Isovaleric Acidemia (IVA)
An Organic Acid Disorder
What is it?
Isovaleric Acidemia (IVA) also known as Isovaleryl-CoA Dehydrogenase Deficiency (IVD) is caused by a defect in the breakdown of the molecule Isovaleryl-CoA. Isovaleryl-CoA is itself a breakdown product of leucine which is an essential amino acid found in protein containing foods.
IVA can present as an acute episode of illness during the first few weeks of a newborn's life, or it may present chronically with intermittent episodes of illness throughout life. Both forms of IVA are caused by the same biochemical defect, and infants who survive an acute neonatal episode will go on to exhibit the chronic intermittent form.
Inheritance and Frequency
The gene defect for IVA is an autosomal recessive genetic trait and is unknowingly passed down from generation to generation. This faulty gene usually emerges when two carriers have children together and pass it to their offspring. For each pregnancy of two such carriers, there is a 25% chance that the child will be born with the disease and a 50% chance the child will be a carrier for the gene defect.
IVA has been identified in various ethnic and racial groups, and both males and females are affected equally. The incidence of IVA is approximately 1 in 50,000 live births.
The gene responsible for IVA has been mapped to human chromosome 15. The precise address on the chromosome is known as 15q14-q15. There are five known different classes of mutations (changes) in the IVD gene. Some of the mutations are single letter alterations in the IVD gene, and some of the mutations consist of large gaps of letters in the gene. The result of either of these changes in the IVD gene is the formation of non-functional IVD protein or the inability to form any IVD protein at all. About 60% of the genes of IVA patients examined thus far contain the defect that leads to the production of protein that fails to function properly. The remaining 40% of the genes of IVA patients have the mutations that makes no IVD protein. While characterization of the mutations in the IVD gene is possible, they are currently being done only on an experimental basis.
Signs & Symptoms
Symptoms of acute IVA are attacks of vomiting, lack of appetite, and listlessness; lethargy, neuromuscular irritability, and hypothermia are other characteristics. Episodes can be triggered by upper respiratory infections or by excessive consumption of high-protein foods.
The acute form of IVA normally presents within the first 14 days after birth of an otherwise healthy baby. The first symptoms include refusal of feeding, vomiting, dehydration, and lethargy. The baby can become hypothermic (reduced body temperature below 98.6° F) and may tremor, or convulse. A foul "sweaty feet" odor is also commonly noticed.
Examination of blood and urine at the hospital will demonstrate metabolic acidosis (increase in acidic metabolites which can alter tissue function) with mild to moderate ketonuria (enhanced presence of ketone bodies, a metabolite, in urine) and lactic acidemia ( increase in lactic acid in the blood) as well as hyperammonemia ( increase in ammonia in the blood). Thrombocytopenia (abnormally small amount of platelets in the blood) and neutropenia (an abnormally low amount of white blood cells in the blood) are also common, as well as hypocalcemiat progressing to coma, acidosis (increase in acidic metabolites which can alter tissue function) with ketonuria (enhanced presence of ketone bodies, a metabolite, in urine) and the characteristic odor of "sweaty feet".
Most episodes will improve with protein restriction and increased glucose
(sugar) intake. Most patients with chronic
intermittent IVA have normal development, but some are developmentally delayed,
and mild to severe mental retardation can occur. Many children with IVA
will develop a natural aversion to protein-rich food.
Long Term Effects
Early detection through newborn screening and
good treatment of IVA generally leads to normal development. However, permanent neurologic damage can occur if an acute episode is not prevented or
misdiagnosed.
Treatment
Treatment involves a protein-restrictive diet and carnitine
supplementation. Oral administration of glycine is lifesaving and may permit
normal growth and development.
In IVA the failure of IVD to function normally results in both the accumulation
of isovaleric acid which is toxic to the central nervous system as well as
inhibiting the normal function of other metabolic pathways. Therefore,
treatment of IVA involves both a primary and secondary stage. The primary
stage in both the acute and chronic forms is to lower the levels of accumulating
isovaleric acid. The secondary stage focuses on correcting the
physiological effects of the elevated metabolite. Leucine cannot be
synthesized by the human body. Therefore an increase in the level of the
amino acid results only from dietary intake of protein or through the breakdown of
previously ingested and stored protein in the body which occurs during times of
illness and fasting.
Primary treatment will involve minimizing the intake
of leucine in the diet. A minimum amount of leucine is still required for
normal growth, as well as other essential amino acids which can all be provided
in a leucine-free medical food supplement. Additionally, glycine and/or
carnitine supplements may be prescribed since these molecules interact with
isovaleric acid to form nontoxic, readily excreted products of isovalerlglycine
and isovalerylcarnitine. Some physicians may also
choose to aggressively treat infections to minimize the release of leucine from
the breakdown of stored proteins. However, aspirin inhibits the favorable
interaction of glycine and carnitine with isovaleric acid and should not be
given to an IVA child.
During an acute episode, a protein restricted diet, administration of
glycine and carnitine may be instituted to reduce the level of isovaleric acid
accumulation. In addition the secondary stage of treatment will be
necessary to treat some of the physiological consequences of the episode.
History
Screening
Visit
the What
Does Your State Screen page to learn about your state's newborn screening program.
Supplemental
Screening
If you live in a state that
does not perform screening on its newborns for all detectable disorders, there
are laboratories that will provide this screening for you no matter the state of residence. For more information about supplemental screening,
visit our supplemental screening page. Also visit our frequently
asked questions page for more information on newborn screening.
References:
The metabolic and molecular bases of inherited disease / editors, Charles R.
Scriver ... [et al.]; consulting editors, John B. Stanbury, James Wyngaarden,
Donald G. Fredrickson. 7th ed. New York : McGraw-Hill, Health Professions
Division, c1995. 3 v. (xxxvi, 4605, 93 p.) : ill.
NOTE: This definition was written by Mylynda Schlesinger for
Save Babies Through Screening Foundation, Inc.
Other Sites
of Reference
Isovaleric Acidemia: New Aspects of Genetic and Phenotypic Heterogeneity by Vockley and Ensenauer- IVA Research - Research and information for families
- A Parent's Guide to IVA
- Genetics Home Reference - Isovaleric Acidemia
- OMIM - Isovaleric Acidemia
- SimulConsult IVA Case Study - Reference for medical professionals
- T Rose IVA Home Page - Personal website of an IVA family
Support Group
Organic Acidemia Association, Inc. (OAA)
13210 35th Avenue
Plymouth, MN 55441
Phone: (763) 559-1797
Contact Person: Kathy Stagni
Email OAA
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