data]

• Absence of facial dysmorphism except the narrow, sloping forehead often noticed in infants with reduced cranial size

• Absence of somatic malformations

• Normal fundus examination. Note: In some forms of microcephaly associated with chorioretinal dysplasia (see Differential Diagnosis), the chorioretinal dysplasia can be asymptomatic; therefore, fundus examination is necessary to make this determination.

• Cranial MRI or computed tomography (CT) showing reduced brain volume with normal architecture (i.e., without gross brain malformations) [Woods et al 2005]. The volume of the cerebral hemispheres can be reduced to one-third of normal. The reduction is particularly evident in the cerebral cortex.

  • Frequently a simplified gyral pattern is observed in ASPM-related MCPH (MCPH5) [Mochida & Walsh 2001; Desir et al 2008; Passemard et al 2009; Verloes, personal observation] and MCPH1 [Trimborn et al 2004].

  • Case reports provide evidence of neuronal migration defects: periventricular neuronal heterotopias in MCPH1 [Trimborn et al 2004, Woods et al 2005] and polymicrogyria in MCPH5 [Passemard et al 2009; Verloes, personal data].

Testing

Cytogenetic testing. An increased frequency of prophase-like cells on routine cytogenetic analysis of peripheral blood (compared to normal reference range of ≤2%) is observed in MCPH1, but not in MCPH2-7. This finding appears to be highly specific and sensitive for MCPH1.

Note: (1) This increase of prophase-like cells results from premature chromatin condensation (PCC) in the early G2 phase of the cell cycle and delayed decondensation in the early G1 phase [Trimborn et al 2004]. (2) An additional feature of the condensation defect is poor metaphase banding resolution in routine cytogenetic testing. It was therefore suggested that analysis of chromosome preparations without colcemid treatment be performed in cases with clinical MCPH and poor metaphase resolution, since the application of the spindle poison attenuates the condensation defect by masking the postmitotic effect in early G1 [Trimborn et al 2005].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes. Genes for five of the seven MCPH loci (MCPH1 - MCPH7) are known. Affected individuals are either homozygous for the same mutation or are compound heterozygous for two mutations in the same gene:

• MCPH1 (locus name MCPH1; chromosome 8p23) [Jackson et al 2002] accounts less than 5% of MCPH.

• CDK5RAP2 (locus name MCPH3; chromosome 9q33.3) [Bond et al 2005] accounts less than 5% of MCPH.

• ASPM (locus name MCPH5; chromosome 1q31) [Bond et al 2002] accounts for 37%-54% of MCPH.

• CENPJ (locus name MCPH6; chromosome 13q12.2) [Bond et al 2005] accounts for less than 5% of MCPH.

• STIL (locus name MCPH7; chromosome 1p32) [Kumar et al 2009] accounts for less than 5% of MCPH.

Other loci. The two mapped loci for which the genes are not known:

• MCPH2 (19q13.1-13.2)

• MCPH4 (15q15-q21)

Clinical testing

• Sequence analysis of ASPM. Sequence analysis of the full coding sequence and intron-exon junctions is performed. Putative mutations detected in a proband should be confirmed in parental DNA.

Research testing

• Sequence analysis of MCPH1, CDK5RAP2, CENPJ, and STIL is available on a research basis only.

• Deletion/duplication analysis of ASPM. Deletion/duplication of an exon, multiple exons, or the whole gene can be detected by several techniques (see Table 1 footnote). One intragenic deletion has been detected in ASPM [Passemard et al 2009]. While intragenic deletion of ASPM is not the primary mutational mechanism, deletion testing may be considered in affected individuals who are apparent homozygotes when one of the parents appears not to be carrier. Intragenic duplication of ASPM has not been reported as a cause of MCPH.

Table 1. Summary of Molecular Genetic Testing Used in Primary Microcephaly Types 1-7

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Gene Symbol (Locus Name)	Proportion of MCPH Attributed to Mutations in This Gene 1	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method	Test Availability
MCPH1 (MCPH1)	<5%	Sequence analysis	Sequence variants	Unknown	Research only 2
(MCPH2)	Unknown	NA	NA	NA	NA
CDK5RAP2 (MCPH3)	<5%	Sequence analysis	Sequence variants	Unknown	Research only 2
(MCPH4)	Unknown	NA	NA	NA	NA
ASPM (MCPH5)	37%-54%	Sequence analysis	Sequence variants	Unknown	Clinical
		Deletion/duplication analysis 3	Exonic and whole gene deletions	Unknown	Research only 2
CENPJ (MCPH6)	<5%	Sequence analysis	Sequence variants	Unknown	Research only 2
STIL (MCPH7)	<5%	Sequence analysis	Sequence variants	Unknown	Research only 2

1. Percent of all causative mutations that can be detected with this test method

2. No laboratories offering clinical molecular genetic testing for this gene are listed in the GeneTests Laboratory Directory; however, clinical confirmation of mutations identified in a research laboratory may be available. For laboratories offering such testing, see .

3. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

Confirming/establishing the diagnosis in a proband

Affected individuals are usually referred for evaluation of small head size, speech delay, developmental disabilities, and hyperactivity.

Clinical evaluation includes assessment of:

• Detailed past medical history (including growth parameters)

• Prenatal history (including possible exposure to alcohol and other teratogens)

• Family history (including measurement of the OFC of parents and sibs)

• Physical examination to look for evidence of systemic involvement/malformations

• Neurologic evaluation including brain MRI

Routine laboratory investigations to exclude other causes of microcephaly based on level of clinical suspicion (see Differential Diagnosis) include:

• Karyotype

• Subtelomeric rearrangement analysis or array genomic hybridization (array GH)

• TORCH (toxoplasmosis, rubella, CMV, herpes simplex) antibody titers

• Maternal serum or a dried blood sample to screen for maternal PKU

• Chromosomal breakage studies

• Serum concentration of IGF1 in children with low normal or short stature

If the clinical and laboratory findings are compatible with the diagnosis of MCPH and:

• If misregulated chromosome condensation (increased proportion of prophase-like cells, poor chromosome banding resolution) is present, an MCPH1 mutation is likely (see Table 1; molecular genetic testing is available on a research basis).

• If there is no evidence of misregulated chromosome condensation, sequence analysis of ASPM (which accounts for the greatest percentage of MCPH cases) could be performed.
  
  Note: (1) Molecular genetic testing for MCPH3 (CDK5RAP2), MCPH6 (CENPJ), and MCPH7 (STIL) is possible on a research basis only. (2) Some research laboratories may be able to pre-screen affected individuals resulting from a consanguineous mating to determine which of the above genes may be the more probable cause. Homozygosity mapping in an affected individual in/near the regions of each of the known genes may provide evidence that suggests which is most likely to be causative. (3) Clinical confirmation of mutations identified in a research laboratory may be available (see ).

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for these autosomal recessive disorders and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in MCPH1, CDK5RAP2, ASPM, CENPJ, and STIL.

Natural History

Nonsyndromic autosomal recessive primary microcephaly (MCPH; for microcephaly primary hereditary) affects males and females equally.

Because MCPH5 is the most common form of MCPH and the only one for which large series have been published, many clinical data are only available for MCPH5. Whether the other types have the same clinical and radiologic spectrum of findings is currently unknown.

Prenatally. Microcephaly arises as a consequence of inappropriate brain growth [Aicardi 1998, Woods et al 2005, Cox et al 2006]. Microcephaly may be evident by the 24th week of gestation through ultrasonographic measurement of the fetal head size or by fetal brain MRI [Tunca et al 2006]. Owing to the pattern of deficient brain growth, in some instances, head circumference (i.e., OFC) remains close to the lower limit of normal (i.e., ~-2 SD) and, therefore, microcephaly may be undiagnosed until term (i.e., 40 weeks’ gestation).

In infancy. Head circumference at birth is classically said to be at least 3 SD below the mean for age and sex. The authors’ experience with MCPH5 (caused by ASPM mutations) is that OFC lies between -2 SD and -4 SD at birth, and declines progressively to reach usually -4 SD to -6 SD at the age of six months [Passemard et al 2009]. In adults with molecularly proven MCPH5, the OFC varies between -3 SD and -13 SD [Bond et al 2003]. Intrafamilial correlation for the OFC is strong; however, some sibs may be discrepant by 2 SD to 3 SD [Passemard et al 2009].

Stature is normal in individuals with MCPH2 - MCPH7. By contrast, those with MCPH1 tend to have shorter stature, often around -2 to 3 SD for age.

Developmental milestones are sometimes normal, but usually mildly delayed. Children are not hypotonic and usually walk unsupported before age two years.

Most children with MCPH display speech delay and acquire language between ages three and four years. The majority have mild to moderate cognitive impairment; however, severe cognitive impairment has been observed in individuals associated with MCPH5 [Bond et al 2003]. Few individuals are able to read and write. Few data have been published on the cognitive function of individuals with molecularly-confirmed MCPH. In individuals with MCPH5 total IQ ranges from below 40 to 70 and does not correlate well with OFC [Passemard et al 2009].

Individuals with MCPH have been described as cheerful and affable and able to follow instructions well [Pattison et al 2000]. However, they often have severe hyperactivity in infancy and childhood. Hyperactivity decreases in late childhood and is usually not a problem in adolescence.

Seizures have been reported in approximately 10% of individuals with MCPH5 [Shen et al 2005, Passemard et al 2009]. Seizures often begin after age two years, are usually tonic and clonic, and can occur during sleep. They appear to be usually easily managed by anticonvulsant medications.

No information is currently available on natural history, co-morbidities, or specific risks in adulthood; however, anecdotal reports describe persons with MCPH who reached their seventies.

To date, no predisposition to cancer has been observed in individuals with MCPH1 - MCPH7. However, the molecular functions of the MCPH1 gene product in DNA damage response and checkpoint control may have as yet unknown effects on an individual’s health.

Neuropathologic findings. Severe depletion of neurons in superficial cortical layers II and III has been reported in fetuses or infants with clinically-diagnosed primary autosomal recessive microcephaly [Evrard et al 1989]. Neuropathologic findings in genetically characterized MCPH types 1-7 have not been reported to date.

Genotype-Phenotype Correlations

MCPH1. Growth retardation is common. Misregulated chromosome condensation is specific to MCPH1.

MCPH2 - MCPH7. No clear genotype-phenotype correlations have been identified.

Inter- and intrafamilial variation in OFC and cognitive abilities has been described.

Nomenclature

Primary autosomal recessive microcephaly (MCPH) was previously called “microcephalia vera” or “true microcephaly”; however, in the past this diagnosis was usually made without the benefit of neuroimaging studies. Thus, it is likely that the entity referred to as microcephalia vera in the literature published before the availability of MRI was much more heterogeneous than MCPH as defined here.

Microcephaly with simplified gyral pattern (MSG) was originally called “microlissencephaly” and assigned an OMIM number; MSG is now thought to be part of the spectrum of primary microcephaly and not of lissencephaly (which results from abnormal neuronal migration), because in lissencephaly the cortex is thickened and shows a disorganized cytoarchitecture whereas in MSG and MCPH5 (caused by ASPM mutations) the cortex is of normal or reduced thickness and has normal organization microscopically. In the original classification of “microlissencephalies,” Barkovich delineated five types (MSG type 1-5). MCPH5 (and probably other MCPHs) may show MSG type 1.

Premature chromosome condensation (PCC) syndrome is identical to MCPH1. Neitzel et al [2002] reported two sibs with severe intellectual disability whose parents were first cousins. They showed low birth weight, short stature, microcephaly, and, on karyotype, an excess of prophase-like cells and metaphases with poor banding quality. Later they were shown to bear MCPH1 mutations [Trimborn et al 2004].

Prevalence

Primary microcephaly has an incidence of 1:30,000 to 1:250,000.

MCPH types 1-7 have been confirmed by molecular genetic testing and reported in fewer than 100 families:

• MCPH1: Five families

• MCPH3 (CDK5RAP2): Four families [Bond et al 2005, Hassan et al 2007]

• MCPH5 (ASPM): At least 85 families reported and 11 unpublished families [Passemard et al 2009]

• MCPH6 (CENPJ): Three families: two reported by Bond et al [2005] and one reported by Gul et al [2006b]

• MCPH7 (STIL): Three families

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with primary autosomal recessive microcephaly types 1-7 (MCPH1 - MCPH7), the following evaluations are recommended:

• Neurologic consultation

• Age-adapted psychomotor or neuropsychological evaluation

• Electroencephalogram if seizures are suspected

Treatment of Manifestations

Therapy is supportive and involves the following:

• Special educators

• Language therapists

• Behavioral therapists

• Occupational therapists

• Community services that provide support for families

Ritalin^® may be helpful in individuals with marked hyperkinesia.

Seizures are usually responsive to monotherapy with standard antiepileptic drugs (AEDs).

Surveillance

• Neurologic evaluation from birth to adulthood with periodic neuropsychologic evaluation in order to adapt interventions and schooling to the level of the individual’s cognitive abilities.

• Ongoing monitoring for manifestations of seizures which can be late-onset.

Testing of Relatives at Risk

See Related Genetic Counseling Issues for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Primary autosomal recessive microcephaly (MCPH) types 1-7 are inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate carriers and therefore carry one heterozygous mutation.

• Heterozygous individuals (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of one affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier if the parents are heterozygous.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

• Heterozygous individuals (carriers) are asymptomatic.

Offspring of a proband. So far, no individual with MCPH1 - MCPH7 has been known to reproduce.

Other family members of a proband. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Carrier testing using molecular genetic techniques is possible if the disease-causing mutations in the family are known.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of the genetic risk is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, mutations and diseases will improve in the future, consideration should be given to banking DNA (typically extracted from white blood cells) of affected individuals for possible future use. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100% or when molecular genetic testing is available on a research basis only. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for MCPH5 caused by ASPM mutations is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. Both disease-causing alleles of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

No laboratories offering molecular genetic testing for prenatal diagnosis of MCPH 1, 3, 6, or 7 are listed in the GeneTests Laboratory Directory. However, prenatal testing for mutations identified in a research laboratory may be available. For laboratories offering custom prenatal testing, see .

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

MCPH-causing genes are highly conserved among species and are suspected to have played a critical role in human brain evolution [Bond et al 2002, Gilbert et al 2005, Ponting & Jackson 2005]. Brain size is determined by the relative rates of proliferation and cell death occurring during neurogenesis. Neural progenitors are generated by symmetric/asymmetric cell divisions. Impairment of neural progenitor divisions and/or impaired cell cycle control could be responsible for marked reduction in neuron production leading to a reduction of cortical area.

MCPH1, CDK5RAP2, ASPM, CENPJ, and STIL encode for predominantly centrosome-associated proteins. Moreover, MCPH1 plays a role in DNA repair processes and control of cell cycle checkpoints. Thus, MCPH-causing genes are implicated in cell proliferation and/or apoptosis.

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Acknowledgments

This publication has been supported by the Fondation Jérome Lejeune and the Fondation pour la Recherche Médicale.

Revision History

• 1 September 2009 (me) Review posted live

• 10 November 2008 (av) Original submission