Prospective diagnosis of MT-ATP6-related mitochondrial disease by newborn screening

Area of Science:

• Biochemistry
• Genetics
• Pediatrics

Background:

• Newborn screening (NBS) panels, including the Recommended Uniform Screening Panel (RUSP), identify elevated citrulline and C5-OH.
• Low citrulline levels can indicate proximal urea cycle disorders.
• Some NBS programs report low citrulline and/or elevated C5-OH.

Purpose of the Study:

• To investigate the significance of combined low citrulline and elevated C5-OH levels detected via NBS.
• To identify the genetic cause and clinical spectrum associated with these biochemical findings.
• To evaluate the efficacy of early diagnosis and treatment for affected individuals.

Main Methods:

• Analysis of six patients with abnormal NBS results (low citrulline and/or elevated C5-OH).
• Confirmatory biochemical testing including plasma amino acid analysis and acylcarnitine profiling.
• Mitochondrial DNA sequencing to identify pathogenic variants.

Main Results:

• All six patients harbored pathogenic variants in MT-ATP6 at high heteroplasmy levels.
• These variants are associated with Leigh syndrome, a neurodegenerative disorder.
• Affected individuals showed no metabolic crises or developmental regression with early treatment.
• Asymptomatic or paucisymptomatic mothers and siblings carried the familial variant, expanding the clinical spectrum.

Conclusions:

• The combination of low citrulline and elevated C5-OH on NBS is specific for pathogenic MT-ATP6 variants.
• Early diagnosis and treatment, including citrulline supplementation, can potentially prevent neurological sequelae of Leigh syndrome.
• Pathogenic MT-ATP6 variants present a broader clinical spectrum than previously recognized, including asymptomatic or mildly affected relatives.