Adrenoleukodystrophy (ALD)
https://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.63995?af=R
Newborn screening for adrenoleukodystrophy (ALD) has enabled early detection and intervention, improving outcomes for affected children. This study examined cases identified through newborn screening in Minnesota, highlighting key findings related to cerebral ALD, adrenal insufficiency (AI), genetic variations, and biochemical markers. Two children diagnosed through newborn screening developed cerebral ALD at ages 3.6 and 5 years. Both underwent haematopoietic stem cell transplantation (HSCT), which stabilised disease progression. Four other children had non-progressive brain abnormalities, and one child with Down syndrome exhibited brain changes unrelated to ALD. Adrenal insufficiency was diagnosed in six children, with one developing complete AI by 8 months old. Five others initially had partial AI and later progressed to complete AI, which required daily hydrocortisone treatment. Routine adrenal function monitoring proved critical for early detection and management. Genetic analysis revealed that most affected individuals inherited pathogenic ABCD1 gene variants from their mothers (97.6%), with only two cases resulting from new (de novo) mutations (2.3%). Additionally, variant classification inconsistencies among laboratories emphasised the need for standardised genetic interpretation. Some cases were associated with variants of uncertain significance, complicating diagnosis, and risk assessment. Biochemical analysis demonstrated that higher levels of C26:0-lysophosphatidylcholine (C26LPC) correlated with more pathogenic gene variants. This suggests that C26LPC may be a more reliable marker than traditional C26:0 VLCFA levels in assessing disease severity. Further findings also indicate a higher-than-expected incidence of ALD, particularly in males, compared to historical estimates. Overall, this study emphasises the value of newborn screening for ALD in enabling timely treatment and reducing disease complications. The findings support expanding ALD screening to other regions and highlight the need for further research to optimise screening and treatment strategies.