What does a borderline newborn screen for X-linked adrenoleukodystrophy (X-ALD) indicate?

Understanding Borderline Newborn Screening Results for X-Linked Adrenoleukodystrophy (X-ALD)

A borderline newborn screen for X-linked adrenoleukodystrophy (X-ALD) indicates mildly abnormal metabolite levels that require comprehensive confirmatory testing to establish a definitive diagnosis, as these results alone are insufficient to confirm or rule out the condition.

What is a Borderline X-ALD Newborn Screen?

• A borderline X-ALD newborn screen typically shows mildly elevated levels of C24:0- and/or C26:0-lysophosphatidylcholine (lyso-PC), but not high enough to be considered definitively positive 1
• These results fall into what specialists refer to as a "metabolite diagnosis" or "gray-zone" - where metabolites are abnormal but not conclusively diagnostic 2
• Borderline results represent an intermediate class of findings that require additional investigation to determine their clinical significance 2

Diagnostic Follow-up Required

• Comprehensive evaluation at a specialty care center is essential for all infants with borderline X-ALD screening results 2
• Follow-up testing should include:
  • Repeat measurement of very long-chain fatty acids (VLCFAs) in plasma 3, 4
  • Genetic testing for pathogenic variants in the ABCD1 gene 4, 1
  • Family history assessment for X-ALD or adrenal insufficiency 4

Clinical Significance and Interpretation

• Borderline results may indicate:
  • True X-ALD with milder biochemical presentation 3
  • X-ALD carrier status in female infants 1
  • Other peroxisomal disorders with similar biochemical profiles 1
  • False positive result requiring no further intervention 2

Importance of Definitive Diagnosis

• Relying solely on borderline metabolite levels without confirmatory testing can lead to:
  • Incorrect or unclear diagnoses 2
  • Inappropriate clinical management 2
  • Unnecessary parental anxiety 2
  • Inaccurate data for refining screening programs 2

Clinical Implications

• Early and accurate diagnosis is critical for:
  • Monitoring for adrenal insufficiency, which can present in early infancy 3
  • Surveillance for cerebral ALD development, which requires regular MRI monitoring 4
  • Timely intervention with hematopoietic stem cell transplantation if cerebral disease develops 4

Pitfalls to Avoid

• Treating a borderline result as definitively diagnostic without confirmatory testing 2
• Dismissing borderline results without appropriate follow-up, as X-ALD can have significant morbidity and mortality if untreated 5, 6
• Failing to refer to a metabolic specialist or geneticist with expertise in X-ALD 2
• Delaying follow-up, as early intervention significantly improves outcomes 4

Current Screening Context

• X-ALD was added to the US Recommended Uniform Screening Panel in 2016, but implementation varies by state 5
• The positive predictive value for first-tier X-ALD screening is approximately 67%, with a false-positive rate of 0.0057% 1
• Newborn screening has revealed that X-ALD may be more common than previously thought 3

Conclusion for Clinical Practice

• All borderline X-ALD newborn screening results warrant prompt referral to a metabolic specialist for comprehensive evaluation 2
• The diagnostic process must be completed to distinguish true disease from false positives and to guide appropriate clinical management 2
• Regular monitoring is essential for all confirmed male patients with X-ALD, regardless of initial symptom status 4