Table 1.
List of potential modifier genes for X-linked adrenoleukodystrophy investigated in various studies
| Series No. | Gene name | Variants studied | No. of cases | Inference | Ref. |
| Genes associated with VLCFA metabolism | |||||
| I | ABCD2 | rs11172566 | 117 | No significance | Maier et al[34] |
| rs11172661 | No significance | ||||
| I | ABCD2 | A/T(5’UTR) | 280 | No significance | Matsukawa et al[35] |
| M94V | No significance | ||||
| II | ABCD3 | rs4148058 | 280 | No significance | Matsukawa et al[35] |
| rs2147794 | No significance | ||||
| rs16946 | No significance | ||||
| rs681187 | No significance | ||||
| rs662813 | No significance | ||||
| rs337592 | No significance | ||||
| III | ABCD4 | rs17182959 | 280 | No significance | Matsukawa et al[35] |
| rs17158118 | No significance | ||||
| rs17782508 | No significance | ||||
| rs2301345 | No significance | ||||
| rs4148077 | No significance | ||||
| rs4148078 | No significance | ||||
| rs3742801 | No significance | ||||
| IV | Cytochrome P450 4F subfamily (CYP4F2) | rs21086622 | 152 | Minor allele A associated with CALD (P = 0.036) | van Engen et al[38] |
| rs3093207 | No significance | ||||
| rs1272 | No significance | ||||
| rs3093200 | No significance | ||||
| rs3093194 | No significance | ||||
| rs3093166 | No significance | ||||
| rs4808400 | No significance | ||||
| rs3093153 | No significance | ||||
| rs3093135 | No significance | ||||
| rs3093105 | No significance | ||||
| Genes associated with methionine metabolism | |||||
| I | Cystathionine β-Synthase (CBS) | c.844_845ins68 | 86 | Associated with pure AMN | Linnebank et al[46] |
| I | Cystathionine β-Synthase (CBS) | c.844_845ins68 | 172 | No significance | Semmler et al[48] |
| II | Methionine synthase (MTR) | c.2756A>G | 86 | No significance | Linnebank et al[45] |
| II | Methionine synthase (MTR) | c.2756A>G | 172 | No significance | Semmler et al[48] |
| III | Methylenetetrahydrofolate reductase (MTHFR) | c.677C>T | 86 | No significance | Linnebank et al[45] |
| III | Methylenetetrahydrofolate reductase (MTHFR) | c.677C>T | 172 | No significance | Semmler et al[48] |
| c.1298A>C | No significance | ||||
| IV | Dihydrofolate reductase (DHFR) | c.594+59del19bp | 172 | No significance | Semmler et al[48] |
| V | 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase (MTRR) | c.60A>G | 172 | No significance | Semmler et al[48] |
| VI | Transcobalamin 2 (TC2) | c. 776C>G | 86 | GG genotype prevalent in AMN with demyelination compared to pure AMN (P = 0.001) | Linnebank et al[45] |
| VI | Transcobalamin 2 (TC2) | c. 776C>G (GG) | 172 | GG genotype associated with demyelination (P = 0.036) | Semmler et al[48] |
| VII | Reduced folate carrier 1 (RFC1) | c.80G>A | 172 | No significance | Semmler et al[48] |
| Genes associated with inflammation | |||||
| I | TNF-α | G- 308A | 15 | No significance | McGuinness et al[64] |
| II | Cluster of differentiation (CD1) | CD1A-CD1E | 139 | No significance | Barbier et al[44] |
| III | Human leukocyte antigen (HLA) | HLA-DRB1*16 | 29 | HLA-DRB1*16 associated with X-ALD (P < 0.02) | Berger et al[40] |
| HLA-DRB1*15 | No significance | ||||
| III | Human leukocyte antigen (HLA) | HLA-DBR1* | 70 | No significance | Schmidt et al[41] |
| III | Human leukocyte antigen (HLA) | HLA-DRB1*16 | 106 | No significance | McGuinness et al[65] |
| HLA-DRB1*15 | |||||
| IV | Interleukin 6 (IL6) | 68 | No significance | Schmidt et al[41] | |
| V | Myelin Oligodendrocyte glycoprotein (MOG) | (TAAA)n | 68 | 226bp (TAAA)n polymorphism associated with the presence of Anti-MOG antibody. (P < 0.05). | Schmidt et al[41] |
| V | Myelin oligodendrocyte glycoprotein (MOG) | G15A | 44 | No significance | Gomez-Lira et al[42] |
| CTC 5 repeats | No significance | ||||
| G511C | No significance | ||||
| G520A | No significance | ||||
| 551+68 A→G | No significance | ||||
| 551+77 C→T | No significance | ||||
| Other genes | |||||
| I | Superoxide oxide dismutase (SOD2) | rs4880 | T-allele associated with cerebral involvement in non-CCALD cases | Brose et al[49] | |
| rs2758352 | No significance | ||||
| rs2842980 | No significance | ||||
| rs2758329 | No significance | ||||
| II | Apolipoprotein E (APOE) | rs7412 rs429358 | 83 | APOE4 associated with cerebral involvement | Orchard et al[52] |
| III | Cytochrome P450 family 7 subfamily A member 1 (CYP2A1) | rs3824260 (c.-533T>C) | Study carried out on a patient diagnosed with AMN with c.659T>C mutation in ABCD1 gene in patient and mother | CC allele observed in patient whereas CT in mother | Płatek et al[50] |
| rs3808607 (c.-267C>A) | AA allele observed in patient whereas CA in mother | ||||
| IV | 3 β-hydroxysteroid dehydrogenase type 7 (HSD3B7) | rs9938550 (c.748A>G) | GG allele observed in both | ||
| rs2305880 (c.1068T>C) | CC allele observed in patient | ||||
| V | Bile acyl-CoA synthetase (SLC27A5) | rs4810274 (c.1668-6T>C) | CC observed in patient | ||
| VI | Aldo-keto reductase family 1 member D1 (AKR1D1) | c.-71G>C | GC observed in patient | ||
| VII | Cytochrome P450 Family 27 Subfamily A Member 1 (CYP27A1) | rs397795841 (c.-357dupC) | Homozygous mutation in both | ||
AMN: Adrenomyeloneuropathy; CALD: Cerebral adrenoleukodystrophy; CCALD: Childhood cerebral adrenoleukodystrophy; VLCFA: Very-long-chain fatty acid; X-ALD: X-linked adrenoleukodystrophy.