Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.
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.
Passemard
S
S
Department of Clinical Genetics, U676, Hôpital Robert Debré, APHP, 75019 Paris, France.
Titomanlio
L
L
Elmaleh
M
M
Afenjar
A
A
Alessandri
J-L
JL
Andria
G
G
de Villemeur
T Billette
TB
Boespflug-Tanguy
O
O
Burglen
L
L
Del Giudice
E
E
Guimiot
F
F
Hyon
C
C
Isidor
B
B
Mégarbané
A
A
Moog
U
U
Odent
S
S
Hernandez
K
K
Pouvreau
N
N
Scala
I
I
Schaer
M
M
Gressens
P
P
Gerard
B
B
Verloes
Alain
A
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006257:Head / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008831:Microcephaly / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D011712:Pyramidal Tracts / Q000503:physiopathology; D011859:Radiography; D012640:Seizures / Q000235:genetics / Q000503:physiopathology; D012886:Skull / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology; D055815:Young Adult
C467202:ASPM protein, human; D009419:Nerve Tissue Proteins