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<p>Isovaleric acidemia (IVA) is a rare autosomal-recessive disorder of leucine metabolism caused by biallelic <i>IVD</i> variants. Clinical phenotypes range from acute neonatal onset to asymptomatic biochemical forms. Diagnosis relies on elevated isovaleryl carnitine (IVC) in blood, isovaleryl glycine (IVG) in urine, and molecular testing. We describe an 8-year-old boy with intermittent IVA who developed acute metabolic decompensation after ingesting ~ 250&#xa0;g of butter. At age 4, he presented with encephalopathy, vomiting, abdominal pain, metabolic acidosis, and ketosis, but normal ammonia. History included a sibling’s neonatal death with pneumonia and encephalopathy. Biochemical testing revealed elevated IVC and IVG. Whole-exome sequencing showed compound heterozygosity for a novel c.1043A &gt; T (p.Asp348Val) variant and a reported c.1222G &gt; A (p.Glu408Lys), both predicted pathogenic. A systematic PubMed and gray-literature review identified 119 genetically confirmed IVA cases; combined with our patient, 120 cases were analysed for demographic, clinical, biochemical, radiologic, and genetic data. Majority of 120 cases (60%) presented neonatally and 24% were asymptomatic at detection. Elevated IVC and IVG occurred in 85.8% and 84%, respectively. Common crisis triggers included infection, fasting, and high-protein intake; this case implicates high-fat ingestion as an additional precipitant. Eighty-nine distinct <i>IVD</i> variants were identified, predominantly missense (63%). Mortality was 8.5%, with variable neurodevelopmental outcomes among survivors. This report expands IVA’s mutational spectrum with a novel <i>IVD</i> variant and highlights that high-fat dietary loads, even with minimal leucine, can provoke metabolic crisis, reinforcing the need for early biochemical and genetic diagnosis to guide management.</p>

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Isovaleric Acidemia: Case-Based Genotype–Phenotype Correlation and Review of Reported Variants

  • 期刊论文

  • 发表日期：

    2026年7月24日

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  • Sanjhi Paliwal,
  • Arushi Gahlot Saini,
  • Suresh Kumar Angurana,
  • Mini Tageja,
  • Satwinder Singh,
  • Charu Sharma,
  • Syeba Attri,
  • Surjeet Kumar Thappa,
  • Savita Verma Attri

摘要

Isovaleric acidemia (IVA) is a rare autosomal-recessive disorder of leucine metabolism caused by biallelic IVD variants. Clinical phenotypes range from acute neonatal onset to asymptomatic biochemical forms. Diagnosis relies on elevated isovaleryl carnitine (IVC) in blood, isovaleryl glycine (IVG) in urine, and molecular testing. We describe an 8-year-old boy with intermittent IVA who developed acute metabolic decompensation after ingesting ~ 250 g of butter. At age 4, he presented with encephalopathy, vomiting, abdominal pain, metabolic acidosis, and ketosis, but normal ammonia. History included a sibling’s neonatal death with pneumonia and encephalopathy. Biochemical testing revealed elevated IVC and IVG. Whole-exome sequencing showed compound heterozygosity for a novel c.1043A > T (p.Asp348Val) variant and a reported c.1222G > A (p.Glu408Lys), both predicted pathogenic. A systematic PubMed and gray-literature review identified 119 genetically confirmed IVA cases; combined with our patient, 120 cases were analysed for demographic, clinical, biochemical, radiologic, and genetic data. Majority of 120 cases (60%) presented neonatally and 24% were asymptomatic at detection. Elevated IVC and IVG occurred in 85.8% and 84%, respectively. Common crisis triggers included infection, fasting, and high-protein intake; this case implicates high-fat ingestion as an additional precipitant. Eighty-nine distinct IVD variants were identified, predominantly missense (63%). Mortality was 8.5%, with variable neurodevelopmental outcomes among survivors. This report expands IVA’s mutational spectrum with a novel IVD variant and highlights that high-fat dietary loads, even with minimal leucine, can provoke metabolic crisis, reinforcing the need for early biochemical and genetic diagnosis to guide management.