Orphanet Journal of Rare Diseases | Isobutyryl-CoA dehydrogenase deficiency: disease, or non-disease?

Recommend:

This study systematically reviewed 172 cases of isobutyryl-CoA dehydrogenase deficiency (IBDD), revealing that most patients are asymptomatic, but some exhibit liver function abnormalities and hepatic steatosis, suggesting the need to re-evaluate its clinical significance in newborn screening.

 

Literature Overview

This article, 'Isobutyryl-CoA dehydrogenase deficiency: disease, or non-disease?', published in the Orphanet Journal of Rare Diseases, reviews and summarizes the clinical phenotypes, molecular profiles, and natural history of isobutyryl-CoA dehydrogenase deficiency (IBDD). Through a systematic literature review, the study integrates data from 172 reported IBDD patients up to December 2024, analyzing biochemical markers, genetic variant characteristics, and clinical manifestations, with a focus on whether IBDD should be classified as a clinical disease or merely an asymptomatic metabolic variant. The study finds that although most patients are identified through newborn screening and remain asymptomatic over the long term, a minority exhibit developmental delay, anemia, and liver function abnormalities, or even hepatic steatosis, suggesting potential organ-specific effects. The research emphasizes the importance of long-term follow-up and liver function monitoring for IBDD and calls for a re-evaluation of current newborn screening strategies. The article ends with a Chinese period.

Background Knowledge

Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive metabolic disorder caused by biallelic pathogenic variants in the ACAD8 gene, leading to functional deficiency of isobutyryl-CoA dehydrogenase (IBD) and impaired catabolism of valine. This enzyme catalyzes the conversion of isobutyryl-CoA to methacrylyl-CoA, a key step linking branched-chain amino acid metabolism to the tricarboxylic acid cycle. IBDD was first described in 1998 in a girl presenting with anemia, dilated cardiomyopathy, and carnitine deficiency, but most subsequent cases have been identified via expanded newborn screening (NBS) based on elevated C4-acylcarnitine levels detected by tandem mass spectrometry. Due to the largely asymptomatic nature of most patients, controversy remains over whether IBDD constitutes a true 'disease' or merely a biochemical variant. International NBS programs vary in their inclusion criteria for IBDD, with some countries listing it as a secondary target or excluding it entirely, primarily due to the lack of clear long-term clinical outcome data and effective interventions. Additionally, diagnostic markers such as urinary isobutyrylglycine have limited sensitivity, and elevated C4-acylcarnitine can also occur in other metabolic disorders (e.g., short-chain acyl-CoA dehydrogenase deficiency), increasing diagnostic complexity. Although animal models have shown that IBDD can lead to hepatic steatosis, evidence of liver injury in humans remains scarce. Therefore, this study aims to systematically evaluate existing literature to clarify the clinical spectrum of IBDD, explore genotype-phenotype correlations, and provide evidence for screening strategies and follow-up recommendations. The article ends with a Chinese period.

 

Useful for preliminarily predicting phenotypes potentially caused by gene knockout before designing experiments.

Learn More

 

Methods and Experiments

The research team conducted a systematic search of the PubMed and HGMD® databases for literature on IBDD published up to November 2024, using keywords including 'isobutyryl-CoA dehydrogenase', 'ACAD8', and 'isobutyrylglycinuria'. Inclusion criteria were individuals diagnosed via metabolic, enzymatic, or genetic testing with sufficient clinical or genetic information. Data extracted included age, sex, family history, biochemical markers, clinical manifestations, genetic variants, treatment, and outcomes. Pathogenicity of variants was assessed using multiple bioinformatics tools (e.g., Mutation Taster, SIFT, PolyPhen-2). Patient populations were classified by geographic ancestry as defined by gnomAD to analyze variant distribution. Statistical analysis used Fisher’s exact test to compare symptom frequencies between different diagnostic groups, with P < 0.05 considered significant. Narrative synthesis was used for descriptive data analysis.

Key Findings and Perspectives

• A total of 172 IBDD patients were included, of whom 165 (95.9%) were identified through newborn screening and 7 were diagnosed through selective screening due to clinical symptoms or family history
• 146 patients remained asymptomatic during follow-up, while 26 exhibited non-specific clinical manifestations including motor developmental delay, growth retardation, hypotonia, language and developmental delay, and anemia, with anemia being the most common abnormality (12 cases)
• All patients showed elevated blood or plasma C4-acylcarnitine, but urinary isobutyrylglycine was elevated only in a subset of patients, highlighting the limitations of this biomarker for diagnosis
• 64 different pathogenic variants in the ACAD8 gene were identified, with c.286G>A p.(Gly96Ser) being the most common, predominantly found in Chinese populations, suggesting a possible founder effect
• 19 patients exhibited liver function abnormalities: 18 had isolated elevations of transaminases and γ-GT, and one 11-year-old boy showed hepatomegaly with ultrasound indicating hepatic steatosis, consistent with IBDD mouse models, suggesting potential liver involvement
• Although the selective screening group had more severe symptoms, the difference in symptom frequency between diagnostic groups was not statistically significant, possibly due to small sample size
• Most patients carrying predicted pathogenic variants remained asymptomatic, suggesting possible compensatory mechanisms or gene-environment interactions, making genotype-phenotype correlations difficult to establish

Research Implications and Outlook

This study provides the most comprehensive clinical and genetic analysis of IBDD to date, revealing that although most patients are asymptomatic, there is a potential risk of liver function abnormalities and hepatic steatosis, suggesting IBDD may not be entirely benign. These findings support including liver function monitoring and abdominal ultrasound in diagnosed individuals to detect potential liver complications early.

The results have significant implications for newborn screening policies. Due to the lack of clear long-term clinical consequences and effective interventions, including IBDD in NBS may lead to overdiagnosis and psychological burden on families. Future efforts should strengthen long-term follow-up studies to clarify the natural history and assess whether specific subgroups (e.g., those carrying certain variants or additional metabolic risks) truly benefit from early identification.

Moreover, the study emphasizes the importance of standardized data reporting, particularly demographics, follow-up duration, and clinical assessment details, to improve comparability across studies. Functional studies to clarify the molecular impact of ACAD8 variants and to explore the mechanistic link between IBDD and liver metabolism will be key directions for future research.

 

Assesses the pathogenic potential of gene variants, providing a reference for analyzing variant functionality.

Learn More

 

Conclusion

This study systematically reviewed 172 patients with isobutyryl-CoA dehydrogenase deficiency (IBDD), finding that the vast majority identified through newborn screening remain asymptomatic, while a minority exhibit developmental delay, anemia, and liver function abnormalities. Notably, 19 patients showed elevated liver enzymes, one with hepatic steatosis, consistent with animal models, suggesting a potential link between IBDD and liver metabolic dysfunction. Although the c.286G>A variant is highly prevalent in East Asian populations, no clear genotype-phenotype correlation has been established, and most individuals carrying pathogenic variants remain clinically unaffected. Therefore, the clinical significance of IBDD remains uncertain, and its inclusion in newborn screening should be carefully weighed against the risks of overdiagnosis. The study calls for long-term follow-up of diagnosed patients, particularly monitoring liver function, and recommends incorporating non-invasive assessments such as abdominal ultrasound into clinical evaluations. Future research should focus on functional validation, mechanistic exploration, and long-term outcome analysis in multicenter cohorts to clarify the true disease burden of IBDD and provide evidence for screening and management strategies. Ultimately, this study emphasizes a paradigm shift from 'whether to screen' to 'how to manage', advancing precision metabolic medicine.

 

María Daniela Santacruz Reyes and Jörn Oliver Sass. Isobutyryl-coenzyme a dehydrogenase deficiency: disease, or non-disease?. Orphanet Journal of Rare Diseases.