Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with microcephaly and intellectual disability

• Type of Material: Article
• Authors: Andres Moreno-De-Luca, Emory University; Karen R Schmidt, Emory University; Paul M Fernhoff, Emory University; David H Ledbetter, Emory University; Sandra Helmers, Emory University; Hui Mao, Emory University; Thomas G. Burns, Emory University; Amanda M. Melton, Emory University; Christa Lese Martin, Emory University
• Language: English
• Date: 2011-02
• Publisher: BMJ Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011, Published by the BMJ Publishing Group Limited.
• Final Published Version (URL): http://dx.crossref.org/10.1136%2Fjmg.2010.082263
• Title of Journal or Parent Work: Journal of Medical Genetics
• ISSN: 0022-2593
• Volume: 48
• Issue: 2
• Start Page: 141
• End Page: 144
• Grant/Funding Information: This work was funded in part by grant MH074090 (to DHL and CLM) from the National Institutes of Health.
• Keywords: motor impairment; genetic abnormality; sensorial disturbances; neurodevelopmental impairment; cognitive disturbances; spastic teraplegic cerebral palsy; brain disorders; hypoxic-ischaemic injury; cerebral palsy; behavioural disturbances
• Research Categories: Biology, Neuroscience; Health Sciences, Rehabilitation and Therapy

Abstract

Background Cerebral palsy is a heterogeneous group of neurodevelopmental brain disorders resulting in motor and posture impairments often associated with cognitive, sensorial, and behavioural disturbances. Hypoxic–ischaemic injury, long considered the most frequent causative factor, accounts for fewer than 10% of cases, whereas a growing body of evidence suggests that diverse genetic abnormalities likely play a major role. Methods and results This report describes an autosomal recessive form of spastic tetraplegic cerebral palsy with profound intellectual disability, microcephaly, epilepsy and white matter loss in a consanguineous family resulting from a homozygous deletion involving AP4E1, one of the four subunits of the adaptor protein complex-4 (AP-4), identified by chromosomal microarray analysis. Conclusion These findings, along with previous reports of human and mouse mutations in other members of the complex, indicate that disruption of any one of the four subunits of AP-4 causes dysfunction of the entire complex, leading to a distinct ‘AP-4 deficiency syndrome’.