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A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency
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A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency
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A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency
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Journal Article
A novel AP4M1 mutation in autosomal recessive cerebral palsy syndrome and clinical expansion of AP-4 deficiency
2014
Overview
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.
Conclusion
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.
Publisher
BioMed Central
Subject
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - deficiency
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
/ Biomedical and Life Sciences
/ Cerebral Palsy - complications
/ Child
/ Clinical-Molecular Genetics and Cytogenetics
/ Genes
/ Humans
/ Infant
/ Intellectual Disability - etiology
/ Intellectual Disability - genetics
/ Male
/ Mutation
/ Pedigree
/ Studies
