IVD gene
Also known as: Isovaleric Acid-Coa-Dehydrogenase deficiency; IVD deficiency; IVA
OMIM#243500 https://omim.org/entry/243500
1. The disease:
IVA is a rare, autosomal recessive, organic aciduria that is characterized by variable clinical presentation ranging from acute neonatal onset of metabolic decompensation to later onset of chronic, non-specific manifestations including failure to thrive and/or developmental delay. All patients are prone to intermittent, acute metabolic decompensation. During metabolic episodes, urine analysis demonstrates elevated isovaleric acid derivatives.
2. The Symptoms:
Patients present as a clinical spectrum. Lack of early signs or symptoms does not exclude the diagnosis.
- Acute, neonatal presentation is characterized by onset in the first two weeks of life with vomiting, seizures, and lethargy, progressing to coma. Metabolic acidosis with an increased anion gap is apparent on laboratory evaluation. High ammonia crisis may occur.
- Later onset is relatively non-specific with failure to thrive and/or developmental delay. Patients who survived an early acute presentation are subsequently indistinguishable from those with the chronic phenotype.
- All patients are prone to intermittent acute episodes of decompensation with minor illnesses. Childhood onset metabolic acidosis is typically brought on by prolonged fasting, increased intake of protein-rich food or infections, and can be fatal if not treated immediately.
- The characteristic smell of isovaleric acid may be present and is likened to sweaty feet/body sweat. Though severe developmental delay and neurologic sequelae are present in some patients, they are likely related to severe biochemical presentations.
3. Actions to take in case of early diagnosis:
- Babies with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in the IVD gene) should continue breastfeeding, avoid fasting or high-protein baby formulas. Early treatment is essential in preventing chronic symptoms.
- Correlation with the biochemical NBS tandem mass spectrometry is essential for confirming the diagnosis (show increased isovalerylcarnitine – C5 and ratios). Result of organic acids in urine, by gas-liquid chromatography or mass spectrometry, includes elevated N‐isovalerylglycine, N‐isovalerylcarnitine and 3‐hydroxyisovaleric acid. The urine organic acids may normalize when a patient is well.
- IVA is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care.
- Emergency treatment in times of metabolic stress (including illness and fasting) is with an anabolic diet. Reducing, but not eliminating, natural protein in the diet for 12-24 hours may help, but only if additional other calories can be given to promote anabolism.
- Supplementing with artificial protein restricted in leucine may be required. L-carnitine and glycine may be prescribed to clear excess isovaleric acid.
- Prognosis for patients diagnosed by newborn screening is excellent with the potential for normal neurodevelopmental outcome with appropriate metabolic management.
- Patients who present symptomatically can have significant neurologic sequelae including neurodevelopmental delay, especially if acidosis and hyperammonemia are severe. So compliance with dietary treatment saves lives.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.
4. For more information
Biblio:
- Vockley J, Ensenauer R. Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. Am J Med Genet C Semin Med Genet. 2006;142C(2):95-103. PMID: 16602101.
- Schlune A, Riederer A, Mayatepek E, Ensenauer R. Aspects of Newborn Screening in Isovaleric Acidemia. Int J Neonatal Screen. 2018;4(1):7. PMID: 33072933.