biostudies-literatureLi XGenome Canada and Genome BC64https://www.ebi.ac.uk/biostudies/studies/S-EPMC12480863biostudies-literatureUnknown10(1)Gamma-butyrobetaine hydroxylase (BBOX1) catalyses the last step of carnitine biosynthesis, converting γ-butyrobetaine (γ-BB) into L-carnitine. Here we show, for the first time, that biallelic variants in BBOX1 are associated with decreased levels of L-carnitine and increased plasma levels of γ-BB in three patients from two unrelated families presenting with myopathic, neurodevelopmental, and late-onset psychiatric manifestations. Using a knockout C. elegans model of BBOX1 homolog, gbh-1, and strains harboring patient-derived variants (gbh-1(D72G) for p.Asp59Gly, gbh-1(G283R) for p.Gly263Arg, and gbh-1(G247Vfs6) for p.Gly227Valfs*6), we show very low L-carnitine levels and significantly elevated γ-BB in c.675delA and c.787G>A mutants, and moderately elevated γ-BB in c.176A>G. Furthermore, wNPJ genomic medicineBiallelic variants in BBOX1 cause L-Carnitine deficiency and elevated γ-butyrobetaine.PMC12480863275SILHorvath GLi XRakic BMwenifumbo JStockler-Ipsiroglu SArbour LVaz FMLehman ATarailo-Graovac MJacob KJYeganeh MSinclair GfalseBiallelic variants in BBOX1 cause L-Carnitine deficiency and elevated γ-butyrobetaine.Gamma-butyrobetaine hydroxylase (BBOX1) catalyses the last step of carnitine biosynthesis, converting γ-butyrobetaine (γ-BB) into L-carnitine. Here we show, for the first time, that biallelic variants in BBOX1 are associated with decreased levels of L-carnitine and increased plasma levels of γ-BB in three patients from two unrelated families presenting with myopathic, neurodevelopmental, and late-onset psychiatric manifestations. Using a knockout C. elegans model of BBOX1 homolog, gbh-1, and strains harboring patient-derived variants (gbh-1(D72G) for p.Asp59Gly, gbh-1(G283R) for p.Gly263Arg, and gbh-1(G247Vfs6) for p.Gly227Valfs*6), we show very low L-carnitine levels and significantly elevated γ-BB in c.675delA and c.787G>A mutants, and moderately elevated γ-BB in c.176A>G. Furthermore, w2025-01-01T00:00:00Z2025 Sep2026-06-03T23:09:41.308Z2026-05-02T03:12:03.574ZS-EPMC124808634102278310.1038/s41525-025-00523-2