Metabolite studies in HIBCH and ECHS1 defects: Implications for screening

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• 3-Hydroxyisobutyryl-CoA hydrolase deficiency (HIBCHD) is a rare inborn error of valine catabolism.
• It is associated with Leigh-like disease, presenting with hypotonia, developmental delay, and cerebral atrophy.

Observation:

• A patient presented with symptoms suggestive of pyruvate dehydrogenase deficiency.
• Urine tandem mass spectrometry revealed elevated methacrylate cysteine conjugate, characteristic of HIBCHD.
• Enzyme assays showed deficient 3-hydroxyisobutyryl-CoA hydrolase activity and novel HIBCH mutations were identified.

Findings:

• Metabolite analysis indicated accumulation and metabolism of methacrylyl-CoA and acryloyl-CoA.
• Secondary propionyl-CoA pathway involvement was suggested by increased acryloyl-CoA derived metabolites.
• Metabolic profiles were similar to ECHS1 mutations, another valine metabolism disorder.

Implications:

• Urine tandem mass spectrometry is beneficial for diagnosing HIBCHD and ECHS1 defects.
• Propionate metabolism may play a role in the pathogenesis of these disorders.
• HIBCHD and ECHS1 defects should be considered in the differential diagnosis of Leigh-like diseases and hypotonia.