ABCMdb

ABCD1 p.Arg518Gln

ClinVar:	c.1553G>A , p.Arg518Gln D , Pathogenic c.1552C>T , p.Arg518Trp D , Pathogenic
Predicted by SNAP2:	A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] ABCD1 mutations and the X-linked adrenoleukodystro... Hum Mutat. 2001 Dec;18(6):499-515. Kemp S, Pujol A, Waterham HR, van Geel BM, Boehm CD, Raymond GV, Cutting GR, Wanders RJ, Moser HW
ABCD1 mutations and the X-linked adrenoleukodystrophy mutation database: role in diagnosis and clinical correlations.
Hum Mutat. 2001 Dec;18(6):499-515., [PMID:11748843]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC half-transporter (ALDP) involved in the import of very long-chain fatty acids (VLCFA) into the peroxisome. The disease is characterized by a striking and unpredictable variation in phenotypic expression. Phenotypes include the rapidly progressive childhood cerebral form (CCALD), the milder adult form, adrenomyeloneuropathy (AMN), and variants without neurologic involvement. There is no apparent correlation between genotype and phenotype. In males, unambiguous diagnosis can be achieved by demonstration of elevated levels of VLCFA in plasma. In 15 to 20% of obligate heterozygotes, however, test results are false-negative. Therefore, mutation analysis is the only reliable method for the identification of heterozygotes. Since most X-ALD kindreds have a unique mutation, a great number of mutations have been identified in the ABCD1 gene in the last seven years. In order to catalog and facilitate the analysis of these mutations, we have established a mutation database for X-ALD ( http://www.x-ald.nl). In this review we report a detailed analysis of all 406 X-ALD mutations currently included in the database. Also, we present 47 novel mutations. In addition, we review the various X-ALD phenotypes, the different diagnostic tools, and the need for extended family screening for the identification of new patients.

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164 X-ALD Mutations Identified in the ABCD1 Gene Allele Exon Mutation Protein Remark fs P42 1 125insC n.d. # fs P84 1 253insC n.d. # E90K 1 268G>A n.d. # S98L 1 293C>T Present S98L 1 293C>T Present R104H 1 311G>A n.d. fs A112 1 337delC Absent # R113C 1 337C>T Present # R113P 1 338G>C n.d. # Q133X 1 397C>T Absent W137X 1 411G>A Absent P143S 1 427C>T n.d. S149N 1 446G>A Present R152S 1 454C>A n.d. R152C 1 454C>T Present R152L 1 455G>T Reduced # S161P 1 481T>C n.d. # R163P 1 488G>C n.d. Y174C 1 521A>G Absent Y174C 1 521A>G n.d. Q177X 1 529C>T Absent Y181C 1 542A>G n.d. fs Y181 1 544ins8bp n.d. # Q195X 1 583C>T n.d. # T198K 1 593C>A n.d. # fs S207 1 621del664bp Absent # SV207-8insAAS 1 622-23ins9bp n.d. # K217E 1 649A>G Present # P218T 1 652C>A n.d. V224E 1 671T>G n.d. # L229P 1 686T>C n.d. L229P 1 686T>C n.d. fs S235 1 706delCGTG n.d. # W242X 1 726G>A Absent G266R 1 796G>A n.d. G266R 1 796G>A n.d. R274W, R280C 1 820C>T, 838C>T n.d. # R285P 1 854G>C n.d. S290X 1 869C>A Absent # E291del 1 871-73delGAG Absent Y296C 1 887A>G n.d. Y296C 1 887A>G n.d. fs E300 IVS1 IVS1+1g>t n.d. # fs E300 IVS1 IVS1-1g>a n.d. # S315X 2 944C>A n.d. # K336M 2 1007A>T n.d. # G343D 2 1028G>A n.d. # R401Q 3 1202G>A Present R401Q 3 1202G>A Present K407X 3 1219A>T n.d. # E427del 4 1279-81delGAA n.d. # Q430X 4 1288C>T n.d. # R464X 4 1390C>T n.d. fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent fs E471 5 1415delAG Absent C511X 6 1533C>A n.d. # R518Q 6 1553G>A Absent fs G528 6 1586-90del Absent # fs Y532 6 1599delG Absent # P543L 6 1628C>T Absent P543L 6 1628C>T Absent fs Q544 6 1628-34duplicated n.d. # fs R545 IVS 6 IVS6+1g>c n.d. # R554H 7 1661G>A Absent fs Q556 7 1670delTG n.d. # (continued) replaced by a pyrimidine (C or T) or vice versa, and transitions, comprising the substitution of one purine by the other, or of one pyrimidine by the other. Login to comment

[hide] Mutational analyses of Taiwanese kindred with X-li... Pediatr Neurol. 2006 Oct;35(4):250-6. Chiu HC, Liang JS, Wang JS, Lu JF
Mutational analyses of Taiwanese kindred with X-linked adrenoleukodystrophy.
Pediatr Neurol. 2006 Oct;35(4):250-6., [PMID:16996397]

Abstract [show]
X-linked adrenoleukodystrophy is a neurodegenerative disorder with highly variable clinical presentation, including the childhood cerebral form, adult form adrenomyeloneuropathy, and Addison disease. The biochemical hallmark of the disorder is the accumulation of saturated very long chain fatty acids in all tissues and body fluids. This accumulation results from mutations in the ABCD1 gene localized to Xq28. Using polymerase chain reaction and direct sequencing of deoxyribonucleic acid, we identified five novel mutations, including a microdeletion (1624 del ATC), a splicing site mutation (intervening sequence 1 [IVS1] -2a>c), and three missense mutations (1172 T>C, 1520 G>A, and 1754 T>C), from Taiwanese kindred with X-linked adrenoleukodystrophy. A polymorphism involving a single nucleotide deletion in the intervening sequence 5 (IVS5 -6 del c) of the ABCD1 gene, previously misattributed as a mutation in the Chinese population, was also identified. The dinucleotide deletion (1415 del AG) mutation common in Japan and Western countries was not found as frequently in the Chinese and Taiwanese populations. Instead, a higher mutation frequency was observed in exon 6 of the ABCD1 gene among Japanese, Chinese, and Taiwanese kindred with X-linked adrenoleukodystrophy, representing a potential mutational hotspot for future mutational screening among these Asian populations.

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126 However, common missense mutations, including G226R, Y296C, R518Q, and S606L [13,33,35], have been observed between Chinese and Japanese (though as yet not identified in Taiwanese) X-linked adrenoleukodystrophy patients, indicating the possibility of inheritance from common ancestors. Login to comment
127 The only common mutation (R518Q) in exon 6 of the ABCD1 gene accounts for 25% (5 of 20) of all exon 6 mutations in Japanese and Chinese X-linked adrenoleukodystrophy families. Login to comment
124 However, common missense mutations, including G226R, Y296C, R518Q, and S606L [13,33,35], have been observed between Chinese and Japanese (though as yet not identified in Taiwanese) X-linked adrenoleukodystrophy patients, indicating the possibility of inheritance from common ancestors. Login to comment
125 The only common mutation (R518Q) in exon 6 of the ABCD1 gene accounts for 25% (5 of 20) of all exon 6 mutations in Japanese and Chinese X-linked adrenoleukodystrophy families. Login to comment

[hide] X-linked adrenoleukodystrophy in Spain. Identifica... Clin Genet. 2005 May;67(5):418-24. Coll MJ, Palau N, Camps C, Ruiz M, Pampols T, Giros M
X-linked adrenoleukodystrophy in Spain. Identification of 26 novel mutations in the ABCD1 gene in 80 patients. Improvement of genetic counseling in 162 relative females.
Clin Genet. 2005 May;67(5):418-24., [PMID:15811009]

Abstract [show]
In this study, we analyzed the ABCD1 gene in 80 X-linked adrenoleukodystrophy (X-ALD) patients from 62 unrelated families. We identified 53 different mutations, of which 26 are novel and two are non-pathogenic sequence variants (L516L and 3'UTR, 2246C/G) that have been previously described. The Spanish population had significant allelic heterogeneity, in which most of the mutations were exclusive to a single family 47/53 (88.7%). Only six mutations (Y174S, G277R, FsE471, R518Q, P543L, and R554H) were found in more than one family. Mutations G277R, P543L, and R554H were the most frequent, each of them being found in three patients (5%). Intra-familiar phenotype variability was observed in most of the families, but in one, with the novel mutation R120P, only the adult mild phenotype was present (five hemizygous family members). We detected 80 heterozygous women by mutation analysis, but only 78 of them showed increased very-long-chain fatty acid levels. In conclusion, this study extends the spectrum of mutations in X-ALD and facilitates the identification of heterozygous females. Our results are also consistent with previous studies reporting the difficulty of predicting genotype-phenotype correlation.

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6 Only six mutations (Y174S, G277R, FsE471, R518Q, P543L, and R554H) were found in more than one family. Login to comment
72 Only six mutations (Y174S, G277R, FsE471, R518Q, P543L, and R554H) have been found repeated in patients belonging to different families. Login to comment

[hide] Baicalein 5,6,7-trimethyl ether, a flavonoid deriv... FEBS Lett. 2005 Jan 17;579(2):409-14. Morita M, Takahashi I, Kanai M, Okafuji F, Iwashima M, Hayashi T, Watanabe S, Hamazaki T, Shimozawa N, Suzuki Y, Furuya H, Yamada T, Imanaka T
Baicalein 5,6,7-trimethyl ether, a flavonoid derivative, stimulates fatty acid beta-oxidation in skin fibroblasts of X-linked adrenoleukodystrophy.
FEBS Lett. 2005 Jan 17;579(2):409-14., [PMID:15642351]

Abstract [show]
The purpose of the present study is to identify bioactive compounds with potential for X-linked adrenoleukodystrophy (X-ALD) pharmacological therapy. Various plant natural products including flavonoids were tested for their ability to ameliorate the abnormality of very long chain fatty acid (VLCFA) metabolism in cultured skin-fibroblasts from X-ALD patients. Of the compounds tested, baicalein 5,6,7-trimethyl ether (baicalein-tri-Me) was found to significantly stimulate the VLCFA beta-oxidation activity. Furthermore, the incorporation of [1-(14)C]lignoceric acid into cholesteryl esters was markedly reduced towards the normal level and the VLCFA (C24:0 and C26:0) content was decreased. These results make baicalein-tri-Me a candidate for the therapeutic compound for X-ALD.

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34 Cell culture Human skin fibroblasts (normal) and X-ALD fibroblasts (R518Q [13] and #163 [14]) were cultured in DMEM (ICN, Aurora, OH), containing 10% fetal bovine serum and maintained in a humidified atmosphere with 95% air and 5% CO2 at 37 °C. Login to comment
60 Effect of various flavonoids on VLCFA b-oxidation in X-ALD fibroblasts The VLCFA b-oxidation activity in X-ALD fibroblasts (R518Q) was decreased by 70% as compared with normal fibroblasts (as shown in Fig. 1). Login to comment
71 X-ALD fibroblasts (R518Q) were incubated in the absence or presence of 20 lM of various flavonoids for 72 h. Media were replaced every 24 h with the addition of fresh reagents. Login to comment
83 Baicalein-tri-Me stimulates LCFA as well as VLCFA b-oxidation To avoid the possibility that the affect was restricted to certain X-ALD missense mutants, we attempted to elucidate the effect of the flavonoid on the activity in different mutant X-ALD fibroblasts; #163 (lacking ALD mRNA and protein, and immortalized by transformation with SV40) and R518Q (harboring the missense mutation of 1939G to A corresponding to the arginine at the 518 amino acid residue). Login to comment
84 Baicalein- tri-Me stimulated VLCFA b-oxidation in both of the mutant X-ALD fibroblasts; #163 by 79% and R518Q by 117% (Table 1), suggesting that the effect was not restricted to a certain missense mutant. Login to comment
96 However, C22:0 was significantly decreased by the Table 1 Effect of baicalein-tri-Me on VLCFA b-oxidation in different X-ALD mutant fibroblasts Palmitic acid (C16:0) (pmol/h/ mg protein) Lignoceric acid (C24:0) (pmol/h/ mg protein) Healthy control None (DMSO) 225.7 ± 3.5 171.3 ± 7.4 Baicalein-tri-Me 357.3 ± 27.2 373.2 ± 1.3 X-ALD (R518Q) None (DMSO) 369.0 ± 90.2 71.1 ± 4.5 Baicalein-tri-Me 488.5 ± 42.2 154.1 ± 17.7 X-ALD (#163) None (DMSO) 296.9 ± 19.0 74.4 ± 1.4 Baicalein-tri-Me 589.9 ± 98.6 133.2 ± 9.5 Healthy control and X-ALD fibroblasts, R518Q and #163, were incubated with 30 lM of baicalein-tri-Me for three days. Login to comment
106 X-ALD fibroblasts (R518Q) were treated with various concentrations of baicalein-tri-Me for three days (A) or cultured in the presence of baicalein-tri-Me at a concentration of 30 lM (B). Login to comment

[hide] Identification of novel SNPs of ABCD1, ABCD2, ABCD... Neurogenetics. 2011 Feb;12(1):41-50. Epub 2010 Jul 27. Matsukawa T, Asheuer M, Takahashi Y, Goto J, Suzuki Y, Shimozawa N, Takano H, Onodera O, Nishizawa M, Aubourg P, Tsuji S
Identification of novel SNPs of ABCD1, ABCD2, ABCD3, and ABCD4 genes in patients with X-linked adrenoleukodystrophy (ALD) based on comprehensive resequencing and association studies with ALD phenotypes.
Neurogenetics. 2011 Feb;12(1):41-50. Epub 2010 Jul 27., [PMID:20661612]

Abstract [show]
Adrenoleukodystrophy (ALD) is an X-linked disorder affecting primarily the white matter of the central nervous system occasionally accompanied by adrenal insufficiency. Despite the discovery of the causative gene, ABCD1, no clear genotype-phenotype correlations have been established. Association studies based on single nucleotide polymorphisms (SNPs) identified by comprehensive resequencing of genes related to ABCD1 may reveal genes modifying ALD phenotypes. We analyzed 40 Japanese patients with ALD. ABCD1 and ABCD2 were analyzed using a newly developed microarray-based resequencing system. ABCD3 and ABCD4 were analyzed by direct nucleotide sequence analysis. Replication studies were conducted on an independent French ALD cohort with extreme phenotypes. All the mutations of ABCD1 were identified, and there was no correlation between the genotypes and phenotypes of ALD. SNPs identified by the comprehensive resequencing of ABCD2, ABCD3, and ABCD4 were used for association studies. There were no significant associations between these SNPs and ALD phenotypes, except for the five SNPs of ABCD4, which are in complete disequilibrium in the Japanese population. These five SNPs were significantly less frequently represented in patients with adrenomyeloneuropathy (AMN) than in controls in the Japanese population (p=0.0468), whereas there were no significant differences in patients with childhood cerebral ALD (CCALD). The replication study employing these five SNPs on an independent French ALD cohort, however, showed no significant associations with CCALD or pure AMN. This study showed that ABCD2, ABCD3, and ABCD4 are less likely the disease-modifying genes, necessitating further studies to identify genes modifying ALD phenotypes.

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84 Interestingly, the five previously described SNPs (rs17782508, rs2301345, rs4148077, rs4148078, and rs3742801) that are in complete linkage disequilibrium were significantly less frequently represented in the patients with Japanese AMN than in the controls in the Japanese population (p=0.0468), whereas Table 2 Identified ABCD1 mutations: mutations of ABCD1 that result in amino acid substitutions or in-frame deletions Patient number Phenotype Mutation of ABCD1 Effect of mutation of ABCD1 Position of mutation 13 CCALD 709C>T S108L Loop1 14 CCALD 709C>T S108L Loop1 15 CCALD 829A>G N148S TM2 16 CCALD 1026A>G N214D TM3 17 CCALD 1182G>A G266R Between TM4 and EAA-like 18 CCALD 1324T>Ca L313P Between EAA-like and TM5 19 CCALD 1938C>T R518W Walker A 20 CCALD 1939G>A R518Q Walker A 21 CCALD 2017A>G Q544R Between Walker A and Cons 22 CCALD 2017A>G Q544R Between Walker A and Cons 23 CCALD 2065C>T P560L Between Walker A and Cons 24 CCALD 2065C>T P560L Between Walker A and Cons 25 CCALD Del. 2145-2156 Del. HILQ587-590 Between Walker A and Cons 26 AdultCer Del. 1257-1259 Del.E291 EAA-like 27 AdultCer 2005T>C F540S Between Walker A and Cons 28 AdultCer 2358C>T R660W C-terminal to Walker B 29 AdultCer 2385C>A H667N C-terminal to Walker B 30 AMN-Cer 1146A>C T254P TM4 31 AMN 636C>T P84S TM1 32 AMN 709C>T S108L Loop1 33 AMN 1182G>A G266R Between TM4 and EAA-like 34 AMN 1197G>A E271K Between TM4 and EAA-like 35 AMN 1215G>Aa G277R Between TM4 and EAA-like 36 AMN 1255C>G S290W EAA-like 37 AMN 1581C>T R401W Between TM6 and Walker A 38 AMN 2233C>A A616D Cons 39 AMN 2385C>A H667N C-terminal to Walker B 40 Asymptomatic 2211G>A E609K Cons Amino acid residue numbers in ALDP are based on Mosser et al. [1]. Login to comment

[hide] Mutational analysis and genotype-phenotype correla... Arch Neurol. 1999 Mar;56(3):295-300. Takano H, Koike R, Onodera O, Sasaki R, Tsuji S
Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.
Arch Neurol. 1999 Mar;56(3):295-300., [PMID:10190819]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (ALD) is an inherited disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. The classic form of ALD usually has onset in childhood (childhood cerebral ALD), with rapid neurologic deterioration leading to a vegetative state. Adult-onset cerebral ALD also presents with rapidly progressive neurologic dysfunction. Milder phenotypes such as adrenomyeloneuropathy and Addison disease only also have been recognized. Despite discovery of the causative gene, a molecular basis for the diverse clinical presentations remains to be elucidated. OBJECTIVES: To conduct mutational analyses in 29 Japanese patients with ALD from 29 unrelated families, to obtain knowledge of the spectrum of mutations in this gene, and to study genotype-phenotype correlations in Japanese patients. METHODS: The 29 patients comprised 13 patients with childhood cerebral ALD, 11 patients with adult-onset cerebral ALD, and 5 patients with adrenomyeloneuropathy. We conducted detailed mutational analyses of 29 unrelated Japanese patients with ALD by genomic Southern blot analysis and direct nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction products derived from total RNA that was extracted from cultured skin fibroblasts, lymphoblastoid cells, or peripheral blood leukocytes. RESULTS: Three patients with adult-onset cerebral ALD were identified as having large genomic rearrangements. The remaining 26 patients were identified as having 21 independent mutations, including 12 novel mutations resulting in small nucleotide alterations in the ALD gene. Eighteen (69%) of 26 mutations were missense mutations. Most missense mutations involved amino acids conserved in homologous gene products, including PMP70, mALDRP, and Pxa1p. The AG dinucleotide deletion at position 1081-1082, which has been reported previously to be the most common mutation in white patients (12%-17%), was also identified as the most common mutation in Japanese patients (12%). All phenotypes were associated with mutations resulting in protein truncation or subtle amino acid changes. There were no differences in phenotypic expressions between missense mutations involving conserved amino acids and those involving nonconserved amino acids. CONCLUSIONS: There are no obvious correlations between the phenotypes of patients with ALD and their genotypes, suggesting that other genetic or environmental factors modify the phenotypic expressions of ALD.

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42 Mutations in the ALD Gene That Result in Amino Acid Substitutions or In-frame Deletions* Patient No. Phenotype Mutation† Exon Effect of Mutation‡ Position of Mutation§ Amino Acid Identityሻ Family DataPMP70 mALDRP Pxa1p Amino Acid Deletion G4010 ACALD del.1256-1258 1 del.E291 EAA-like motif E E E CCALD G4011(s) ACALD del.2146-2157¶ 7 del.HILQ587-590 Between Walker A and B# HILE HIVQ YLLK No family history Missense Mutation G4012 CCALD A829G 1 N148S TM3 N N N AMN G1986 CCALD G984A¶ 1 D200N TM4 D D D ACALD G4013 CCALD A1026G¶ 1 N214D TM4 N N N Not available G4014 AMN G1182A 1 G266R Between TM5 and EAA motif G G Non AMN G4015(s) CCALD G1182A 1 G266R Between TM5 and EAA motif G G Non No family history G4016(s) AMN G1197A 1 E271K Between TM5 and EAA motif T E R No family history G4017(s) ACALD A1273G¶ 1 Y296C EAA motif Y Y Y No family history G4018 CCALD A1273G¶ 1 Y296C EAA motif Y Y Y Not available G4019 AMN C1587T¶ 3 R401W Between TM6 and Walker A R R R Asymptomatic carrier G4020 CCALD G1906T¶ 6 G507V Walker A# G G G Not available G4021 CCALD G1939A 6 R518Q Walker A# R R R CCALD G4022 CCALD G1939A 6 R518Q Walker A# R R R Not available G4023 ACALD T2005C¶ 6 F540S Between Walker A and B# F F F Adult asymptomatic carrier G4024(s) CCALD A2017G 6 Q544R Between Walker A and B# Q Q Q No family history G4025 CCALD C2065T 7 S560L Between Walker A and B# P P P Adult asymptomatic carrier G2469(s) ACALD C2157T¶ 7 R591W Between Walker A and B# R R R No family history G2022(s) AMN C2203T 8 S606L Between Walker A and B# S S S No family history G4026 ACALD C2364T 8 R660W C-terminal to Walker B R R R ACALD *ALD indicates adrenoleukodystrophy; ACALD, adult-onset cerebral ALD; CCALD, childhood cerebral ALD; AMN, adrenomyeloneuropathy; (s), apparently sporadic patients; and del., delete. Login to comment

[hide] Two novel missense mutations in the ATP-binding do... Clin Genet. 1997 May;51(5):322-5. Imamura A, Suzuki Y, Song XQ, Fukao T, Uchiyama A, Shimozawa N, Kamijo K, Hashimoto T, Orii T, Kondo N
Two novel missense mutations in the ATP-binding domain of the adrenoleukodystrophy gene: immunoblotting and immunocytological study of two patients.
Clin Genet. 1997 May;51(5):322-5., [PMID:9212180]

Abstract [show]
Two novel missense mutations, 1939G to A (R518Q) and 2017A to G (Q544R) were identified in Japanese patients with adrenoleukodystrophy (ALD). They are located in exon 6, which encodes part of the putative adenosine triphosphate binding domain of ALD protein. The ALD protein carrying the R518Q mutation was undetectable in fibroblasts, by immunoblot and immunofluorescence analysis, while the Q544R mutation had no apparent effect on the stability and localization of the ALD protein, but is expected to affect its function.

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3 0 Munksgaard, 1997 Two novel missense mutations, 19390 to A (R518Q)and 2017A to G (QSJJR)were identified in Japanese patients with adrenoleukodystrophy (ALD). Login to comment
37 Two novel missense mutations patients 1 and 2 had a single base substitution of G for A at position 1939, which led to replacement of arginine for glutamine at position 518 (R518Q), and of A for G at position 2017, which led to replacement of glutamine for arginine at position 544 (Q544R) (Fig. 1 A,B). Login to comment
43 The R518Q mutation has recently been reported in a Japanese patient with ALD (Koike et al. 1994), but this case belongs to another, unrelated family. Login to comment
55 Lane 1: control; Lane 2: ALD patient with Q590STOP mutation in Uchiyama et al. (1994); Lane 3: patient 1 with R518Q mutation; Lane 4: patient 2 with Q544R mutation. Login to comment
58 a: patient 1 with R518Q mutation; b patient 2 with Q544R mutation; c: control. Login to comment
61 The mutation in patient 1 (R518Q) is located in the alpha B helix of the Walker A motif, while that of patient 2 (Q544R) resides in the alpha C helix between Walker A and B (Hyde et al. 1990). Login to comment

[hide] Molecular characterization of 21 X-ALD Portuguese ... Mol Genet Metab. 2002 May;76(1):62-7. Guimaraes CP, Lemos M, Sa-Miranda C, Azevedo JE
Molecular characterization of 21 X-ALD Portuguese families: identification of eight novel mutations in the ABCD1 gene.
Mol Genet Metab. 2002 May;76(1):62-7., [PMID:12175782]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder. The gene associated with X-ALD, ABCD1, encodes a peroxisomal ATP-binding cassette half-transporter. In this study, we describe the molecular characterization of 21 affected Portuguese families. The complete coding region of the ABCD1 gene was amplified by reverse transcription polymerase chain reaction (RT-PCR) or genomic PCR. After conformation-sensitive gel electrophoresis analysis, fragments with a conformational heteroduplex pattern were sequenced. Using this strategy, we have identified 14 missense mutations, two nonsense mutations, two splicing site defects, and three small deletions, two of them resulting in frameshifts. Eight of the genetic alterations characterized in this study are novel. The levels of the ABCD1 transcript as well as the levels of ALDP in cultured skin fibroblasts of male probands were also determined in most cases. The levels of the ABCD1 transcript in one patient (corresponding to a nonsense mutation) were below the detection limit of Northern-blotting analysis. ALDP was found at normal levels in only three patients, absent in five (corresponding to a double missense, two nonsense, and two frameshift mutations), and decreased in all the others.

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66 Type of genetic alteration Exon RT-PCR fragmenta Nucleotide change Amplicon usedb /RFLP associatedc ALDP (WB) ABCD1 mRNA (NB) References Missense 1 S103R 1 F2 c.309C > G ALDe1A/þCfoI Diminished Detectable [19] 2 S108W 1 - c.323C > G ALDe1B/þRleAI Not done Not done [18] 3 S108L 1 - c.323C > T - Normal Not done [20] 4 L114P 1 F2 c.341T > C ALDe1B/ÀEcoRII Diminished Detectable Novel mutation 5 ½R236H; G512S 1 F3 [c.707G > A; ALDe1C/þNcoI Novel mutation 6 F6 c.1534G > A] ALDe6/þPstI Not detectable Not done [16,17] 6 G266R 1 F3 c.796G > A - Normal Detectable [21] 7 R518W 6 F6 c.1552C > T ALDe6/ÀHpaII Diminished Detectable [22] 8 R518Q 6 F6 c.1153G > A ALDe6/ÀBamHI Diminished Not done [23] 9 R545W 6 - c.1633A > T ALDe6/þTspRI Not done Not done Novel mutation 10 R591W 7 F7 c.1171C > T ALDe7/ÀAciI Normal Not done [24] 11 L655P 9 F8 c.1964T > C ALDe8/9/ÀSapId Diminished Detectable Novel mutation 12 R660W 9 F7/F8 c.1978C > T ALDe8/9/þBsrI Diminished Detectable [16,17,25] 13 H667L 10 F8 c.2000A > T ALDe10/þDdeId Diminished Detectable Novel mutation Nonsense 14 Q574X 7 F6 c.1720C > T ALDe7/ÀAlwNI Not detectable Detectable Novel mutation 15 W601X 8 F7 c.1802G > A ALDe8/9/ÀBsrI Not detectable Not detectable [9] Frameshift 16 fs G298 1 F3 [c.893delG; c.894C > T] ALDe1C/ÀNlaIV Not detectable Detectable Novel mutation 17, 18 fs E472 5 F5 c.1415-1416delAG - Not detectable Detectable [21,26,27] Microdeletion 19 F175del 1 F2 c.522-524delCTT d Diminished Detectable Novel mutation Splicing defect 20 Splicing IVS1 - c.900G > A - Not done Not done [10] 21 Splicing IVS7 - c.1760+1G > A - Not done Not done [18] Polymorphism 1, 5 F673F 8 F8 c.2019C > T ÀTaqI - - [28] 1, 2, 5, 11, 13 30 UTR F8 - ÀDrdI - - [27] a RT-PCR fragment (defined according to [10]) which shows heteroduplex molecules in a CSGE analysis. Login to comment

[hide] Eight novel ABCD1 gene mutations and three polymor... Hum Mutat. 2001;18(1):52-60. Dvorakova L, Storkanova G, Unterrainer G, Hujova J, Kmoch S, Zeman J, Hrebicek M, Berger J
Eight novel ABCD1 gene mutations and three polymorphisms in patients with X-linked adrenoleukodystrophy: The first polymorphism causing an amino acid exchange.
Hum Mutat. 2001;18(1):52-60., [PMID:11438993]

Abstract [show]
X-ALD is a neurological disorder associated with inherited defects in the ABCD1 (ALD) gene located on Xq28 and with impaired peroxisomal very long-chain fatty acid beta-oxidation. We examined the ABCD1 gene in probands from 11 unrelated X-ALD Czech and Slovak families by the direct sequencing of cDNA or genomic PCR products. In 10 families there were 10 different mutations, eight of which were novel. The spectrum of mutations consists of six point mutations, three microdeletions (1bp, 2bp, 4 bp), and one large deletion (229bp). In the 11th family we detected two novel single-base pair substitutions in exon 1 (c.38 A>C and c.649 A>G), both causing amino acid exchanges (N13T and K217E). Expression studies revealed that only K217E is a deleterious mutation, because a plasmid encoding ALDP with K217E was ineffective in the restoration of defective beta-oxidation in X-ALD fibroblasts. The N13T amino acid exchange, on the other hand, did not affect ALDP function. Thus, N13T represents the first polymorphism causing an amino acid exchange in the ABCD1 gene. As this polymorphism was observed neither in 100 control alleles nor in 300 X-ALD patients who have been sequenced so far world-wide, it seems to be very rare or unique. Two additional novel polymorphisms were found by the sequencing of the ABCD1 gene from our patients: c.-59 C/T in the 5'untranslated region and c.2019 C/T (F673F) in exon 10. The frequencies of these two polymorphisms, were 11/150 and 2/150 control alleles, respectively.

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46 Phenotype (years) Therapy Exon (ATG=1) Allele residues site Polymorphisms 1 1 ccALD 15 None 1 c.97-100 Fs V32 +BsmFI c.2246 G>C del/TACC 2 2 ccALD 6 LO, GTO, BMT 1+IVS1 g.697-925/del 3 3 AMN 33 LO, GTO 3 c.1092/del/C Fs E363 -BsuRI 4 4 ccALD Died at None 5 c.1415-1416/del Fs E471 +TaaIe the age of 9 AGf 5 5 AMN 20 LO, GTO 1 c.293 C>Tg S98L TMS 1c -Eco52I c.2019 C>T c.2246 G>C 6 6 AMN 18 LO, GTO 1 c.296 C>A A99D TMS 1 +BsaHI c.1548 G>A c.2246 G>C 7 7a ADO 14 LO, GTO 1 c.649 A>G K217E TMS 3 +AvaIe c.38 A>C 7 7b ADO 9 LO, GTO 1 c.649 A>G K217E TMS 3 +AvaIe c.38 A>C 8 8 AMN 22 LO, GTO 6 c.1553 G>Ah R518Q Walker Ad +PflMI 9 9 ccALD 17b LO, GTO 8 c.1823 G>A G608D C sequenced +HphI c.-59 C>T c.1548 G>A c.2246 G>C 10 10 Asymptomatic 9 LO,GTO 9 c.1898 G>T S633I Conserved in mouse +MslI 11 11 ccALD 9 None 9 c.1979 G>C R660P Conserved in mouse -Cfr10I a Novel variants in boldface type. Login to comment
54 h R518Q: ccALD [Imamura et al., 1997; Takano et al., 1999]. Login to comment

[hide] ABCD1 gene mutations in Chinese patients with X-li... Pediatr Neurol. 2005 Aug;33(2):114-20. Pan H, Xiong H, Wu Y, Zhang YH, Bao XH, Jiang YW, Wu XR
ABCD1 gene mutations in Chinese patients with X-linked adrenoleukodystrophy.
Pediatr Neurol. 2005 Aug;33(2):114-20., [PMID:16087056]

Abstract [show]
X-linked adrenoleukodystrophy is a neurodegenerative disorder caused by mutations in the adrenoleukodystrophy (ALD) protein gene ABCD1. This study used direct sequencing of genomic polymerase chain reaction products to perform mutational analysis of ABCD1 in 34 unrelated Chinese X-linked adrenoleukodystrophy patients and 27 of their maternal relatives. Thirty-two different mutations were identified in 34 patients. Most of the mutations (62.5%, 20/32) were missense mutations, six of which are novel. One novel single nucleotide polymorphism, c.1047 C>A, was also found in three patients and their mothers, which can also be observed in 1 of 120 normal control alleles. Two synonymous mutations (p.L516L and p.V349V) appeared in two unrelated patients, and no other mutations were evident after screening the gene's 10 exons. Seventeen of the probands' mothers were found to be heterozygous for the same mutations present in their sons' ABCD1 gene. Eight of the 10 screened sisters and cousins were identified as carriers. There were no hot spot mutations in the ABCD1 gene of Chinese patients with X-linked adrenoleukodystrophy. However, over half of the mutations (19/34) were located in exon 1 and exon 6, suggesting possible hot exons. No obvious relationship between genotype and phenotype was observed.

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58 All were private mutations, except for the R518Q allele that was present in two unrelated patients. Login to comment
59 All were private mutations, except for the R518Q allele that was present in two unrelated patients. Login to comment

[hide] Mutations, clinical findings and survival estimate... PLoS One. 2012;7(3):e34195. doi: 10.1371/journal.pone.0034195. Epub 2012 Mar 29. Pereira Fdos S, Matte U, Habekost CT, de Castilhos RM, El Husny AS, Lourenco CM, Vianna-Morgante AM, Giuliani L, Galera MF, Honjo R, Kim CA, Politei J, Vargas CR, Jardim LB
Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.
PLoS One. 2012;7(3):e34195. doi: 10.1371/journal.pone.0034195. Epub 2012 Mar 29., [PMID:22479560]

Abstract [show]
In this study, we analyzed the ABCD1 gene in X-linked adrenoleukodystrophy (X-ALD) patients and relatives from 38 unrelated families from South America, as well as phenotypic proportions, survival estimates, and the potential effect of geographical origin in clinical characteristics. METHODS: X- ALD patients from Brazil, Argentina and Uruguay were invited to participate in molecular studies to determine their genetic status, characterize the mutations and improve the genetic counseling of their families. All samples were screened by SSCP analysis of PCR fragments, followed by automated DNA sequencing to establish the specific mutation in each family. Age at onset and at death, male phenotypes, genetic status of women, and the effect of family and of latitude of origin were also studied. RESULTS: We identified thirty-six different mutations (twelve novel). This population had an important allelic heterogeneity, as only p.Arg518Gln was repeatedly found (three families). Four cases carried de novo mutations. Intra-familiar phenotype variability was observed in all families. Out of 87 affected males identified, 65% had the cerebral phenotype (CALD). The mean (95% CI) ages at onset and at death of the CALD were 10.9 (9.1-12.7) and 24.7 (19.8-29.6) years. No association was found between phenotypic manifestations and latitude of origin. One index-case was a girl with CALD who carried an ABCD1 mutation, and had completely skewed X inactivation. CONCLUSIONS: This study extends the spectrum of mutations in X-ALD, confirms the high rates of de novo mutations and the absence of common mutations, and suggests a possible high frequency of cerebral forms in our population.

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5 This population had an important allelic heterogeneity, as only p.Arg518Gln was repeatedly found (three families). Login to comment
24 Family/Index case Phenotype at diagnosis Mutation Exon/IVS Mutation type Effect on protein (cDNA) Effect on protein (mRNA) Protein localization Origin of mutations Origin of family 1/Female asymptomatic p.Gly512Ser (Feigenbaum V et al. 1996) E6 Missense c.1534G.A GGC.AGC NBF de novo Southern Brazil 2/Female asymptomatic p.Ser606Leu (Fanen P et al., 1994) E8 Missense c.1817C.T UCG.UUG NBF Inherited Southern Brazil 3/Male AMN p.Trp601X (Gartner J et al.,1998) E8 Stop codon c.1802C.A Truncated NBF Inherited Southern Brazil 4/Female asymptomatic p.Arg617His (Fanen P et al., 1994) E8 Missense c.1850G.A CGC.CAC NBF ND Southern Brazil 5/Male AMN p.Pro623Leu # E9 Missense c.1868C.T CCC.CUC NBF Inherited Southern Brazil 6/Male AO p.Trp326X (Barcelo A et al, 1996) E2 Stop codon c.978G.A Truncated TMD Inherited Southern Brazil 8/Female asymptomatic p.Glu577X # E7 Stop codon c.1729G.T Truncated NBF Inherited Southern Brazil 9/Male asymptomatic p.Arg554His (Smith KD et al., 1999) E7 Missense c.1661G.A CGU.CAU NBF Inherited Southern Brazil 10/Male CALD p.Arg518Gln (Imamura A et al., 1997) E6 Missense c.1553G.A CGG.CAG NBF Inherited Southern Brazil 11/Male AO p.Tyr33_Pro34fsX34 # E1A Frameshift+stop codon c.99_102delC Truncated - Inherited Southern Brazil 12/Female asymptomatic p.Gly266Arg (Fuchs S et al., 1994) E7 Missense c.1653insG Truncated TMD ND Southern Brazil 20/Male CALD p.Arg538fs # E6 Frameshift c.1614_1615dup27 Elonged NBF de novo Southern Brazil 21/Male CALD p.Ala232fsX64 # E2 Frameshift+stop codon c.696_697del11 Truncated TMD Inherited Southern Brazil 22/Male CALD p.Trp137fsX57 # E1B Frameshift+stop codon c.411_412insC Truncated TMD Inherited Northern Brazil 23/Male asymptomatic p.Trp679X (Waterham HR et al, 1998) E10 Stop codon c.2037G.A Truncated NBF ND Southern Brazil 24/Male AO p.Tyr296Cys (Takano H et al., 1999) E2 Missense c.887A.G UAU.UGU TMD Inherited Southern Brazil 27/Male CALD p.Leu628Glu # E9 Missense c.1883T.A CUG.GAG NBF Inherited Southern Brazil 29/Male CALD p.Pro546fsX? Login to comment
26 NBF Inherited Northern Brazil 31/Male CALD p.Arg518Gln (Imamura A et al., 1997) E6 Missense c.1553G.A CGG.CAG NBF de novo Southern Brazil 32/Male CALD p.Arg401Trp (Takano H et al., 1999) E3 Missense c.1201C.T CGG.UGG - ND Southern Brazil 33/Male CALD p.Thr632Pro (http://www.x-ald.nl) E9 Missense c.1894A.C ACC.CCC NBF de novo Southern Brazil 36/Male CALD p.Arg518Gln (Imamura A et al., 1997) E6 Missense c.1553G.A CGG.CAG NBF Inherited Northern Brazil 37/Male CALD p.Ser358X (Coll MJ et al., 2005) E2 Stop codon c.1073C.G UCA.UGA TMD Inherited Southern Brazil 38/Male CALD p.Ile481Phe # E5 Missense c.1441A.T AUC.UUC NBF Inherited Northern Brazil 39/Male AMN p.Arg389Gly (Krasemann EW et al., 1996) E3 Missense c.1165C.G CGC.GGC - ND Argentina 40/Male AMN p.Gln472fsX83 (Barcelo &#b4; A et al., 1994) E5 Frameshift+stop codon c.1415_1416delAG Truncated - Inherited Uruguay 41/Male CALD p.Ala95fsX11 # E1B Frameshift+stop codon c.283_284ins9 Elonged TMD Inherited Southern Brazil 44/Male CALD p.Ser606Pro (Feigenbaum V et al. 1996) E8 Missense c.1816T.C UCG.CCG NBF Inherited Northern Brazil 45/Male CALD p.Gln55X # E1A Stop codon c.163C.T Truncated - Inherited Northern Brazil 46/Male CALD p.Glu199Lys (http://www.x-ald.nl) E1C Missense c.595G.A GAG.AAG TMD ND Northern Brazil common central demyelinative disease. Login to comment
86 The already described p.Arg518Gln mutation [14] was found in three families from Rio Grande do Sul: one of these affected families was due to a de novo mutation in the maternal germ line. Login to comment
87 We can not rule out the possibility that the other two p.Arg518Gln pedigrees have a common ancestral origin, given their geographical proximity. Login to comment
129 Our rate of 34% of new mutations is in agreement with this overall picture, moreover if we remember that even the only recurrent mutation in our case series (p.Arg518Gln) has emerged at least once from a de novo phenomenon (Table 1 and Figure 2). Login to comment

[hide] Adrenoleukodystrophy in Norway: high rate of de no... Pediatr Neurol. 2013 Mar;48(3):212-9. doi: 10.1016/j.pediatrneurol.2012.12.007. Horn MA, Retterstol L, Abdelnoor M, Skjeldal OH, Tallaksen CM
Adrenoleukodystrophy in Norway: high rate of de novo mutations and age-dependent penetrance.
Pediatr Neurol. 2013 Mar;48(3):212-9. doi: 10.1016/j.pediatrneurol.2012.12.007., [PMID:23419472]

Abstract [show]
To investigate X-linked adrenoleukodystrophy in an unselected population, we performed a population based, cross-sectional prevalence study, supplemented by a retrospective study of deceased subjects. Sixty-three subjects (34 males, 29 females) belonging to 22 kindreds were included. Thirty-nine subjects (13 males, 26 females) were alive, and 24 (21 males, 3 females) were deceased on the prevalence day. The point prevalence of X-linked adrenoleukodystrophy in Norway on July 1, 2011, was 0.8 per 100,000 inhabitants. The incidence at birth in the period 1956-1995 was 1.6 per 100,000 inhabitants. An age-dependent penetrance was observed among males and females, with more severe phenotypes appearing with rising age. Only 5% of deceased males had not developed cerebral leukodystrophy. No female older than 50 years was neurologically intact. Sixteen mutations in the ABCD1 gene were identified. De novo mutations were found in 19% of probands. The frequency of X-linked adrenoleukodystrophy was lower in Norway than reported in the literature. A more severe natural course than previously reported was observed, indicating a need for better follow-up of both male and female patients. Given the high rate of de novo mutations, identification programs such as newborn screening may be required to offer timely treatment to all patients.

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145 ABCD1 gene mutations found in 21 Norwegian kindred with X-ALD* Gene Effect Amino Acid Effect Exon Reported n Kindred c.99C>A p.Y33X 1 No 1 c.139C>T p.Q47X 1 Yes 1 c.293C>A p.S98X 1 No 1 c.589_590delCT p.L197DfsX103 1 No 1 c.761C>T p.T254M 1 Yes 1 c.796G>A p.G266A 1 Yes 1 c.1202G>A p.R401Q 3 Yes 3 c.1390C>T p.R464X 4 Yes 2 c.1415_1416delAG p.Q472RfsX83 5 Yes 1 c.1497-1505del p.E499-H505delinsD 6 No 1 c.1553G>A p.R518Q 6 Yes 3 c.1581C>A p.Y527X 6 No 1 c.1585_1587delGGT p.G529del 6 Yes 1 c.1731delA p.A578PfsX58 7 No 1 c.1772G>C p.R591P 7 Yes 1 c.1822G>A p.G608S 8 Yes 1 Abbreviation: n &#bc; kindred sharing this mutation * One kindred was unavailable for genotyping. concerning the number of at-risk subjects and their health status was obtained. Login to comment

[hide] ABCD1 mutations and phenotype distribution in Chin... Gene. 2013 Jun 10;522(1):117-20. doi: 10.1016/j.gene.2013.03.067. Epub 2013 Apr 5. Niu YF, Ni W, Wu ZY
ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy.
Gene. 2013 Jun 10;522(1):117-20. doi: 10.1016/j.gene.2013.03.067. Epub 2013 Apr 5., [PMID:23566833]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder resulting from mutations within the ABCD1 gene. Adrenomyeloneuropathy (AMN) and childhood cerebral ALD (CCALD) are most common phenotypes in the Western ALD patients. Here we performed mutation analysis of ABCD1 in 10 Chinese ALD families and identified 8 mutations, including one novel deletion (c.1477_1488+11del23) and 7 known mutations. Mutations c.1772G>A and c.1816T>C were first reported in the Chinese patients. Mutations c.1661G>A and c.1679C>T were demonstrated to be de novo mutations. The dinucleotide deletion 1415_16delAG, described as a mutational hotspot in different ethnic groups, was identified in two families. In addition, we performed a retrospective nation-wide mutation study of X-linked ALD in China based on a literature review. The retrospective study further confirmed the hypothesis that exon 6 is a potential mutation cluster region in the Asian populations. Furthermore, it suggested that CCALD is the most common phenotype in China.

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74 Exon Nucleotide change Amino acid change Phenotype P1 None None None CCALD P2 7 c.1661G>A p.Arg554His CCALD P3 5 c.1477_1488 + 11del 23 p.Leu493_Arg496del Adolescent ALD P4 2 c.1028G>T p.Gly343Val CCALD P5 6 c.1553G>A p.Arg518Gln CCALD P6 5 c.1415_16delAG p.Gln472fsX83 CCALD P7 6 c.1534G>A p.Gly512Ser Adolescent ALD P8 7 c.1679C>T p.Pro560Leu CCALD P9 7 c.1772G>A p.Arg591Gln ACALD P10 5 c.1415_16delAG p.Gln472fsX83 ACALD Fig. 1. Login to comment

[hide] Progression rate of myelopathy in X-linked adrenol... Metab Brain Dis. 2015 Oct;30(5):1279-84. doi: 10.1007/s11011-015-9672-2. Epub 2015 Apr 30. Habekost CT, Pereira FS, Vargas CR, Coelho DM, Torrez V, Oses JP, Portela LV, Schestatsky P, Felix VT, Matte U, Torman VL, Jardim LB
Progression rate of myelopathy in X-linked adrenoleukodystrophy heterozygotes.
Metab Brain Dis. 2015 Oct;30(5):1279-84. doi: 10.1007/s11011-015-9672-2. Epub 2015 Apr 30., [PMID:25920484]

Abstract [show]
X-linked adrenoleukodystrophy heterozygote women can present adult onset myeloneuropathy and little is known about its natural history. We aimed to describe the progression rate of the neurological impairment in the prospective follow-up of our cohort and to look for prognostic factors. The neurological scales Japanese Orthopaedic Association (JOA) and Severity Score System for Progressive Myelopathy (SSPROM) were applied at baseline in 29 symptomatic carriers and in follow-up visits. Age at onset, disease duration, X inactivation pattern, determination of the allele expressed, plasma levels of the very long chain fatty acids and of the neuron-specific enolase, and somato-sensory evoked potentials, were taken at baseline. The slope of the linear regression of both JOA and SSPROM versus disease duration since the first symptom was estimated using mixed modeling. JOA and SSPROM decreased 0.42 and 1.87 points per year, respectively (p < 0.001). None of the parameters under study influenced these rates. We estimated that the number of carriers per arm needed in a future 12 month trial with 80% power and a 50% reduction in disease progression would be 225 women for JOA and 750 for SSPROM. The progression rates of the studied neurological scales were small, did not depend on any modifier factor known, and reflected the characteristically slow worsening of symptoms in X-ALD heterozygotes. Better biomarkers are still necessary for future studies.

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46 Primers for exons 3, 6, 7 and 8, where the mutations carried by those with skewed inactivation patterns - p.Arg401Trp, p.Arg518Gln, p.Glu577X and p.Arg617His - are located, were used to amplify the cDNA. Login to comment

[hide] Clinical, biochemical, neuroimaging and molecular ... Metab Brain Dis. 2015 Dec;30(6):1439-44. doi: 10.1007/s11011-015-9717-6. Epub 2015 Aug 12. Jiang MY, Cai YN, Liang CL, Peng MZ, Sheng HY, Fan LP, Lin RZ, Jiang H, Huang Y, Liu L
Clinical, biochemical, neuroimaging and molecular findings of X-linked Adrenoleukodystrophy patients in South China.
Metab Brain Dis. 2015 Dec;30(6):1439-44. doi: 10.1007/s11011-015-9717-6. Epub 2015 Aug 12., [PMID:26260157]

Abstract [show]
X-linked adrenoleukodystrophy is a common X-linked recessive peroxisomal disorder caused by the mutations in the ABCD1 gene. In this study, we analyzed 19 male patients and 9 female carriers with X-linked adrenoleukodystrophy in South China. By sequencing the ABCD1 gene, 13 different mutations were identified, including 7 novel mutations, and 6 known mutations, and 1 reported polymorphism. Mutation c.1180delG was demonstrated to be de novo mutation. 26.3 % (5/19) patients carried the deletion c.1415_16delAG, which may be the mutational hot spot in South China population. In addition, 73.7 % (14/19) patients were type of childhood cerebral adrenoleukodystrophy, 26.3 %(5/19) were in Addison only. Half of the childhood cerebral adrenoleukodystrophy patients had the adrenocortical insufficiency preceded the onset of neurological symptoms. Furthermore, 5 of 19 cases underwent hematopoietic stem cell transplantation. Our data showed that hematopoietic stem cell transplantation performed at an advanced stage of the cerebral X- linked adrenoleukodystrophy would accelerate the progression of the disease. Good clinical outcome achieved when hematopoietic stem cell transplantation performed at the very early stage of the disease.

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74 Reference range Table 1 ABCD1 mutations and phenotypes of 19 X-linked adrenoleukodystrophy male patients Patient Exon Nucleotide change Amino acid change Phenotype 1 1 c.102_103insCa p.Leu35LeufsX159a AO 2 1 c.347_348delGAinsATa p.Gly116Aspa CCALD 3 1 c.521A>G p.Tyr174Cys CCALD 4 1 c.785C>Aa p.Ser262Xa CCALD 5 2 c.982G>Ta p.Val328Phea AO 6 3 c.1109 T>Aa p.Leu370xa CCALD 7 3 c.1180delGab p.Ala394ArgfsX15a CCALD 8 3 c.1180delGab p.Ala394ArgfsX15a CCALD 9 5 c.1415_16delAG p.Gln472Argfs*83 CCALD 10 5 c.1415_16delAG p.Gln472Argfs*83 CCALD 11 5 c.1415_16delAG p.Gln472Argfs*83 CCALD 12 5 c.1415_16delAG p.Gln472Argfs*83 AO 13 5 c.1415_16delAG p.Gln472Argfs*83 CCALD 14 6 c.1553G>A; c.1548G>A p.Arg518Gln; p.Leu516Leu CCALD 15 7 c.1661G>A p.Arg554His CCALD 16 7 c.1724_1725insCa p.Leu576ProfsX24a AO 17 9 c.1894A>C p.Thr632Pro CCALD 18 - IVS2_IVS5del - CCALD 19 - IVS2_IVS5del - AO a Novel mutation b De novo mutation have been identified in the ABCD1 gene, in which 695 (44 %) mutations appear to be non-recurrent. Login to comment