RARE DISEASE
Isovaleric acidemia
Isovaleric acidemia
Isovaleric acidemia
Synonyms: Isovaleric acid CoA dehydrogenase deficiency
Synonyms: Isovaleric acid CoA dehydrogenase deficiency
Synonyms: Isovaleric acid CoA dehydrogenase deficiency
Drug discovery
1
drug
With orphan designation
Overview
Isovaleric acidemia (IVA) is an autosomal recessive disorder of leucine metabolism caused by deficiency of isovaleryl-CoA dehydrogenase, leading to toxic accumulation of isovaleric acid and metabolites. It presents with variable severity, ranging from acute neonatal-onset metabolic crises (vomiting, acidosis, encephalopathy) to chronic intermittent forms triggered by infections or catabolic stress. Diagnosis relies on elevated isovalerylglycine in urine and C5-carnitine in blood. Management combines dietary leucine restriction, carnitine/glycine supplementation, and aggressive metabolic support during decompensation [1][2][4][11].
Burden
Mortality reaches 33% in untreated neonatal-onset cases; survivors risk neurodevelopmental deficits [4][20]
Requires lifelong metabolic monitoring, emergency protocols for illnesses, and caregiver education [13][16]
Economic burden stems from specialized formulas, medications, and hospitalizations during decompensation [4][13]
Therapies
Dietary control: Leucine-restricted diet with medical formulas to prevent toxicity [3][9][18]
Detoxification: L-carnitine (100 mg/kg/day) and/or glycine (150-300 mg/kg/day) to enhance excretion of isovaleryl-CoA conjugates [3][8][13]
Acute crisis management: IV hydration, glucose infusion, bicarbonate for acidosis, and hemodialysis for refractory hyperammonemia (>600 μmol/L) [1][13][18]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
76 drug discovery papers about Isovaleric acidemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
76 drug discovery papers about Isovaleric acidemia, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-29 | Immune dysregulation syndrome associated with inborn errors of metabolism - hemophagocytic lymphohistiocytosis in the context of isovaleric acidemia: a case report.
Hemophagocytic lymphohistiocytosis (HLH) continues to pose a diagnostic challenge in pediatric critical care, not only because of its severity but also due to the wide range of conditions that can underlie its presentation. Among these, metabolic disorders are often overlooked. We describe an 18-month-old boy who initially presented with persistent fever and respiratory symptoms, later evolving to pancytopenia, hepatosplenomegaly, and neurological deterioration, the patient fulfilled seven of the eight HLH-2004 criteria. Along the way, adenovirus and parainfluenza virus type III were identified, and anti-NMDA receptor encephalitis was confirmed, adding further complexity to the clinical picture. What proved decisive was the identification of a homozygous pathogenic variant in the IVD gene (c.1174C > T; p.Arg392Cys), establishing the diagnosis of isovaleric acidemia. This finding reframed the case. Rather than an isolated hyperinflammatory syndrome, the clinical course can be better understood as the result of a metabolic disorder capable of amplifying immune dysregulation, particularly in the setting of intercurrent infection. In this context, the features of HLH appear not as a separate entity but as part of a broader process, where metabolic decompensation, accumulation of toxic intermediates, and systemic inflammation converge. This overlap is likely underrecognized in clinical practice. Recognizing this possibility has practical implications. It shifts the diagnostic focus, but also opens the door to more tailored management strategies. In similar cases, HLH may be less an endpoint diagnosis and more a signal pointing toward an underlying metabolic or genetic condition that requires specific attention.
2026-06-12 | Data Sheet 1_Immune dysregulation syndrome associated with inborn errors of metabolism – hemophagocytic lymphohistiocytosis in the context of isovaleric acidemia: a case report.pdf
Hemophagocytic lymphohistiocytosis (HLH) continues to pose a diagnostic challenge in pediatric critical care, not only because of its severity but also due to the wide range of conditions that can underlie its presentation. Among these, metabolic disorders are often overlooked. We describe an 18-month-old boy who initially presented with persistent fever and respiratory symptoms, later evolving to pancytopenia, hepatosplenomegaly, and neurological deterioration, the patient fulfilled seven of the eight HLH-2004 criteria. Along the way, adenovirus and parainfluenza virus type III were identified, and anti-NMDA receptor encephalitis was confirmed, adding further complexity to the clinical picture. What proved decisive was the identification of a homozygous pathogenic variant in the IVD gene (c.1174C > T; p.Arg392Cys), establishing the diagnosis of isovaleric acidemia. This finding reframed the case. Rather than an isolated hyperinflammatory syndrome, the clinical course can be better understood as the result of a metabolic disorder capable of amplifying immune dysregulation, particularly in the setting of intercurrent infection. In this context, the features of HLH appear not as a separate entity but as part of a broader process, where metabolic decompensation, accumulation of toxic intermediates, and systemic inflammation converge. This overlap is likely underrecognized in clinical practice. Recognizing this possibility has practical implications. It shifts the diagnostic focus, but also opens the door to more tailored management strategies. In similar cases, HLH may be less an endpoint diagnosis and more a signal pointing toward an underlying metabolic or genetic condition that requires specific attention.
2026-05-21 | The role of essential fatty acid deficiencies in cognitive function among patients with organic acidemias
Objective: Organic acidemias (OAs) are metabolic disorders characterized by enzyme deficiencies that impair amino acid catabolism, leading to metabolic imbalances. Essential fatty acids (EFAs), particularly Omega-3 and Omega-6, are vital for cellular and neurological functions but are often affected by protein-restricted diets used in OA management. The aim of this study was to evaluate the plasma EFA levels in OA patients and explores their clinical relevance. Materials and Methods: A prospective, case-control design was adopted, including 26 OA patients (methylmalonic acidemia, propionic acidemia, isovaleric acidemia, maple syrup urine disease) and 22 healthy age- and gender-matched controls. Plasma EFA levels were quantified via gas chromatography-mass spectrometry. Cognitive and psychiatric evaluations were performed using standardized tests, including DSM-V-TR criteria, Wechsler Intelligence Scale for Children, and other psychometric tools. Statistical analyses assessed the relationships between EFA levels and clinical findings. Results: Organic acidemias patients exhibited significantly lower levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) + DHA, and Omega-3 compared to controls, with higher Omega-6/Omega-3 ratios. Despite these findings, no significant correlations emerged between EFA levels and cognitive or psychiatric outcomes. Conclusion: EFA deficiencies are prevalent among OA patients on protein-restricted diets, underscoring the potential need for targeted nutritional interventions. However, the absence of a direct association with clinical findings suggests multifactorial influences on disease outcomes. Future research should explore the longitudinal effects of EFA supplementation and its role in mitigating neurodevelopmental impairments in OA.
2026-05-14 | [N-carbamylglutamate in the treatment of neonatal organic acidemia crisis: a report of five cases].
Five neonates with organic acidemia complicated by severe hyperammonemia were reported, including one case of isovaleric acidemia (IVA), three cases of methylmalonic acidemia (MMA), and one case of propionic acidemia (PA). The neonates were 3 to 19 days old. All presented with nonspecific symptoms such as poor feeding and decreased responsiveness, some with vomiting. All had dyspnea, and one had seizures. All cases were genetically confirmed: the IVA case carried a homozygous IVD variant, the three MMA cases carried compound heterozygous MMUT variants, and the PA case carried a homozygous PCCA variant. During the acute hyperammonemic phase, all five received N-carbamylglutamate (NCG). Two critically ill infants with peak ammonia >1 500 μmol/L underwent continuous veno-venous hemodialysis first and were started on oral NCG after ammonia fell below 200 μmol/L; the other three received oral NCG directly. Blood ammonia levels declined markedly in all cases, feeding was resumed successfully, and protein intake was gradually increased. In the chronic phase, all were maintained on oral NCG. One MMA infant died at 6 days of age due to treatment withdrawal by the family; the remaining four maintained ammonia <80 μmol/L. Over more than 12 months of follow-up, all four survivors had growth parameters (length, weight, and head circumference) within normal ranges, with two exhibiting mild delays in gross motor and language comprehension. NCG shows good safety and effectiveness for both acute rescue and long-term management of organic-acidemia-related hyperammonemia, and provides a reference strategy for clinical care.
2026-04-28 | Metformin-glycine combination for metabolic rewiring in isovaleric acidemia
Metformin activates AMPK to enhance alternative leucine catabolism pathways while glycine conjugation reduces toxic isovaleric acid accumulation. AMPK activation upregulates BCAT1 and BCAT2 for branched-chain amino acid metabolism bypass.
2026-06-29 | Immune dysregulation syndrome associated with inborn errors of metabolism - hemophagocytic lymphohistiocytosis in the context of isovaleric acidemia: a case report.
Hemophagocytic lymphohistiocytosis (HLH) continues to pose a diagnostic challenge in pediatric critical care, not only because of its severity but also due to the wide range of conditions that can underlie its presentation. Among these, metabolic disorders are often overlooked. We describe an 18-month-old boy who initially presented with persistent fever and respiratory symptoms, later evolving to pancytopenia, hepatosplenomegaly, and neurological deterioration, the patient fulfilled seven of the eight HLH-2004 criteria. Along the way, adenovirus and parainfluenza virus type III were identified, and anti-NMDA receptor encephalitis was confirmed, adding further complexity to the clinical picture. What proved decisive was the identification of a homozygous pathogenic variant in the IVD gene (c.1174C > T; p.Arg392Cys), establishing the diagnosis of isovaleric acidemia. This finding reframed the case. Rather than an isolated hyperinflammatory syndrome, the clinical course can be better understood as the result of a metabolic disorder capable of amplifying immune dysregulation, particularly in the setting of intercurrent infection. In this context, the features of HLH appear not as a separate entity but as part of a broader process, where metabolic decompensation, accumulation of toxic intermediates, and systemic inflammation converge. This overlap is likely underrecognized in clinical practice. Recognizing this possibility has practical implications. It shifts the diagnostic focus, but also opens the door to more tailored management strategies. In similar cases, HLH may be less an endpoint diagnosis and more a signal pointing toward an underlying metabolic or genetic condition that requires specific attention.
2026-06-12 | Data Sheet 1_Immune dysregulation syndrome associated with inborn errors of metabolism – hemophagocytic lymphohistiocytosis in the context of isovaleric acidemia: a case report.pdf
Hemophagocytic lymphohistiocytosis (HLH) continues to pose a diagnostic challenge in pediatric critical care, not only because of its severity but also due to the wide range of conditions that can underlie its presentation. Among these, metabolic disorders are often overlooked. We describe an 18-month-old boy who initially presented with persistent fever and respiratory symptoms, later evolving to pancytopenia, hepatosplenomegaly, and neurological deterioration, the patient fulfilled seven of the eight HLH-2004 criteria. Along the way, adenovirus and parainfluenza virus type III were identified, and anti-NMDA receptor encephalitis was confirmed, adding further complexity to the clinical picture. What proved decisive was the identification of a homozygous pathogenic variant in the IVD gene (c.1174C > T; p.Arg392Cys), establishing the diagnosis of isovaleric acidemia. This finding reframed the case. Rather than an isolated hyperinflammatory syndrome, the clinical course can be better understood as the result of a metabolic disorder capable of amplifying immune dysregulation, particularly in the setting of intercurrent infection. In this context, the features of HLH appear not as a separate entity but as part of a broader process, where metabolic decompensation, accumulation of toxic intermediates, and systemic inflammation converge. This overlap is likely underrecognized in clinical practice. Recognizing this possibility has practical implications. It shifts the diagnostic focus, but also opens the door to more tailored management strategies. In similar cases, HLH may be less an endpoint diagnosis and more a signal pointing toward an underlying metabolic or genetic condition that requires specific attention.
2026-05-21 | The role of essential fatty acid deficiencies in cognitive function among patients with organic acidemias
Objective: Organic acidemias (OAs) are metabolic disorders characterized by enzyme deficiencies that impair amino acid catabolism, leading to metabolic imbalances. Essential fatty acids (EFAs), particularly Omega-3 and Omega-6, are vital for cellular and neurological functions but are often affected by protein-restricted diets used in OA management. The aim of this study was to evaluate the plasma EFA levels in OA patients and explores their clinical relevance. Materials and Methods: A prospective, case-control design was adopted, including 26 OA patients (methylmalonic acidemia, propionic acidemia, isovaleric acidemia, maple syrup urine disease) and 22 healthy age- and gender-matched controls. Plasma EFA levels were quantified via gas chromatography-mass spectrometry. Cognitive and psychiatric evaluations were performed using standardized tests, including DSM-V-TR criteria, Wechsler Intelligence Scale for Children, and other psychometric tools. Statistical analyses assessed the relationships between EFA levels and clinical findings. Results: Organic acidemias patients exhibited significantly lower levels of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) + DHA, and Omega-3 compared to controls, with higher Omega-6/Omega-3 ratios. Despite these findings, no significant correlations emerged between EFA levels and cognitive or psychiatric outcomes. Conclusion: EFA deficiencies are prevalent among OA patients on protein-restricted diets, underscoring the potential need for targeted nutritional interventions. However, the absence of a direct association with clinical findings suggests multifactorial influences on disease outcomes. Future research should explore the longitudinal effects of EFA supplementation and its role in mitigating neurodevelopmental impairments in OA.
2026-05-14 | [N-carbamylglutamate in the treatment of neonatal organic acidemia crisis: a report of five cases].
Five neonates with organic acidemia complicated by severe hyperammonemia were reported, including one case of isovaleric acidemia (IVA), three cases of methylmalonic acidemia (MMA), and one case of propionic acidemia (PA). The neonates were 3 to 19 days old. All presented with nonspecific symptoms such as poor feeding and decreased responsiveness, some with vomiting. All had dyspnea, and one had seizures. All cases were genetically confirmed: the IVA case carried a homozygous IVD variant, the three MMA cases carried compound heterozygous MMUT variants, and the PA case carried a homozygous PCCA variant. During the acute hyperammonemic phase, all five received N-carbamylglutamate (NCG). Two critically ill infants with peak ammonia >1 500 μmol/L underwent continuous veno-venous hemodialysis first and were started on oral NCG after ammonia fell below 200 μmol/L; the other three received oral NCG directly. Blood ammonia levels declined markedly in all cases, feeding was resumed successfully, and protein intake was gradually increased. In the chronic phase, all were maintained on oral NCG. One MMA infant died at 6 days of age due to treatment withdrawal by the family; the remaining four maintained ammonia <80 μmol/L. Over more than 12 months of follow-up, all four survivors had growth parameters (length, weight, and head circumference) within normal ranges, with two exhibiting mild delays in gross motor and language comprehension. NCG shows good safety and effectiveness for both acute rescue and long-term management of organic-acidemia-related hyperammonemia, and provides a reference strategy for clinical care.
2026-04-28 | Metformin-glycine combination for metabolic rewiring in isovaleric acidemia
Metformin activates AMPK to enhance alternative leucine catabolism pathways while glycine conjugation reduces toxic isovaleric acid accumulation. AMPK activation upregulates BCAT1 and BCAT2 for branched-chain amino acid metabolism bypass.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Isovaleric acidemia.
1 orphan drug designation for Isovaleric acidemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Carglumic acid [Carbaglu] | — | EMA | 2008-11-07 | — | Recordati Rare Diseases |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.