A novel form of isovaleric acidemia (IVA) associated with a common gene alteration and mild biochemical abnormalities that is diagnosed by newborn screening

Regina Ensenauer, M.D.

Pediatric Research Center, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University Munich, Germany

1. What did we know about IVA prior to newborn screening by tandem mass spectrometry (MS/MS) ?

Isovaleric acidemia (IVA) is an inborn error of metabolism of the branched-chain amino acid leucine. It has been considered a severe, potentially life-threatening organic acidemia manifesting with acute neonatal coma in about half of affected individuals (“acute form”), and recurrent episodes of vomiting, lethargy, and varying degrees of developmental delay in the other half of patients (“chronic form”). However, asymptomatic benign forms of IVA were not known prior to newborn screening by MS/MS.

Fever, fasting or excessive protein intake (“metabolic stress”) may trigger a metabolic crisis and if not treated promptly, symptoms may progress to seizures, metabolic acidosis, coma, and even death. Blood ammonia levels can be elevated, and white cell and platelet counts can be low. During times of very poor metabolic control the patient may present with the typical odor of isovaleric acid, also called “sweaty feet odor”.

The disorder is caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) which catalyzes the third step in the breakdown of leucine.

High levels of isovaleric acid (that accumulates before the enzyme block) and its derivatives in blood can be toxic to the organs including the brain. The biochemical diagnosis is based on the analysis of plasma and blood spots for the presence of isovaleryl (C5) carnitine and urine for the presence of isovalerylglycine (and other metabolites, such as 3-hydroxyisovaleric acid). Expanded newborn screening allows for early diagnosis from blood spots and immediate management of patients with IVA. In addition to the prevention of metabolic crises during illness, management generally includes protein restriction and therapy with carnitine and/or glycine.

IVA is inherited in an autosomal recessive manner. In an autosomal recessive disorder, each parent is generally a carrier harboring one abnormal copy of the gene. Consequently, each child of two carriers for a condition has a 1 in 4 risk of inheriting both mutant genes (and hence the disease), a 1 in 2 risk of being a carrier, and a 1 in 4 likelihood of receiving two normal copies of the gene. Each offspring from an affected parent with IVA (who has two abnormal copies of the gene) will be an obligate carrier, assuming that the other parent is not similarly affected by the same disease or a carrier of the disease-causing gene alteration (mutation).

In recent years, analysis of patients with IVA for the underlying changes in the IVD gene has led to the identification of various different gene mutations. Some changes result in the production of an abnormal enzyme that does not function properly, while others do not allow the enzyme to be produced at all. It has been difficult to correlate most of the gene changes with disease outcome.

2. What is new about IVA ?

With the implementation of newborn screening by MS/MS, many metabolic disorders can now be identified very early in life allowing for initiation of treatment of affected individuals prior to the onset of symptoms and prevention of mental retardation or even death. Expanded newborn screening, however, also has led to the identification of individuals with mild and benign variants of some disorders, complicating the treatment choices for these infants as well as genetic counseling of families. Examples are medium-chain acyl-CoA dehydrogenase (MCAD) and 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiencies. We recently identified a novel form of IVA in patients diagnosed by newborn screening that is associated with mild metabolic abnormalities and one particular recurring IVD gene mutation – with as yet unknown clinical relevance (Ensenauer et al., 2004).

In the past one to two years, we have identified a large proportion of patients with IVA who presented with mild biochemical abnormalities at the time of newborn screening and follow up (C5 acylcarnitine levels approximately < 6 µmol/L and urine isovalerylglycine levels approximately < 200-300 mmol/mol creatinine). Molecular genetic analysis in these newborns demonstrated the presence of one particular mutation, 932C>T (A282V), that was present either on both copies of the disease-causing gene IVD or it was present on one copy of the gene in combination with another mutation on the second copy of the gene. This specific mutation was present in almost 70% of IVA patients of a newborn screening cohort and thus was termed “common IVA mutation”. All patients have developed normally so far.

We initiated family screening which identified, among siblings, one additional child with similarly mild biochemical abnormalities and identical genetic changes in 75% of families with a newborn that carried the 932C>T mutation either on both copies of the IVD gene or on one copy (with a different mutation on the other copy). Interestingly, each of the siblings, ages 3 to 11 years at the time of identification, had normal development and had remained without symptoms during episodes of “metabolic stress” (such as febrile illnesses).

Experimental laboratory studies of the common IVA mutation have shown that although it led to considerable residual enzyme activity, enzyme function appears to be impaired (Mohsen et al., 1998). At this point in time, it remains unclear whether individuals with IVD deficiency diagnosed by newborn screening and who carry the common 932C>T mutation either on both copies of the IVD gene or on one copy (with a different mutation on the other copy of the gene) exhibit a new mild, potentially asymptomatic type of IVA. This is a major departure from our previous understanding of the natural history of IVA. The long-term implications of the common IVA mutation are not clear as yet, and we are performing further studies to address the question whether the common mutation confers a disease risk or whether it is just a benign variant. To this end, all patients with IVA, regardless of the type of IVA, should be monitored carefully; specifically, when exposed to “metabolic stressors”, such as febrile illnesses.

References

Ensenauer R, Vockley J, Willard JM, Huey JC, Sass JO, Edland SD, Burton BK, Berry SA, Santer R, Grünert S, Koch HG, Marquardt I, Rinaldo P, Hahn S, Matern D (2004). A common mutation is associated with a mild, potentially asymptomatic phenotype in patients with isovaleric acidemia diagnosed by newborn screening. Am J Hum Genet 75:1136-1142.

Mohsen AW, Anderson BD, Volchenboum SL, Battaile KP, Tiffany K, Roberts D, Kim JJ, Vockley J (1998). Characterization of molecular defects in isovaleryl-CoA dehydrogenase in patients with isovaleric acidemia. Biochemistry 37:10325-10335.