Identifying Metabolic Markers for the Early Differentiation of LCHAD and TFP Deficiencies: Insights from Acylcarnitine Profiling
Biochemical/Metabolic and Therapeutics
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Primary Categories:
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Secondary Categories:
Introduction:
Background:
Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are rare mitochondrial disorders caused by defects in enzymes involved in the β-oxidation of long-chain fatty acids. Differentiating between LCHAD and TFP deficiency is crucial due to distinct clinical presentations and outcomes. While TFP deficiency can range from severe neonatal cardiac and hepatic involvement to milder forms with exercise-induced rhabdomyolysis, peripheral neuropathy, or skeletal myopathy, LCHAD typically presents with severe neonatal hypoketotic hypoglycemia, cardiomyopathy, liver dysfunction, and long-term complications such as retinopathy. Acylcarnitine profiling using tandem mass spectrometry (MS/MS) is a valuable diagnostic tool for these disorders. This study aims to identify specific acylcarnitine markers that can differentiate between LCHAD and TFP deficiencies, improving early diagnostic precision.
Methods:
Methods:
We conducted a retrospective analysis of acylcarnitine profiles from our electronic medical record (EMR) database (n=24), examining data from 21 patients diagnosed with LCHAD (n=11) and TFP deficiency (n=10). Acylcarnitine levels in plasma were quantified using MS/MS, and statistical comparisons were made between the two groups to identify distinct metabolic patterns that could serve as diagnostic markers.
Results:
Results:
The patients were predominantly male in TFP (M:F=9:1, in LCHAD, M:F=5:9). Our analysis revealed significant differences in the acylcarnitine profiles between LCHAD and TFP patients. Notably, C2 acylcarnitine levels were higher in LCHAD patients (7.5 µM vs. 17.3 µM, p=0.07, Mann Whitney). C18:2-OH levels were significantly lower in LCHAD patients compared to TFP (0.165 µM vs. 0.061 µM, p=0.03, t-test). Additionally, LCHAD patients exhibited elevated levels of C12 and C14 species, while TFP patients showed higher levels of C16 and C18 species.
Conclusion:
Conclusions:
These findings suggest that specific acylcarnitine species C2, C12, C14, C16 and C18 species could serve as key markers to differentiate between LCHAD and TFP deficiencies and early detection and differentiation is essential for acute management, long-term prognosis, and genetic counseling. TFP deficiency may require different interventions, particularly for severe neonatal cardiac symptoms, while LCHAD is associated with chronic cardiomyopathy, liver dysfunction, and retinopathy. This study underscores the potential of acylcarnitine profiling as a diagnostic tool for differentiating LCHAD and TFP deficiencies. Identifying specific acylcarnitine markers, can improve diagnostic accuracy, reduce the incidence of false-negative results, and enhance patient care by enabling earlier detection and more targeted therapeutic interventions. Further validation in larger cohorts is needed to confirm the clinical utility of these markers, contributing to the refinement of diagnostic techniques for mitochondrial fatty acid oxidation disorders.
Background:
Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are rare mitochondrial disorders caused by defects in enzymes involved in the β-oxidation of long-chain fatty acids. Differentiating between LCHAD and TFP deficiency is crucial due to distinct clinical presentations and outcomes. While TFP deficiency can range from severe neonatal cardiac and hepatic involvement to milder forms with exercise-induced rhabdomyolysis, peripheral neuropathy, or skeletal myopathy, LCHAD typically presents with severe neonatal hypoketotic hypoglycemia, cardiomyopathy, liver dysfunction, and long-term complications such as retinopathy. Acylcarnitine profiling using tandem mass spectrometry (MS/MS) is a valuable diagnostic tool for these disorders. This study aims to identify specific acylcarnitine markers that can differentiate between LCHAD and TFP deficiencies, improving early diagnostic precision.
Methods:
Methods:
We conducted a retrospective analysis of acylcarnitine profiles from our electronic medical record (EMR) database (n=24), examining data from 21 patients diagnosed with LCHAD (n=11) and TFP deficiency (n=10). Acylcarnitine levels in plasma were quantified using MS/MS, and statistical comparisons were made between the two groups to identify distinct metabolic patterns that could serve as diagnostic markers.
Results:
Results:
The patients were predominantly male in TFP (M:F=9:1, in LCHAD, M:F=5:9). Our analysis revealed significant differences in the acylcarnitine profiles between LCHAD and TFP patients. Notably, C2 acylcarnitine levels were higher in LCHAD patients (7.5 µM vs. 17.3 µM, p=0.07, Mann Whitney). C18:2-OH levels were significantly lower in LCHAD patients compared to TFP (0.165 µM vs. 0.061 µM, p=0.03, t-test). Additionally, LCHAD patients exhibited elevated levels of C12 and C14 species, while TFP patients showed higher levels of C16 and C18 species.
Conclusion:
Conclusions:
These findings suggest that specific acylcarnitine species C2, C12, C14, C16 and C18 species could serve as key markers to differentiate between LCHAD and TFP deficiencies and early detection and differentiation is essential for acute management, long-term prognosis, and genetic counseling. TFP deficiency may require different interventions, particularly for severe neonatal cardiac symptoms, while LCHAD is associated with chronic cardiomyopathy, liver dysfunction, and retinopathy. This study underscores the potential of acylcarnitine profiling as a diagnostic tool for differentiating LCHAD and TFP deficiencies. Identifying specific acylcarnitine markers, can improve diagnostic accuracy, reduce the incidence of false-negative results, and enhance patient care by enabling earlier detection and more targeted therapeutic interventions. Further validation in larger cohorts is needed to confirm the clinical utility of these markers, contributing to the refinement of diagnostic techniques for mitochondrial fatty acid oxidation disorders.