Adaptor protein complex-4 (AP-4) deficiency causes a novel autosomal recessive cerebral palsy syndrome with
Andres Moreno-De-Luca1, Sandra L Helmers, Hui Mao
1Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
Insights
Genetic mutations, not just hypoxic-ischaemic injury, are key causes of cerebral palsy. A specific gene deletion in adaptor protein complex-4 (AP-4) causes a severe neurological disorder, highlighting AP-4 deficiency syndrome.
Area of Science:
- Neurogenetics
- Developmental Neuroscience
- Clinical Genetics
Background:
- Cerebral palsy (CP) is a complex neurodevelopmental disorder affecting motor function, posture, and potentially cognitive and sensory abilities.
- While hypoxic-ischaemic injury was historically considered the primary cause of CP, recent evidence points to a significant role for genetic factors.
- Genetic abnormalities are increasingly recognized as major contributors to the diverse spectrum of CP.
Purpose of the Study:
- To investigate the genetic underpinnings of a severe form of cerebral palsy within a consanguineous family.
- To identify the specific genetic mutation responsible for spastic tetraplegic cerebral palsy, intellectual disability, microcephaly, epilepsy, and white matter loss.
Main Methods:
- Utilized chromosomal microarray analysis to detect genetic variations.
- Performed genetic analysis to identify homozygous deletions in affected family members.
Main Results:
- Identified a homozygous deletion in the AP4E1 gene, a subunit of the adaptor protein complex-4 (AP-4).
- This deletion was found in a family presenting with autosomal recessive spastic tetraplegic cerebral palsy, profound intellectual disability, microcephaly, epilepsy, and white matter loss.
- The identified mutation disrupts the function of the entire AP-4 complex.
Conclusions:
- Disruption of any subunit of the AP-4 complex leads to the dysfunction of the entire complex.
- These findings establish a distinct genetic disorder, termed 'AP-4 deficiency syndrome', caused by mutations in AP-4 subunits.
- This syndrome is characterized by severe neurological impairments, including cerebral palsy and intellectual disability.
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'.
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