Expanding the genetic and phenotypic spectrum of branched‐chain amino acid transferase 2 deficiency
Open accessAbstract
The first step in branched‐chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched‐chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra‐rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low‐normal branched‐chain keto acids (BCKAs) with undetectable l‐allo‐isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide‐ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein‐restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.
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Additional BCAT2 mutations have been identified, ranging between homozygous or compound heterozygous BCAT2 mutations.
“A more recent study identified several additional BCAT2 mutations that ranged between homozygous or compound heterozygous BCAT2 mutations (Knerr et al. 2019).”
From Alzheimer’s disease: Targeting the glutamatergic system (2020) · cites this paper as Knerr et al. 2019
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- Authors
- Knerr, I., Colombo, R., Urquhart, J., Morais, A., Merinero, B., Oyarzabal, A., Pérez, B., Jones, S. A., Perveen, R., Preece, M. A., Rogers, Y., Treacy, E. P., Mayne, P., Zampino, G., MacKinnon, S., Wassmer, E., Yue, W. W., Robinson, I., Rodríguez‐Pombo, P., Olpin, S. E., & Banka, S.
- Affiliations
- Temple Street Children's University Hospital (IE)
- Università Cattolica del Sacro Cuore (IT)
- St Mary's Hospital (GB)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Centro de Diagnostico de Enfermedades Moleculares, Departamento de Biologia Molecular, Centro de Biologia Molecular Severo Ochoa, Centro de Investigacion Biomedica en Red de Enfermedades Raras Universidad Autonoma de Madrid Spain
- University of Manchester (GB)
- Birmingham Women’s and Children’s NHS Foundation Trust (GB)
- Mater Misericordiae University Hospital (IE)
- University of Oxford (GB)
- Sheffield Children's NHS Foundation Trust (GB)
- Corresponding author
- Knerr, Ina
- ORCID
- Venue
- Journal of Inherited Metabolic Disease
- Publisher
- Wiley
- Published
- 2019-08
- Volume
- 42
- Issue
- 5
- Pages
- 809-817
- ISSN
- 0141-8955 (ISSN-L)
- 1573-2665
- OpenAlex
- W2948459858
- Cited by
- 25
- References
- 23
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 1
- FWCI
- 2.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Inherited Metabolic Disease (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- European Regional Development Fund (PI12/02078)
- Ministerio de Economía y Competitividad
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- BCAT2, branched-chain amino acid catabolism, maple syrup urine disease, inborn errors of metabolism, branched-chain keto acids, developmental delay, autism spectrum disorder, phenotypic variability, low-protein diet, compound heterozygosity, homozygous mutation
- MeSH terms
- Adolescent, Adult, Amino Acid Metabolism, Inborn Errors, Amino Acids, Branched-Chain, Transaminases, Brain, Child, Child, Preschool, Female, Homozygote, Humans, Magnetic Resonance Imaging, Male, Mitochondria, Mutation, Phenotype, Pregnancy Proteins, Minor Histocompatibility Antigens
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