Isovaleric Acidemia
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[edit] Name of Condition
[edit] Definition
A protein metabolism disorder characterized by accumulation of isovaleric acid and isovaleric acid complexes in blood and urine. Accumulation results from a deficiency of isovaleryl co-a dehydrogenase, an enzyme involved in metabolizing the amino acid Leucine.
[edit] Description, Signs and Symptoms
A deficiency of mitochondrial enzyme Isovaleryl Co-A Dehydrogenase causes accumulation of isovaleric acid when the amino acid Leucine is metabolized for energy. This enzyme is encoded on the long arm of chromosome 15.
Affected people have times of normal or near normal activity and function, with episodic crises. Crises may be triggered by high-protein feasting, but are often triggered by other illnesses, such as influenza, that cause patients to fast or metabolize their body's muscle-protein stores.
Some patients - if parents permit - develop aversion to high protein foods that helps with dietary management. At least one patient was found self-limiting Leucine when diagnosed at age 8, this behavior began at age 3.
Symptoms of crisis include nausea, vomiting, dehydration, fatigue, coma, and possible death.
Old literature describes an odor of sweaty feet - but this is not a reliable sign. Old literature also suggests moderate mental impairment, but IQ of over 125 has been reported.
There have been two phenotypes reported - a severe infant-onset phenotype with frequent crises and a moderate later-onset (or sometimes occult) phenotype with less-frequent crises. Biochemical analysis does not always correlate with apparent phenotype.
A mild phenotype associated with partially-functional enzyme has also been reported, associated with a particular mutation having a cluster in Germany.
[edit] Inheritance
Autosomal recessive, chromosome 15Q15.
There are several dozen known mutations in isovaleryl co-A dehydrogenase that cause IVA.
Some of these produce nonfunctional enzyme, others are in a relocation-recognition tail portion and produce functional enzyme that remains in cytoplasm instead of properly locate into mitochondria.
[edit] Demographics
Rare.
[edit] Diagnosis
The enhanced newborn screening program in some states includes testing for IVA.
Isovaleric acid and complexes of Isovaleric Acid with amino acids can be detected in urine of patients with gas chromatography-mass spectrometry.
Skin fibroblasts from patients can be cultured and will show degraded metabolism of isovaleric acid.
[edit] Treatment and Management
During normal life: Low protein diet, restrict leucine content. Some natural protein is normally consumed. Synthetic amino-acid supplements, providing essential amino acids other than leucine. These taste awful, so patient compliance is often a problem.
L-Carnitine supplementation has been helpful in some patients. Isovaleric acid complexes with Carnitine and is excreted in urine. In some patients this causes carnitine deficiency and supplementation helps with fat metabolism. In others, carnitine is used to help excretion of isovaleric acid.
Glycine supplementation has been used in some patients but can cause irritability
During crises: START IV IMMEDIATELY.
Patients often become dehydrated due to sweating, vomiting and urination. Veins may collapse requiring cut-down if access is not obtained early. Ideally - start IV and obtain blood samples immediately on arrival at the ER
IV Glucose, 10%, should be provided early to limit protein catabolism and prevent hypoglycemia in patients. Maintain blood glucose levels above 75mg/dl. As 10% glucose is hyperosmolar, restart infiltrated lines immediately.
Rehydrate and adjust electrolytes as necessary.
Treat underlying or associated illnesses as necessary Many crises are triggered by other illnesses that trigger nausea & vomiting
Pregnancy, labor, and even lactation have been successfully managed in patients.
[edit] Prognosis
Prognosis of IVA is highly variable, depending on residual isovaleryl co-A dehydrogenase activity, diet in infancy and childhood, age at diagnosis, treatment both at home and during crises, adherence to treatment, and other factors. In those diagnosed late, nursing v. bottle feeding may be a factor as cow and soy based formulas have higher protein content than breastmilk.
While some patients die in infancy, others have lived into adulthood with little or no neurological impairment. At least one patient is a certified physics and math teacher with two children despite negligible isovaleryl co-a dehydrogenase activity.
[edit] Resources
AccessDNA.com - Isovaleric Acidemia[1]
Organic Acidemia Association http://www.oaanews.org http://www.ivaresearch.org
