Newborn screening for X-linked adrenoleukodystrophy in Italy: Diagnostic algorithm and disease monitoring

Abstract

IntroductionX-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder caused by variants in the ABCD1 gene. The main phenotypes observed in men with X-ALD are primary adrenal insufficiency, adrenomyeloneuropathy, and cerebral ALD (cALD). Cerebral ALD consists of a demyelinating progressive cerebral white matter (WM) disease associated with rapid clinical decline and is fatal if left untreated. Hematopoietic stem cell transplantation is the standard treatment for cALD as it stabilizes WM degeneration when performed early in the disease. For this reason, early diagnosis is crucial, and several countries have already implemented their newborn screening programs (NBS) with the assessment of C26:0-lysophosphatidylcholine (C26:0-LPC) values as screening for X-ALD.MethodsIn June 2021, an Italian group in Lombardy launched a pilot study for the implementation of X-ALD in the Italian NBS program. A three-tiered approach was adopted, and it involved quantifying the values of C26:0-LPC and other metabolites in dried blood spots with FIA-MS/MS first, followed by the more specific ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) technique and, finally, the genetic confirmation via focused NGS.DiscussionGenetically confirmed patients are set to undergo a follow-up protocol and are periodically evaluated to promptly start a specific treatment if and when the first signs of brain damage appear, as suggested by international guidelines. A specific disease monitoring protocol has been created based on literature data and personal direct experience.ConclusionThe primary aim of this study was to develop a model able to improve the early diagnosis and subsequent follow-up and timely treatment of X-ALD.EthicsThe study was approved by the local ethics committee. The research was conducted in the absence of any commercial or financial relationship that could be construed as a potential conflict of interest.

Addison’s Disease: Diagnosis and Management Strategies

“…The dramatic disease associates AD, adrenomyeloneuropathy and cerebral leukodystrophy (white matter progressive disease) requiring hematopoietic stem cell transplant for survival, thus the importance of early detection. 51 …”

The experiences of parents of children diagnosed with cerebral adrenoleukodystrophy

“…In recent years, several countries including the United States, Taiwan and The Netherlands have incorporated ALD into their national newborn screening programme (NBS) and pilot studies are currently underway in Italy and Japan (Albersen et al, 2023; Bonaventura et al, 2022; Chen et al, 2022; Moser et al, 2016; Shimozawa et al, 2021). Families affected by ALD are supportive of including ALD within the NBS programme that would enable those at risk of disease to be identified and then screened prospectively so they can receive timely treatment (Schaller et al, 2007; Schwan et al, 2019).…”

Analysis of genomics implementation in newborn screening for inherited metabolic disorders: an IRDiRC initiative

“…However, there is a group of IMDs without reliable biochemical markers in DBS (e.g., some urea cycle disorders or citrin deficiency), while other IMDs may need different methods than MS/MS (e.g., galactosemia, biotinidase deficiency), such as enzyme activities [15] . For the screening of some diseases such as GALT deficiency and lysosomal disorders, the enzyme activities may be measured by MS/MS, but the workflow must be adapted to the individual NBS center [16] . Moreover, in some disorders such as cystinuria and orotic aciduria, the specific biomarker is more accurately analyzed in urine samples, sometimes used to complement DBS.…”