RGD Reference Report - Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations. - Rat Genome Database

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Expanding the clinical and neuroradiologic phenotype of primary microcephaly due to ASPM mutations.

Authors: Passemard, S  Titomanlio, L  Elmaleh, M  Afenjar, A  Alessandri, J-L  Andria, G  de Villemeur, T Billette  Boespflug-Tanguy, O  Burglen, L  Del Giudice, E  Guimiot, F  Hyon, C  Isidor, B  Mégarbané, A  Moog, U  Odent, S  Hernandez, K  Pouvreau, N  Scala, I  Schaer, M  Gressens, P  Gerard, B  Verloes, Alain 
Citation: Passemard S, etal., Neurology. 2009 Sep 22;73(12):962-9. doi: 10.1212/WNL.0b013e3181b8799a.
RGD ID: 13442485
Pubmed: PMID:19770472   (View Abstract at PubMed)
DOI: DOI:10.1212/WNL.0b013e3181b8799a   (Journal Full-text)


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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
primary autosomal recessive microcephaly  IAGP 13442485DNA:mutations: :RGD 
primary autosomal recessive microcephaly  ISOASPM (Homo sapiens)13442485; 13442485DNA:mutations: :RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Delayed speech and language development  IAGP 13442485DNA:mutations: :RGD 
Simplified gyral pattern  IAGP 13442485DNA:mutations: :RGD 
Objects Annotated

Genes (Rattus norvegicus)
Aspm  (assembly factor for spindle microtubules)

Genes (Mus musculus)
Aspm  (abnormal spindle microtubule assembly)

Genes (Homo sapiens)
ASPM  (assembly factor for spindle microtubules)


Additional Information