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Case Report: a novel PNPLA2 homozygous frameshift variant causing severe neutral lipid storage disease with myopathy

Elena Faedo1,2, Mary Marcela Araujo Chumacero3, Sara Missaglia4,5

  • 1Reference Center for Neuromuscular Disorders, APHP Henri Mondor University Hospital, Créteil, France.

Frontiers in Genetics
|June 10, 2026
PubMed

Insights

Neutral lipid storage disease with myopathy (NLSDM) is a rare genetic disorder affecting lipid metabolism. A novel PNPLA2 variant was identified in a patient, expanding our understanding of this condition.

Area of Science:

  • Genetics
  • Metabolic Disorders
  • Molecular Biology

Background:

  • Neutral lipid storage disease with myopathy (NLSDM) is an ultra-rare autosomal recessive disorder.
  • It stems from PNPLA2 variants, impairing adipose triglyceride lipase (ATGL) and causing triglyceride buildup.
  • The clinical spectrum and molecular basis of NLSDM are not fully understood.

Purpose of the Study:

  • To characterize a novel PNPLA2 variant in a patient with NLSDM.
  • To expand the phenotypic and molecular understanding of NLSDM.

Main Methods:

  • Clinical presentation and diagnostic workup of a 57-year-old Moroccan man.
  • Whole-body muscle MRI, deltoid muscle biopsy, peripheral blood smear analysis.
  • Next-generation sequencing, bioinformatics protein modeling, and Western blotting.

Main Results:

  • The patient presented with diabetes, hearing loss, cataracts, hypertrophic cardiomyopathy, and asymmetric weakness.
  • Muscle MRI showed severe fatty infiltration; muscle biopsy revealed lipid-filled vacuoles and Jordans' anomaly.
  • A novel homozygous PNPLA2 frameshift variant (c.1043del, p.Phe348SerfsTer18) was identified, predicted to disrupt ATGL function.
  • Protein modeling and Western blotting confirmed the variant leads to a truncated ATGL protein.

Conclusions:

  • This case expands the known clinical and molecular spectrum of NLSDM.
  • The identified PNPLA2 variant provides functional insights into ATGL deficiency.
  • Further research is needed to fully elucidate NLSDM pathogenesis and therapeutic strategies.
Keywords:
Jordans’ anomalyPNPLA2 genelipid droplet accumulationneutral lipid storage disease with myopathyneutral lipid storage diseases

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