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:
categories:
Small molecules
small molecules
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.
proteins
2025-08-25 | Structural Insights into Isovaleryl-Coenzyme A Dehydrogenase: Mechanisms of Substrate Specificity and Implications of Isovaleric Acidemia-Associated Mutations.
Isovaleryl-CoA (coenzyme A) dehydrogenase (IVD) plays a pivotal role in the catabolism of leucine, converting isovaleryl-CoA to 3-methylcrotonyl-CoA. Dysfunction of IVD is linked to isovaleric acidemia (IVA), a rare metabolic disorder characterized by the accumulation of toxic metabolites. In this study, we present the cryo-electron microscopy structures of human IVD, resolved both in its apo form and in complex with its substrates, isovaleryl-CoA and butyryl-CoA. Our findings reveal a tetrameric architecture with distinct substrate-binding pockets that facilitate the enzyme's preference for short branched-chain acyl-CoAs. Key residues involved in FAD binding and substrate interaction were identified, elucidating the catalytic mechanism of IVD. Additionally, we investigated the impact of various disease-associated hotspot mutations derived from different regions, demonstrating their effects on enzyme stability and activity. Notably, mutations such as A314V, S281G/F382V, and E411K resulted in substantial loss of function, while others exhibited milder effects, which is consistent with our structural analyses. These insights enhance our understanding of IVD's enzymatic properties and provide a foundation for developing targeted therapies for IVA.
2023-06-12 | Amyloid Mimicking Assemblies of Homogentisic Acid, N-Acetyl Aspartic Acid and Isovaleric Acid and its Implications in associated Rare Metabolic Diseases
Herein, we have studied the self-assembling and aggregation properties of Homogentisic acid (HA), N-acetyl aspartic Acid (NAA) and Isovaleric acid (IVA) with the aim to understand the effect of aggregation of these metabolites on the toxicities associated with rare metabolic diseases caused by their accumulation. To our surprise, we noted aggregation of HA, NAA and IVA follow amyloidogenic pathway and as these metabolites are aged small globules tend to merge and form fibrillar aggregates. These assemblies were characterized by conventional microscopy tools and their amyloidogenic nature was assessed by Thioflavin T binding assays. The cytotoxicity analysis by MTT assay suggest cellular viability was decreased in presence of metabolites in a dose dependent manner implicating their cytotoxic nature. Hence, the results presented in the manuscript are of significant interest as they can be of great practical implications in understanding the etiology/pathophysiology of rare metabolic diseases caused by the accumulation of these metabolites namely Alkaptonuria, Canavan diseases and Isovaleric academia from an amyloid perspective and may have possible implications in its therapeutic cure in future.
1995-01-01 | High-level expression of an altered cDNA encoding human isovaleryl-CoA dehydrogenase in Escherichia coli
Isovaleryl-CoA dehydrogenase (IVD) catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA in the leucine catabolism pathway. The cDNA encoding the mature human IVD polypeptide was cloned in a prokaryotic expression vector, but the level of expression in Escherichia coli was extremely low and attempts to purify the enzyme to homogeneity were unsuccessful. To enhance expression, the nucleotide sequence of 22 codons within the 111-bp region at the 5′-end of the cDNA was altered to accommodate E. coli codon usage without altering the amino-acid coding sequence. The altered IVD cDNA was synthesized by PCR, using a primer containing the desired modifications. Following overnight induction of the E. coli transformed with this cDNA, the enzyme was purified to homogeneity using diethylaminoethyl agarose and high-pressure ceramic hydroxyapatite resins. IVD activity was increased 165-fold in the crude extract of cells containing the modified cDNA, as compared to that containing the wild-type cDNA.
gene therapies
2025-02-25 | Functional analysis of a novel homozygous missense IVD gene variant: a case report with dual genetic diagnoses.
Genomic or exome sequencing is beneficial for identifying more than one pathogenic variation causing blended atypical and/or severe phenotypes. Herein, we are the first to report a 5-year-old boy with the blended phenotypes of infantile hypotonia, severe neurodevelopmental disorder, patent ductus arteriosus, cryptorchidism, obesity, distinctive facial features, and elevated isovaleryl carnitine. Trio-based whole-exome sequencing was performed on genomic DNA from peripheral blood samples from the boy and his parents. Functional analysis of the IVD variant in vitro was performed. Mutant IVD gene pcDNA3.1(+)-MUT-3xFlag and control pcDNA3.1(+)-WT-3xFlag mammalian expression vectors were constructed. Both vectors were transformed into HEK293T cells. The assays of relative IVD gene mRNA expression, IVD protein expression, and enzymatic activity were used. Whole-exome sequencing identified a novel homozygous missense variant in the IVD gene (NM_002225.5) c.1006T>C (p.Cys336Arg) within a region of homozygosity of 15q11.2-q21.3. Our in vitro functional and computer simulation findings revealed that this variant was associated with haploinsufficiency, which resulted in dramatically reducing the formation of IVD protein due to unstable mutant protein and not a lack of mRNA expression. The boy was diagnosed with the dual genetic disorders of Prader-Willi syndrome and isovaleric acidemia. This case provides a useful reference for genetic counseling for complex and diverse clinical phenotypes. The presence of two or more likely pathogenic or pathogenic variations in an individual with neurodevelopmental phenotypes is not an "exceptional" phenomenon.
small molecules
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.
proteins
2025-08-25 | Structural Insights into Isovaleryl-Coenzyme A Dehydrogenase: Mechanisms of Substrate Specificity and Implications of Isovaleric Acidemia-Associated Mutations.
Isovaleryl-CoA (coenzyme A) dehydrogenase (IVD) plays a pivotal role in the catabolism of leucine, converting isovaleryl-CoA to 3-methylcrotonyl-CoA. Dysfunction of IVD is linked to isovaleric acidemia (IVA), a rare metabolic disorder characterized by the accumulation of toxic metabolites. In this study, we present the cryo-electron microscopy structures of human IVD, resolved both in its apo form and in complex with its substrates, isovaleryl-CoA and butyryl-CoA. Our findings reveal a tetrameric architecture with distinct substrate-binding pockets that facilitate the enzyme's preference for short branched-chain acyl-CoAs. Key residues involved in FAD binding and substrate interaction were identified, elucidating the catalytic mechanism of IVD. Additionally, we investigated the impact of various disease-associated hotspot mutations derived from different regions, demonstrating their effects on enzyme stability and activity. Notably, mutations such as A314V, S281G/F382V, and E411K resulted in substantial loss of function, while others exhibited milder effects, which is consistent with our structural analyses. These insights enhance our understanding of IVD's enzymatic properties and provide a foundation for developing targeted therapies for IVA.
2023-06-12 | Amyloid Mimicking Assemblies of Homogentisic Acid, N-Acetyl Aspartic Acid and Isovaleric Acid and its Implications in associated Rare Metabolic Diseases
Herein, we have studied the self-assembling and aggregation properties of Homogentisic acid (HA), N-acetyl aspartic Acid (NAA) and Isovaleric acid (IVA) with the aim to understand the effect of aggregation of these metabolites on the toxicities associated with rare metabolic diseases caused by their accumulation. To our surprise, we noted aggregation of HA, NAA and IVA follow amyloidogenic pathway and as these metabolites are aged small globules tend to merge and form fibrillar aggregates. These assemblies were characterized by conventional microscopy tools and their amyloidogenic nature was assessed by Thioflavin T binding assays. The cytotoxicity analysis by MTT assay suggest cellular viability was decreased in presence of metabolites in a dose dependent manner implicating their cytotoxic nature. Hence, the results presented in the manuscript are of significant interest as they can be of great practical implications in understanding the etiology/pathophysiology of rare metabolic diseases caused by the accumulation of these metabolites namely Alkaptonuria, Canavan diseases and Isovaleric academia from an amyloid perspective and may have possible implications in its therapeutic cure in future.
1995-01-01 | High-level expression of an altered cDNA encoding human isovaleryl-CoA dehydrogenase in Escherichia coli
Isovaleryl-CoA dehydrogenase (IVD) catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA in the leucine catabolism pathway. The cDNA encoding the mature human IVD polypeptide was cloned in a prokaryotic expression vector, but the level of expression in Escherichia coli was extremely low and attempts to purify the enzyme to homogeneity were unsuccessful. To enhance expression, the nucleotide sequence of 22 codons within the 111-bp region at the 5′-end of the cDNA was altered to accommodate E. coli codon usage without altering the amino-acid coding sequence. The altered IVD cDNA was synthesized by PCR, using a primer containing the desired modifications. Following overnight induction of the E. coli transformed with this cDNA, the enzyme was purified to homogeneity using diethylaminoethyl agarose and high-pressure ceramic hydroxyapatite resins. IVD activity was increased 165-fold in the crude extract of cells containing the modified cDNA, as compared to that containing the wild-type cDNA.
gene therapies
2025-02-25 | Functional analysis of a novel homozygous missense IVD gene variant: a case report with dual genetic diagnoses.
Genomic or exome sequencing is beneficial for identifying more than one pathogenic variation causing blended atypical and/or severe phenotypes. Herein, we are the first to report a 5-year-old boy with the blended phenotypes of infantile hypotonia, severe neurodevelopmental disorder, patent ductus arteriosus, cryptorchidism, obesity, distinctive facial features, and elevated isovaleryl carnitine. Trio-based whole-exome sequencing was performed on genomic DNA from peripheral blood samples from the boy and his parents. Functional analysis of the IVD variant in vitro was performed. Mutant IVD gene pcDNA3.1(+)-MUT-3xFlag and control pcDNA3.1(+)-WT-3xFlag mammalian expression vectors were constructed. Both vectors were transformed into HEK293T cells. The assays of relative IVD gene mRNA expression, IVD protein expression, and enzymatic activity were used. Whole-exome sequencing identified a novel homozygous missense variant in the IVD gene (NM_002225.5) c.1006T>C (p.Cys336Arg) within a region of homozygosity of 15q11.2-q21.3. Our in vitro functional and computer simulation findings revealed that this variant was associated with haploinsufficiency, which resulted in dramatically reducing the formation of IVD protein due to unstable mutant protein and not a lack of mRNA expression. The boy was diagnosed with the dual genetic disorders of Prader-Willi syndrome and isovaleric acidemia. This case provides a useful reference for genetic counseling for complex and diverse clinical phenotypes. The presence of two or more likely pathogenic or pathogenic variations in an individual with neurodevelopmental phenotypes is not an "exceptional" phenomenon.
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 |
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