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

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'.

Figure 1

Pedigree and 15q21.2 deletion region. (A) Pedigree structure of the family. Deletion status is shown for available individuals and represented with −/−, homozygous deletion; +/−, heterozygous deletion; and +/+, non-deleted. Subject III-1 was not available; however, he was described as healthy and is inferred to be a carrier of the deleted allele, indicated by parenthesis. (B) Chromosome 15q21.2 schematic showing the deletion found in our patients, depicted as a horizontal red line. Vertical black bars represent probes from the whole genome 44K array and the tiling 60K array used to fine map the deletion breakpoints. The two genes involved are SPPL2A and AP4E1. (C) Array comparative genomic hybridisation (CGH) results of patient IV-5 used to represent the deletion in both patients. The x-axis displays the genomic position of the probes and the y-axis displays the log₂ ratios of the patient sample hybridised against a normal control. Each dot represents a single probe; normal copy number probes are coloured in black and deleted probes in green. The deleted region is highlighted in green. (D) Metaphase fluorescent in situ hybridisation (FISH) results for chromosome 15. The probe within the deleted region is labelled in red; the control probe, located in the centromeric region of chromosome 15, is labelled in green. Top panel, normal FISH results from the younger sibling (IV-6); middle panel, heterozygous deletion identified in the mother and older sister (III-2, IV-3); bottom panel, homozygous deletion found in both probands (IV-4, IV-5).