title: A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency.
abstract: 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 AP4M1 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 AP4M1 mutation c.194_195delAT, p.Y65Ffs*50 in the affected brothers. Quantitative RT-PCR analysis showed markedly reduced AP4M1 mRNA levels suggesting partial non-sense mediated mRNA decay. Several clinical and MRI features were consistent with AP-4 complex deficiency. However, in contrast to previously reported cases with AP4M1 mutations our patients show an aggressive behavior and a relatively late onset of disease.
  
  
  CONCLUSIONS
  This study shows an AP4M1 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.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Jameel
authors.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.forename: Muhammad
authors.initials: M
authors.lastname: Tariq
authors.forename: Abubakar
authors.initials: A
authors.lastname: Moawia
authors.forename: Naveed
authors.initials: N
authors.lastname: Altaf Malik
authors.forename: Syeda
authors.initials: S
authors.lastname: Seema Waseem
authors.forename: Uzma
authors.initials: U
authors.lastname: Abdullah
authors.forename: Tahir
authors.initials: T
authors.lastname: Naeem Khan
authors.forename: Raili
authors.initials: R
authors.lastname: Raininko
authors.forename: Shahid Mahmood
authors.initials: SM
authors.lastname: Baig
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala 751 08, Sweden. niklas.dahl@igp.uu.se.
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000293:Adolescent; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000172:deficiency* / Q000235:genetics*; D002547:Cerebral Palsy / Q000150:complications / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000209:etiology / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C404766:REPIN1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins