Autosomal Recessive Primary Microcephaly

Autosomal recessive primary microcephaly (MCPH) is a rare genetically heterogeneous disorder of neurogenic brain development characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.

Epidemiology

Exact prevalence of non-syndromic microcephaly is not known. MCPH is more common in Asian and Middle Eastern populations than in Caucasians, in whom an annual incidence of 1/1,000,000 is reported. It is more common in specific populations, e.g. northern Pakistanis. Consanguinity appears to play a role in incidence.

Clinical description

Patients have a reduction in head circumference (HC) at birth of at least 2 standard deviations (SD) below ethnically matched, age- and sex-related mean values. Microcephaly can be observed by week 32 of pregnancy. Subsequent head growth is very slow, and HC worsens during infancy: below -3SD before 6 months, and usually between -4SD and -12SD in adults. Mild to moderate non-progressive intellectual impairment is found, in the absence of any significant neurological deficit. Seizures may be present (10%). Delay in early motor milestones and speech delay are common. Most patients have hyperactive behavior.

Etiology

Ten subtypes based on the 11 genes have been differentiated. However, patients are basically phenotypically indistinguishable. MCPH is caused by mutations in MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ, STIL, CEP63, CEP135 , CASC5 and PHC1. These mutations appear to lead to reduced generation of cerebral cortical neurons during embryonic neurogenesis. Some patients do not harbor these mutations. Some carry mutations in one of the genes of Meier-Gorlin syndrome (see this term), i.e. CDC6, CDT1, ORC1, ORC4, ORC6.

Diagnostic methods

Diagnosis is generally based on clinical signs. Reduced occipitofrontal circumference along with mild to moderate cognitive impairment, in the absence of other malformations or dysmorphism, and with normal height to mildly shortened height, are the most common diagnostic criteria. MRI shows grossly normal, proportionately small-sized brain with some degree of gyral simplification, and small normal brainstem and cerebellum. Patients with mutations in WDR62 may show more severe cortical anomalies and may not fulfill the common criteria of MCPH. Molecular genetic testing is available for several genes. The condition can be diagnosed on prenatal ultrasound but absence of microcephaly does not exclude the diagnosis.

Differential diagnosis

MCPH and Seckel syndrome belong to a clinical continuum, as mutations of some genes (CENPJ, CEP152) result in either phenotype. The distinction between MCPH and Seckel relies on a historical distinction between microcephalic patients with normal stature and patients with reduced stature. Normal fundus examination is important to distinguish MCPH from the microcephaly-chorioretinopathy syndromes. MRI is crucial to distinguish MCPH from other disorders with congenital microcephaly, such as lissencephaly, Norman-Roberts type (see this term) or infectious embryofetopathies. Assessment of maternal serum phenylalaninemia is mandatory to exclude maternal phenylketonuria (see this term).

Antenatal diagnosis

Prenatal testing and carrier testing are available for families with known gene mutations. When no mutation is identified, fetal MRI could be advised, but normal findings do not exclude the diagnosis.

Genetic counseling

Inheritance is autosomal recessive. Exact genotype-phenotype correlations have not been established.

Management and treatment

There is no specific etiologic treatment. Physical and speech therapy may be beneficial. Seizures are usually stabilized with common anticonvulsants. Ritalin may reduce hyperactivity.

Prognosis

Vital prognosis depends on severity and related manifestations but is generally good.