Aspm Primary Microcephaly

Clinical characteristics.

ASPM primary microcephaly (ASPM-MCPH) is characterized by: (1) significant microcephaly (below -3 SD 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 as 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 to -3 SDs) 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.

Suggestive Findings

ASPM primary microcephaly (ASPM-MCPH) should be suspected in individuals with the following clinical and neuroimaging findings.

Clinical findings

• Congenital microcephaly (usually identified before birth by ultrasound examination) with an occipitofrontal circumference equal to or below -2 SDs at birth, and below -3.5 SDs before age one year
• Mild intrauterine growth restriction with postnatal catch up (Growth retardation does not persist after age two years.)
• No other congenital abnormalities
• Normal or subnormal motor development
• Usually mild intellectual disability (ID) with preserved memory but variable (range: borderline normal intellectual functioning to severe ID)
• Seizures (rare)
• Nonspecific facial features (i.e., narrow sloping forehead)

Brain MRI findings

• Reduced brain volume that affects supratentorial structures, and, to a lesser extent, the cerebellum [Passemard et al 2009] and brain stem. The mean reduction of cerebral volume is 50%, affecting both the cerebral cortex and white matter; it is more pronounced in the prefrontal and cingulate cortices than in the mesial temporal regions. The volume of the hippocampus is not affected. The cortex is thicker, especially in the prefrontal region [Passemard et al 2016].
• Commonly simplified gyral pattern with reduced gyrification index and surface of the cerebral cortex [Létard et al 2018]
• Mild lateral ventricle enlargement
• Corpus callosum dysplasia/hypoplasia [Passemard et al 2016]
• Cortical dysplasia (rare), which can be bilateral polymicrogyria [Hu et al 2014] or focal polymicrogyria [Passemard et al 2009]) and migration anomalies (heterotopias)

Establishing the Diagnosis

The diagnosis of ASPM-MCPH is established in a proband with biallelic pathogenic variants in ASPM identified by molecular genetic testing (see Table 1).

Because the phenotype of ASPM-MCPH may be indistinguishable from many other primary microcephalies, recommended molecular genetic testing approaches include use of a multigene panel (see Option 1) or comprehensive genomic testing (see Option 2).

Note: Single-gene testing (sequence analysis of ASPM, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

Clinical Description

ASPM primary microcephaly (ASPM-MCPH) is characterized by: (1) significant microcephaly (below -3 SD for age) usually present at birth and always present before age one year and (2) the absence of another congenital anomalies. While developmental motor milestones are usually normal in young children, older children have variable levels of language delay and intellectual disability. Neurologic examination is usually normal except for mild spasticity. Fewer than 15% of affected individuals have seizures.

Growth. While weight and length are most often normal at birth, intrauterine growth restriction may be present in some. Growth may be delayed within the first months of life because of transient feeding difficulties. All children have normal height after age two years.

Occipitofrontal circumference (OFC). Microcephaly is often detected prior to birth, typically during the third trimester of pregnancy and rarely during the second trimester. OFC is between -2 and -8 SD at birth (32 cm and 26 cm, respectively). A clinical characteristic of ASPM-MCPH is a decline in brain growth with age such that OFC is between -4 and -14 SD in adulthood.

Neurologic findings – in the absence of brain malformations – are limited to a mild pyramidal syndrome (i.e., mild spasticity of the lower limbs).

Intellectual disability (ID). Early motor development is normal (in ~50%) or mildly delayed. Language is often delayed (first use of sentences after age 3 years in 80%), with poorly articulated speech or speech limited mostly to single words or short sentences.

Individuals with ASPM-MCPH have mild-to-severe ID. They have preserved memory despite their ID [Passemard et al 2016]. While they may have success with vocational training in crafts or services, affected individuals are likely unable to live independently.

Behavior issues. Preschool age may be very difficult because the children may become angry and hit or bite other children due to their lack of vocabulary.

Before age ten to 12 years, children are easily frustrated with learning activities and appear inattentive to others or to classroom activities. Inattentiveness (inability to listen to or carry out instructions), hyperkinesia (e.g., excessive movement, inability to sit still), and impulsiveness (no sense of danger) tend to appear at an early age and become more noticeable when children start school. Such behaviors are often considered more deleterious to functioning in a classroom than speech delay.

After age 12 years, hyperactivity and impulsiveness disappear. Teenagers are calmer and more attentive. They can appear introverted. They become cheerful, affable, and cooperative [Pattison et al 2000].

Autistic features have not been described in ASPM-MCPH.

Epilepsy. Fewer than 15% of individuals with ASPM-MCPH have epilepsy. Epilepsy is more likely to occur when brain MRI shows cortical anomalies (polymicrogyria, cortical dysplasia). Seizures that often begin after age two years are variable: focal or tonic and tonic-clonic generalized seizures have been reported. Focal seizures should prompt the clinician to search for a focal dysplasia or unilateral polymicrogyria [Passemard et al 2009]. West syndrome has not been reported.

EEG may be normal or show focal spikes.

Other findings. Some individuals with ASPM-MCPH have hypo- and/or hyperpigmented macules [Létard et al 2018].

Findings that are rare, without a recurrent pattern, and are likely coincidental include: scoliosis (2 families [Létard et al 2018]), middle ear hypoplasia [Létard et al 2018], deafness [Darvish et al 2010], preaxial polydactyly [Ahmad et al 2017], unilateral cystic kidney [Passemard et al 2009], and tricuspid insufficiency [Ariani et al 2013].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified.

Nomenclature

Age of onset is used to distinguish primary from secondary microcephaly. Primary microcephaly (PM) is congenital (present at birth) while secondary microcephaly refers to a normal OFC at birth followed by postnatal microcephaly.

Microcephalia vera is a general term used to describe congenital microcephaly associated with neurologic features.

ASPM-MCPH is also designated as MCPH5 (i.e., the 5th primary microcephaly [MCPH] locus to be identified).

Prevalence

A review of the literature in 2019 identified 685 individuals with ASPM-MCPH belonging to 321 families. Most families come from the Asian subcontinent and Middle East (Pakistan, Saudi Arabia, Egypt, and Iran). A few families are from Europe and the Americas [Létard et al 2018].

ASPM-MCPH is the most common form of primary microcephaly. To date, biallelic ASPM pathogenic variants explain 30%-50% of MCPH depending on the geographic origin of the individual and the rate of consanguinity in the population.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ASPM primary microcephaly (ASPM-MCPH), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Surveillance