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Hypolipidaemia among patients with PMM2-CDG is associated with low circulating PCSK9 levels: a case report followed by observational and experimental studies
  1. Michael Chong1,2,
  2. Grace Yoon3,4,
  3. Delia Susan-Resiga5,
  4. Ann Chamberland5,
  5. David Cheillan6,
  6. Guillaume Paré1,7,
  7. Nabil G Seidah5
  1. 1 Genetic & Molecular Epidemiology Laboratory, Population Health Research Institute, David Braley Cardiac Vascular and Stroke Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
  2. 2 Department of Biochemistry & Biomedical Sciences, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  3. 3 Department of Neurology and Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
  4. 4 Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada
  5. 5 Department of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec, Canada
  6. 6 Service de Biochimie et Biologie Moléculaire Grand Est, Unité Médicale Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Lyon, France
  7. 7 Department of Pathology and Molecular Medicine, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  1. Correspondence to Dr Nabil G Seidah, Biochemical neuroendocrinology, Clinical Research Institute of Montreal, Montreal, QC H2W 1R7, Canada; seidahn{at}


Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel therapeutics for reducing low-density lipoprotein cholesterol (LDLc). While serious side-effects have not been observed in short-term clinical trials, there remain concerns that long-term PCSK9 inhibition may cause neurocognitive side-effects.

Methods and results An adult male with childhood-onset global developmental delay, cerebellar atrophy and severe hypolipidaemia underwent extensive biochemical and genetic investigations. Initial testing revealed low circulating PCSK9 levels and a common loss-of-function PCSK9 polymorphism, but these findings did not fully account for severe hypolipidaemia. Whole-exome sequencing was subsequently performed and identified two pathogenic phosphomannose mutase 2 (PMM2) variants (p.Arg141His and p.Pro69Ser) known to cause PMM2-associated congenital disorder of glycosylation (PMM2-CDG). A diagnosis of PMM2-CDG was consistent with the proband’s neurological symptoms and severe hypolipidaemia. Given that PMM2-CDG is characterised by defective protein N-glycosylation and that PCSK9 is a negative regulator of LDLc, we postulated that loss of PCSK9 N-glycosylation mediates hypolipidaemia among patients with PMM2-CDG. First, in an independent cohort of patients with PMM2-CDG (N=8), we verified that circulating PCSK9 levels were significantly lower in patients than controls (p=0.0006). Second, we conducted in vitro experiments in hepatocyte-derived cells to evaluate the effects of PCSK9 N-glycosylation loss on LDL receptor (LDLR) activity. Experimental results suggest that defective PCSK9 N-glycosylation reduces the ability of circulating PCSK9 to degrade LDLR.

Conclusion Life-long exposure to genetically lower PCSK9 per se is unlikely to cause neurocognitive impairment. Both observational and experimental findings suggest that hypolipidaemia in PMM2-CDG may be partially mediated by loss of PCSK9 N-glycosylation and/or its regulators.

  • PCSK9
  • neurocognitive side-effects
  • LDL cholesterol
  • PMM2
  • congenital disorder of glycosylation

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  • Correction notice This article has been corrected since it was published Online First. On page 3, two errors related to Pro69 and P69S have been corrected.

  • Contributors MC and GP analysed and interpreted exome sequencing results and performed all statistical analyses. GY recruited the index case and performed the clinical evaluation of the patient and his father. NS and DSR conducted all in vitro experiments. AC measured circulating PCSK9 levels in PMM2-CDG patients and the index cases’ father. DC provided the secondary cohort of PMM2-CDG cases. MC, NS, and GY were major contributors in writing the manuscript. All authors read and approved the final manuscript. GP and NS are co-last authors.

  • Funding This work was supported by the Canadian Institutes of Health Research grants Foundation Scheme 148363, a Canada Research Chair 231335, and a Fondation Leducq grant #13CVD03.

  • Competing interests GP has received consulting fees from Sanofi, Bristol-Myers Squibb, Lexicomp and Amgen and has received support for research through his institution from Sanofi. MC, GY, DSR, AC, DC and NS declare no competing interests.

  • Patient consent for publication Obtained.

  • Ethics approval This study was approved by the Research Ethics Board of the Hospital for Sick Children, REB #1000009004.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.