X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Abstract

Adrenoleukodystrophy (ALD) is a rare X‐linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell‐ and tissue‐specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long‐chain fatty acid (VLCFA) chain length‐dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety‐specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.

Metabolomic analysis coupled with extreme phenotype sampling identified that lysophosphatidylcholines are associated with multisite musculoskeletal pain

“…Interestingly, clinical presentation of adult-form X-ALD includes pain, bladder dysfunction, and impaired movement. 59 The association between MSMP and incontinence in the current study is consistent with this. LysoPC28:1 was found to be negatively associated with microvascular function improvement of hyperlipidemic patients undergoing lipoprotein apheresis, 51 which seemed to be attributed to lysoPC's ability of downregulating endothelial nitric oxide synthase, enhancing production of reactive oxygen species, inducing endothelial cell apoptosis, and inhibiting cell migration during damage repair.…”

“…LysoPC 26:0 is clinically used as the diagnostic marker for X-linked adrenoleukodystrophy (X-ALD), a condition caused by mutations in ATP-binding cassette subfamily D member 1 ( ABCD1 ) gene that encodes a peroxisomal transmembrane protein, resulting in accumulation of very-long-chain fatty acids, particularly C26:0, and subsequent PC 26:0 and lysoPC 26:0 before the onset of demyelination. 13 , 57 , 59 Gong et al 20 reported that in cultured ABCD1-deficient microglia, lysoPC 26:0 enhanced the expression of phagocytosis-related marker milk fat globule-EGF factor 8 (MFGE8), aggravated phagocytosis, and led to neuronal injury. Interestingly, clinical presentation of adult-form X-ALD includes pain, bladder dysfunction, and impaired movement.…”

Current Insights Into Adrenal Insufficiency in the Newborn and Young Infant

“…Adrenoleukodystrophy (ALD) is a very important cause of PAI because of associated progressive neurological features ( 90 ). The X-linked form of ALD due to defects in ABCD1 usually presents in childhood, and sometimes with adrenal-only features.…”

Cystic Fibrosis and Genotype-Dependent Therapy: Is There a Need for a Sex-Specific Therapy?

“…31 Similarly, the ABC transport adrenoleukodystrophy protein ( ABCD1 ) is present in peroxisomal membranes and works to transport fatty acids into peroxisomes for degradation. Mutations in ALDP are associated with X-linked adrenoleukodystrophy, 32,33 a condition brought to the attention of many through the Hollywood movie “Lorenzo’s Oil.” Cystic fibrosis transmembrane conductance regulator is a 1480 amino acid integral membrane protein that normally resides in the apical membrane of polarized epithelial cells lining the airways, GI tract, vas deferens, pancreatic duct, biliary tree, and sweat gland ducts. 5,34 -38 Like all members of the ABC family, CFTR is composed of 2 membrane-spanning domains (TMD-1 and -2), which anchor the protein in the plasma membrane, and 2 nucleotide-binding domains (NBD-1 and -2), which form a heterodimer to bind and hydrolyze ATP, presumably to control channel gating (CFTR opening and closing).…”

“…31 Similarly, the ABC transport adrenoleukodystrophy protein (ABCD1) is present in peroxisomal membranes and works to transport fatty acids into peroxisomes for degradation. Mutations in ALDP are associated with X-linked adrenoleukodystrophy, 32,33 a condition brought to the attention of many through the Hollywood movie "Lorenzo's Oil." Cystic fibrosis transmembrane conductance regulator is a 1480 amino acid integral membrane protein that normally resides in the apical membrane of polarized epithelial cells lining the airways, GI tract, vas deferens, pancreatic duct, biliary tree, and sweat gland ducts.…”