Case Report

Berardinelli-Seip syndrome patient with novel AGPAT2 splicesite mutation and concomitant development of non-diabetic polyneuropathy

10.4274/jcrpe.0227

  • Joanna Oswiecimska
  • Mateusz Dawidziuk
  • Tomasz Gambin
  • Katarzyna Ziora
  • Marta Marek
  • Sylwia Rzonca
  • D. Lys Guilbride
  • Shalini N. Jhangiani
  • Anna Obuchowicz
  • Alicja Sikora
  • James R. Lupski
  • Wojciech Wiszniewski
  • Pawel Gawlinski

J Clin Res Pediatr Endocrinol 0;0(0):0-0 [e-Pub] PMID: 30563316

Primary polyneuropathy in the context of Seip-Berardinelli type 1 seipinopathy, or congenital lipodystrophy type 1 (CGL1) is previously unknown. We report the case history of a 27 year old female CGL1 patient presenting with unusual additional development of non-diabetic peripheral neuropathy (PN) and learning disabilities in early adolescence. Whole exome sequencing (WES) of the patient genome identifies a novel rare variant homozygous for a 52 bp intronic deletion in the AGPAT2 locus uniquely associated with CGL1 seipinopathies, with no molecular evidence for dual diagnosis. Functional studies using RNA isolated from patient peripheral blood leucocytes show abnormal RNA splicing resulting in the loss of 25 amino acids from patient AGPAT2 protein coding sequence. Stability and transcription levels for the misspliced AGPAT2 mRNA in our patient nonetheless remain normal. Any AGPAT2 protein produced in our patient is therefore likely to be dysfunctional. However, formal linkage of this deletion to the neuropathy observed remains to be shown. The classical clinical presentation of a patient with AGPAT2-associated lipodystrophy shows normal cognition and no development of polyneuropathy. Cognitive disabilities and polyneuropathy are features to date associated exclusively with clinical CGL type 2 arising from BSCL2 gene mutations. This case study suggests that in some genetic contexts, AGPAT2 mutations can also produce phenotypes with primary polyneuropathy.

Keywords: Berardinelli-Seip syndrome, seipinopathy, congenital generalized lipodystrophy, polyneuropathy, AGPAT2, fat biology