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Deficiency of the alkaline ceramidase ACER3 manifests in early childhood by progressive leukodystrophy
  1. Simon Edvardson1,
  2. Jae Kyo Yi2,3,5,
  3. Chaim Jalas4,
  4. Ruijuan Xu3,5,
  5. Bryn D Webb6,
  6. Justin Snider2,3,
  7. Anastasia Fedick7,8,
  8. Elisheva Kleinman4,
  9. Nathan R Treff7,8,
  10. Cungui Mao3,5,
  11. Orly Elpeleg1
  1. 1The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
  2. 2Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA
  3. 3Department of Medicine, Stony Brook University, Stony Brook, New York, USA
  4. 4Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA
  5. 5Stony Brook Cancer Center, Stony Brook, New York, USA
  6. 6Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  7. 7Departments of Molecular Genetics, Microbiology and Immunology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA
  8. 8Reproductive Medicine Associates of New Jersey, Morristown, New Jersey, USA
  1. Correspondence to Professor Orly Elpeleg, The Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Ein karem, Jerusalem 91120, Israel; Elpeleg{at}hadassah.org.il Professor Cungui Mao, Department of Medicine and Stony Brook Cancer Center, The State University of New York at Stony Brook, Health Sciences Center, T15-023 Stony Brook, NY 11794-8155, USA; cungui.mao@stonybrookmedicine.edu

Abstract

Background/aims Leukodystrophies due to abnormal production of myelin cause extensive morbidity in early life; their genetic background is still largely unknown. We aimed at reaching a molecular diagnosis in Ashkenazi-Jewish patients who suffered from developmental regression at 6–13 months, leukodystrophy and peripheral neuropathy.

Methods Exome analysis, determination of alkaline ceramidase activity catalysing the conversion of C18:1-ceramide to sphingosine and D-ribo-C12-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) (NBD)-phytoceramide to NBD-C12-fatty acid using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and thin layer chromatography, respectively, and sphingolipid analysis in patients’ blood by LC-MS/MS.

Results The patients were homozygous for p.E33G in the ACER3, which encodes a C18:1-alkaline ceramidase and C20:1-alkaline ceramidase. The mutation abolished ACER3 catalytic activity in the patients’ cells and failed to restore alkaline ceramidase activity in yeast mutant strain. The levels of ACER3 substrates, C18:1-ceramides and dihydroceramides and C20:1-ceramides and dihydroceramides and other long-chain ceramides and dihydroceramides were markedly increased in the patients’ plasma, along with that of complex sphingolipids, including monohexosylceramides and lactosylceramides.

Conclusions Homozygosity for the p.E33G mutation in the ACER3 gene results in inactivation of ACER3, leading to the accumulation of various sphingolipids in blood and probably in brain, likely accounting for this new form of childhood leukodystrophy.

  • Neurology

https://doi.org/10.1136/jmedgenet-2015-103457

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