ODC1 – Bachmann-Bupp Syndrome

Bachmann-Bupp syndrome (BABS) is an ultra-rare autosomal dominant neurodevelopmental disorder characterized by global developmental delay, hypotonia, macrosomia, macrocephaly, and a distinctive pattern of non-congenital alopecia. The condition is caused by gain-of-function variants clustering at the C-terminus of the ornithine decarboxylase 1 gene (Gene Symbol; Disease Name).

Genetic evidence supports a strong association: at least seven unrelated probands harbor de novo truncating variants in the ODC1 C-terminus, including c.1313_1316del (p.Pro438ArgfsTer9) (PMID:36443247) and c.1342A>T (p.Lys448Ter) (PMID:30239107). A multi-patient series added four new cases with similar clinical and molecular findings (PMID:34477286). All variants act through a gain-of-function mechanism, with de novo occurrence and no evidence of segregation beyond the proband.

Functional studies demonstrate that C-terminal truncations disrupt a ubiquitin-independent degron, preventing proteasomal degradation and leading to marked accumulation of catalytically active ODC in patient cells. Primary dermal fibroblasts from affected individuals show 12- to 17-fold increased ODC activity and red blood cells exhibit 125- to 137-fold elevation compared to controls; both measures are normalized by the ODC inhibitor α-difluoromethylornithine (DFMO) (PMID:31249027). These data confirm a gain-of-function pathogenic mechanism amenable to pharmacologic rescue.

Therapeutically, compassionate use of DFMO in multiple patients led to improved hair regrowth, increased muscle tone, and developmental gains, highlighting a targeted approach for this metabolic disorder (PMID:36443247; PMID:37469105).

No conflicting evidence has been reported. The convergence of de novo genetic findings, robust functional assays, and positive treatment responses supports a Strong clinical validity classification.

Key take-home: Dominant de novo C-terminal truncating variants in ODC1 cause Bachmann-Bupp syndrome via ODC accumulation, and DFMO offers a precision therapy.

References

• Developmental medicine and child neurology • 2024 • Bachmann-Bupp syndrome and treatment. PMID:37469105
• American journal of medical genetics. Part A • 2021 • Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome. PMID:34477286
• Journal of medical genetics • 2022 • Two Bachmann-Bupp syndrome patients treated with difluoromethylornithine. PMID:36443247
• American journal of medical genetics. Part A • 2018 • Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features. PMID:30239107
• The Biochemical journal • 2019 • Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation. PMID:31249027

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