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Holocarboxylase synthase (HCS) deficiency is an extremely rare metabolic disorder typically presenting as severe neonatal metabolic acidosis, lethargy, hypotonia, vomiting, and seizures. This report describes two siblings in a family with late-onset forms of HCS deficiency. The younger sister presented at the age of 11 years and manifested as acute metabolic acidosis, which promptly resolved following rehydration and biotin administration. The results of the organic urine profile confirmed multiple carboxylase deficiency, and genetic testing revealed a novel pathogenic variant in the HLCS gene (NM&#95;000411.8) in the homozygous state: c.995A>G; p. (Gln332Arg). No further decompensation was observed for her during the 3-year follow-up period. His older brother was diagnosed at the age of 23 years-old through biochemical tests, without any history of acidotic decompensation. A mini-review of HCS deficiency with late onset (>1 year) or early onset (<1 month) revealed that splice variants are associated with late onset, while both variants p. (Leu216Arg) and p. (Leu237Pro) are associated with early onset. However, the majority of genotypes do not show a clear correlation with the timing of HCS deficiency onset. The most significant point here is the description of extremely late-onset cases of HCS deficiency. This can prompt metabolic investigations and raise suspicion of this rare disease in cases of unexplained metabolic acidosis, even beyond early childhood., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gaschignard, Domenach, Lamireau, Guibet, Roche, Richard, Redonnet-Vernhet, Mesli and Lebreton.)

Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive metabolic disorder usually associated with mutations in genes AMT , GLDC or GCSH involved in the glycine cleavage complex. Other genes have been linked with less severe NKH, associated with deficiency of lipoate cofactor such as GLRX5, LIAS, BOLA3 . We identified a new case of GLRX5-mediated NKH who presented at 2-month with severe developmental delay and seizures. The initial suspicion was raised by the MRI and then confirmed by glycine measurements in cerebrospinal fluid and blood. Genetic analysis revealed a previously undescribed homozygous variant in the GLRX5 gene [NM&#95;016417.3:c.367G>C; p. (Asp123His)]. Despite medication and supportive care, he died at the age of 4 months after a sudden neurological deterioration. It was decided to limit therapeutic interventions due to the severity of the prognosis. The case was more severe than the previous GLRX5-mediated NKH described, regarding the early age at onset and the severity. Moreover, the genetic variant was located at a potentially crucial site for glutathione binding in the GLRX5 protein. This report, thereby, expands our understanding of NKH's genetic underpinnings and phenotypic variability, highlighting the crucial role of GLRX5 and other related genes in variant NKH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Marin, Lebreton, Guibet, Mesli, Redonnet-Vernhet, Dexant, Lamireau, Roche, Gaschignard, Delmas, Margot and Bar.)