Diagnostic Criteria

Suggestive Findings

Scenario 1: Abnormal Newborn Screening (NBS) Result

NBS for classic isovaleric acidemia (IVA) is based on the quantification of the first-tier analyte isovalerylcarnitine (as C5-carnitine) in dried blood spots. C5-carnitine (C5) values above the cutoff reported by the screening laboratory are considered positive and suggest a diagnosis of classic IVA; additional testing of urinary organic acids is required to . An algorithm has been proposed for elevated C5 NBS result . Additional testing to decrease false positives includes C5 isobar analysis (when available), which can distinguish isovalerylcarnitine from other isobaric carnitines (pivaloylcarnitine, 2-methylbutyrylcarnitine, and N-valerylcarnitine) that cannot be distinguished by tandem mass spectrometry .

Source: GeneReviews — "Classic Isovaleric Acidemia"

Differential Diagnosis

Scenario 1: Abnormal Newborn Screening (NBS) Result

Table 4a.

Genes of Interest in the Differential Diagnosis of an Infant with NBS Results and/or Other Laboratory Findings Suggestive of Classic Isovaleric Acidemia

Gene(s) | Disorder | MOI | Laboratory Findings | Clinical Findings

ACADSB

| Short/branched-chain acyl-CoA dehydrogenase deficiency (2-methylbutyrylglycinuria) (OMIM 610006) | AR | C51 | • DD

• Seizures

• Autism

• Majority of persons remain asymptomatic

ETFA

ETFB

ETFDH

| Multiple acyl-CoA dehydrogenase deficiency (MADD, glutaric aciduria II) | AR | • C5

• Metabolic acidosis

• Hypoglycemia1

| • Muscular hypotonia weakness

• Liver dysfunction

• Cardiomyopathy

Management Guidelines

When classic isovaleric acidemia (IVA) is suspected during the diagnostic evaluation, that is, because of increased C5-carnitine concentrations in dried blood spots (acylcarnitine profile) or isovalerylglycine in urine (urine organic acids), metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with classic IVA, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Classic Isovaleric Acidemia: Recommended Evaluations Following Initial Diagnosis

Evaluation | Comment

Consultation w/metabolic physician/ biochemical geneticist specialist metabolic dietitian1 | • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended)

• Consideration of short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance emergency treatment, prognosis, risks for acute encephalopathic crises)

Nutrition/

Feeding assessment

| In symptomatic children w/feeding problems, ...

Source: GeneReviews — "Classic Isovaleric Acidemia"

Surveillance Guidelines

In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations. Table 7. Classic Isovaleric Acidemia: Recommended Surveillance

Source: GeneReviews — "Classic Isovaleric Acidemia"