Bachmann-Bupp syndrome (BABS) is caused by typically a de novo pathogenic variant in ODC1.
Molecular Genetics
ODC1 codes for ornithine decarboxylase (ODC), a rate-limiting enzyme in the polyamine pathway, converting ornithine into the polyamine metabolite putrescine. Polyamines (putrescine, spermidine, spermine) are polycationic molecules involved in many physiologic and cell development processes. The C-terminus of ODC contains a 37-amino acid region (amino acids 425-461 using the NM_002539.3 transcript) which is functionally important as a destabilization region. In vitro deletions in this region cause a catalytically functional ODC protein that is more stable due to reduced proteasomal degradation, resulting in elevated ODC protein and polyamine levels, mainly putrescine and N-acetyl-putrescine.
When intracellular putrescine and other polyamine levels are elevated, these metabolites are acetylated. Acetylated polyamines are shuttled out of the cell in an attempt to regain homeostasis, resulting in elevated plasma N-acetylputrescine. In cell experiments using high-performance liquid chromatography (HPLC), increased putrescine is observed because HPLC is not able to separate putrescine from N-acetylputrescine; however, mass spectrometry does have this capability.
A transgenic mouse model created in 1995 in which a C-terminally deleted ODC (p.Pro427Ter) protein was constitutively overexpressed in skin cells showed higher ODC enzyme levels and increased polyamine metabolites. Phenotypically these mice demonstrated skin, nail, and hair follicle abnormalities after birth similar to those seen in BABS patients. Of note, those mice were born with hair that fell out after the first hair cycle, around 1-2 weeks of life. Treatment of the mice with alpha-difluoromethylornithine (DFMO, also referred to as eflornithine) prevented hair loss and allowed partial regrowth of hair.
ODC1