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A Rare CTBP1-Related Neurodevelopmental Disorder Is Associated with Impaired Mitochondrial Bioenergetics: A
Zdravko Ivanov1,2, Maria Gevezova3,4, Iliyana Pacheva1,4
1Pediatrics Clinic, St. George University Hospital, 4002 Plovdiv, Bulgaria.
International Journal of Molecular Sciences
|May 13, 2026
Summary
This study highlights mitochondrial dysfunction in CTBP1 mutations causing Hypotonia, Ataxia, Developmental Delay and Tooth enamel defect Syndrome (HADDTS). Nutritional support improved bioenergetics but not neurological outcomes in a HADDTS patient.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Metabolic Disorders
Background:
- C-terminal binding protein 1 (CTBP1) mutations are rare, causing Hypotonia, Ataxia, Developmental Delay and Tooth enamel defect Syndrome (HADDTS).
- Previous studies suggested mitochondrial dysfunction in HADDTS, but comprehensive metabolic data were lacking.
Purpose of the Study:
- To investigate the metabolic phenotype in a HADDTS patient with a known CTBP1 mutation.
- To assess mitochondrial function using real-time cellular respiration assays.
- To evaluate the impact of mitochondria-targeted nutritional support.
Main Methods:
- Case study of a 10-year-old female with HADDTS and a de novo heterozygous CTBP1 mutation (c.991C>T).
- Mitochondrial respiration was quantified in peripheral blood mononuclear cells (PBMCs) using a Seahorse XFp analyzer.
- Nutritional support was administered for one year, with follow-up assessments.
Main Results:
- Profound mitochondrial dysfunction was observed, with significantly reduced maximal respiration and spare respiratory capacity in the patient's PBMCs compared to controls.
- Mitochondria-targeted nutritional support led to measurable bioenergetic improvements and fewer respiratory infections.
- No significant neurological recovery or new skill acquisition was observed despite nutritional intervention.
Conclusions:
- This study presents a novel case of CTBP1-related neurodevelopmental disorder and provides the first real-time assessment of mitochondrial function in HADDTS.
- The findings confirm mitochondrial dysfunction as a key feature of HADDTS.
- While nutritional support can improve bioenergetics, it does not reverse established neurological deficits in this condition.
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