Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations
S Passemard1, L Titomanlio, M Elmaleh
1Department of Clinical Genetics, U676, Hôpital Robert Debré, APHP, 75019 Paris, France.
Objective:
To determine the spectrum of clinical, neuropsychological, and neuroradiologic features in patients with autosomal recessive primary microcephaly (MCPH) due to ASPM gene mutations.
Methods:
ASPM was sequenced in 52 unrelated MCPH probands. In patients with ASPM mutations, we evaluated the clinical phenotype, cognition, behavior, brain MRI, and family.
Results:
We found homozygous or compound heterozygous ASPM loss-of-function mutations in 11 (22%) probands and 5 siblings. The probands harbored 18 different mutations, of which 16 were new. Microcephaly was severe after 1 year of age in all 16 patients, although in 4 patients the occipital-frontal circumference (OFC) at birth was decreased by only 2 SD. The OFC Z score consistently decreased after birth. Late-onset seizures occurred in 3 patients and significant pyramidal tract involvement in 1 patient. Intellectual quotients ranged from borderline-normal to severe mental retardation. Mild motor delay was noted in 7/16 patients. Language development was delayed in all patients older than 3 years. Brain MRI (n = 12) showed a simplified gyral pattern in 9 patients and several malformations including ventricle enlargement (n = 7), partial corpus callosum agenesis (n = 3), mild cerebellar hypoplasia (n = 1), focal cortical dysplasia (n = 1), and unilateral polymicrogyria (n = 1). Non-neurologic abnormalities consisted of short stature (n = 1), idiopathic premature puberty (n = 1), and renal dysplasia (n = 1).
Conclusions:
We provide a detailed description of features associated with ASPM mutations. Borderline microcephaly at birth, borderline-normal intellectual efficiency, and brain malformations can occur in ASPM-related primary hereditary microcephaly.
Insights
Mutations in the ASPM gene cause autosomal recessive primary microcephaly (MCPH), leading to severe head size reduction and developmental delays. Some patients may present with borderline microcephaly at birth and varying intellectual abilities.
Area of Science:
- Genetics
- Neurology
- Developmental Biology
Background:
- Autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder characterized by reduced head circumference.
- Mutations in the ASPM gene are a known cause of MCPH, but the full spectrum of associated features requires further elucidation.
Purpose of the Study:
- To comprehensively characterize the clinical, neuropsychological, and neuroradiologic features in patients with MCPH resulting from ASPM gene mutations.
Main Methods:
- Sequencing of the ASPM gene in 52 unrelated MCPH probands.
- Detailed evaluation of clinical phenotype, cognition, behavior, and brain MRI in patients identified with ASPM mutations.
Main Results:
- ASPM loss-of-function mutations were identified in 22% of probands, with 16 novel mutations found.
- Patients exhibited severe microcephaly postnatally, with variable intellectual quotients and significant language delays.
- Brain MRI revealed simplified gyral patterns and various malformations, including ventricle enlargement and corpus callosum agenesis.
Conclusions:
- ASPM mutations present a spectrum of features in primary hereditary microcephaly, including potential borderline microcephaly at birth.
- Intellectual efficiency can range from borderline-normal to severe mental retardation.
- Associated brain malformations are common and contribute to the clinical phenotype.
