Lethal neonatal acidosis: Multiomic investigation of a novel HIBCH variant as the underlying cause
HIBCH (3-Hydroxyisobutyryl-CoA hydrolase) deficiency is a rare, autosomal recessive inborn error of metabolism caused by pathogenic variants in HIBCH and typically presenting in the first year of life with hypotonia, seizures, global developmental delay, poor feeding, and ataxia. Biochemical abnorma...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-06-01
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| Series: | Molecular Genetics and Metabolism Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2214426925000382 |
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| Summary: | HIBCH (3-Hydroxyisobutyryl-CoA hydrolase) deficiency is a rare, autosomal recessive inborn error of metabolism caused by pathogenic variants in HIBCH and typically presenting in the first year of life with hypotonia, seizures, global developmental delay, poor feeding, and ataxia. Biochemical abnormalities such as lactic acidosis and hyperammonemia may also be seen due to disruption of mitochondrial function, and the diagnosis may also be suspected by the presence of elevated hydroxy-C4-carnitine (C4-OH) detected from a blood sample with a definitive diagnosis obtainable by genetic analysis. We describe a neonate with mild hypotonia at birth who rapidly developed a severe metabolic acidosis, with her venous pH reaching a nadir of 6.374 within hours of life and death occurring within 15 h of life despite supportive measures. A genomic autopsy was undertaken using a blood sample saved prior to the neonatal death. Postmortem trio exome sequencing of the neonate and both parents revealed the neonate to be homozygous for a novel variant in HIBCH predicted to impact splicing, presumably resulting in severe deficiency of HIBCH enzyme activity. As both parents were carriers of the causal variant, anticipatory guidance was provided for risk reduction in future pregnancies. This case highlights the importance of comprehensive postmortem evaluation to evaluate severe, neonatal lethal conditions. |
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| ISSN: | 2214-4269 |