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Severe congenital microcephaly with AP4M1 mutation, a case report

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Abstract
Background: Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset. Case presentation: We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly. Conclusions: Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly.
Keywords
NEURAL PROGENITORS, PROTEIN COMPLEX, RECOGNITION, DEFICIENCY, EXPANSION, FRAMEWORK, SIGNALS, Exome sequencing, Brain development, Consanguinity, Intellectual, disability, Case report

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MLA
Duerinckx, Sarah, HELENE VERHELST, Camille Perazzolo, et al. “Severe Congenital Microcephaly with AP4M1 Mutation, a Case Report.” BMC MEDICAL GENETICS 18 (2017): n. pag. Print.
APA
Duerinckx, S., VERHELST, H., Perazzolo, C., David, P., Desmyter, L., Pirson, I., & Abramowicz, M. (2017). Severe congenital microcephaly with AP4M1 mutation, a case report. BMC MEDICAL GENETICS, 18.
Chicago author-date
Duerinckx, Sarah, HELENE VERHELST, Camille Perazzolo, Philippe David, Laurence Desmyter, Isabelle Pirson, and Marc Abramowicz. 2017. “Severe Congenital Microcephaly with AP4M1 Mutation, a Case Report.” Bmc Medical Genetics 18.
Chicago author-date (all authors)
Duerinckx, Sarah, HELENE VERHELST, Camille Perazzolo, Philippe David, Laurence Desmyter, Isabelle Pirson, and Marc Abramowicz. 2017. “Severe Congenital Microcephaly with AP4M1 Mutation, a Case Report.” Bmc Medical Genetics 18.
Vancouver
1.
Duerinckx S, VERHELST H, Perazzolo C, David P, Desmyter L, Pirson I, et al. Severe congenital microcephaly with AP4M1 mutation, a case report. BMC MEDICAL GENETICS. 2017;18.
IEEE
[1]
S. Duerinckx et al., “Severe congenital microcephaly with AP4M1 mutation, a case report,” BMC MEDICAL GENETICS, vol. 18, 2017.
@article{8525495,
  abstract     = {Background: Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset. 
Case presentation: We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly. 
Conclusions: Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly.},
  articleno    = {48},
  author       = {Duerinckx, Sarah and Verhelst, Helene and Perazzolo, Camille and David, Philippe and Desmyter, Laurence and Pirson, Isabelle and Abramowicz, Marc},
  issn         = {1471-2350},
  journal      = {BMC MEDICAL GENETICS},
  keywords     = {NEURAL PROGENITORS,PROTEIN COMPLEX,RECOGNITION,DEFICIENCY,EXPANSION,FRAMEWORK,SIGNALS,Exome sequencing,Brain development,Consanguinity,Intellectual,disability,Case report},
  language     = {eng},
  pages        = {5},
  title        = {Severe congenital microcephaly with AP4M1 mutation, a case report},
  url          = {http://dx.doi.org/10.1186/s12881-017-0412-9},
  volume       = {18},
  year         = {2017},
}

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