A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency

Muhammad Jameel, Joakim Klar, Muhammad Tariq, Abubakar Moawia, Naveed Altaf Malik, Syeda Seema Waseem, Uzma Abdullah, Tahir Naeem Khan, Raili Raininko, Shahid Mahmood Baig, Niklas Dahl

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23 Citations (Scopus)


Background: Cerebral palsy (CP) is a heterogeneous neurodevelopmental disorder associated with intellectual disability in one-third of cases. Recent findings support Mendelian inheritance in subgroups of patients with the disease. The purpose of this study was to identify a novel genetic cause of paraplegic CP with intellectual disability in a consanguineous Pakistani family. Methods: We performed whole-exome sequencing (WES) in two brothers with CP and intellectual disability. Analysis of mRNA was performed using quantitative real-time PCR on total RNA from cultured fibroblasts. The brothers were investigated clinically and by MRI. Results: We identified a novel homozygous mutation c.194_195delAT, p.Y65Ffs*50 in the affected brothers. Quantitative RT-PCR analysis showed markedly reduced mRNA levels suggesting partial non-sense mediated mRNA decay. Several clinical and MRI features were consistent with complex deficiency. However, in contrast to previously reported cases with mutations our patients show an aggressive behavior and a relatively late onset of disease. Conclusion: This study shows an mutation associated with aggressive behavior in addition to mild dysmorphic features, intellectual disability, spastic paraparesis and reduced head circumference. Our findings expand the clinical spectrum associated with AP-4 complex deficiency and the study illustrates the importance of MRI and WES in the diagnosis of patients with CP and intellectual disability.

Original languageEnglish
Article number133
JournalBMC Medical Genetics
Issue number1
Publication statusPublished - 14 Dec 2014
Externally publishedYes


  • AP-4 deficiency
  • AP4M1 gene
  • Cerebral palsy
  • Clinical variability
  • Mutation


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