ASPM Primary Microcephaly

Clinical characteristics: ASPM primary microcephaly (ASPM-MCPH) is characterized by: (1) significant microcephaly (>3 standard deviations [SD] below the mean for age) usually present at birth and always present before age one year and (2) the absence of other congenital anomalies. While developmental milestones are usually normal in young children, older children have variable levels of intellectual disability. Neurologic examination is usually normal except for mild spasticity. Seizures are not common.

Diagnosis/testing: The diagnosis of ASPM-MCPH is established in a proband with biallelic pathogenic variants in ASPM identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment is symptomatic and focused on interventions to address developmental delay / intellectual disability, speech delay, and behavior issues. The management of epilepsy and spasticity is per standard care.

Surveillance: Routine monitoring of: growth; response of seizures to treatment or new-onset seizures; management of spasticity; developmental progress, including speech and language development; educational needs; and behavior for anxiety, attention, and aggressive or self-injurious behavior. Assess family need for social work support (e.g., respite care, other local resources).

Agents/circumstances to avoid: Limit the use of methylphenidate, which exacerbates hyperactivity.

Genetic counseling: ASPM-MCPH is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a heterozygote (carrier), and a 25% chance of being unaffected and not a carrier. Heterozygotes may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with ASPM-MCPH. Once the ASPM pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.