ABCMdb

ABCD1 p.Arg401Gln

ClinVar:	c.1201C>G , p.Arg401Gly D , Likely pathogenic c.1202G>A , p.Arg401Gln 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] Identification of new mutations in Israeli patient... Genet Test. 2001 Spring;5(1):65-8. Neumann S, Topper A, Mandel H, Shapira I, Golan O, Gazit E, Loewenthal R
Identification of new mutations in Israeli patients with X-linked adrenoleukodystrophy.
Genet Test. 2001 Spring;5(1):65-8., [PMID:11336405]

Abstract [show]
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder characterized by impaired peroxisomal betaoxidation of very-long-chain fatty acids (VLCFAs). This is probably due to reduced activation of the VLCFAs and results in demyelination of the nervous system and adrenocortical insufficiency. The ALD gene is localized on Xq28, has 10 exons and encodes a protein of 745 amino acids with significant homology to the membrane peroxisomal protein PMP70. Characterizing the disease causing mutations is of importance in prenatal diagnosis because 12-20% of women who are obligatory carriers show false-negative results when tested for VLCFA in plasma. We have analyzed DNA from blood samples of 7 Jewish (5 Sephardi and 2 Ashkenazi) and 3 Arab Israeli families suffering from ALD. Five missense-type mutations were identified: R104H, Y174C, L229P, R401Q, and G512C. A single mutation, R464X, was nonsense, and two, Y171 frameshift and E471 frameshift, were frameshift. Interestingly, a single mutation was identified in three families of Moroccan Jewish descent, probably due to a founder effect.

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6 Five missense-type mutations were identified: R104H, Y174C, L229P, R401Q, and G512C. Login to comment
45 The R401Q mutation involves a change in charge. Login to comment
50 Three of the mutations-R104H, R401Q, and R464X-were previouslydescribedin patients with ALD and are substitutions of arginine (Fanen et al., 1994; Fuchs et al., 1994; Braun et al., 1995). Login to comment
53 MUTATIONS IN THE ALD GENE Family number Exon cDNA alteration Amino acid alteration Missense: 1 1 G697A R104H 2 1 A907G Y174C 3, 4, 5 1 T1072C L229P 6 3 G1588A R401Q 7 6 G1920T G512C Nonsense: 8 4 C1776T R464X Frameshift: 9 1 901insC Y171 frameshift 10 5 1800insC E471 frameshift FIG. 1. Login to comment

[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] X-linked adrenomyeloneuropathy associated with 14 ... Hum Genet. 1999 Jul-Aug;105(1-2):116-9. Wichers M, Kohler W, Brennemann W, Boese V, Sokolowski P, Bidlingmaier F, Ludwig M
X-linked adrenomyeloneuropathy associated with 14 novel ALD-gene mutations: no correlation between type of mutation and age of onset.
Hum Genet. 1999 Jul-Aug;105(1-2):116-9., [PMID:10480364]

Abstract [show]
Adrenomyeloneuropathy (AMN) represents a milder form of X-linked adrenoleukodystrophy (ALD), the most frequent peroxisomal disorder. The disease is characterised by an abnormal accumulation of saturated, very long chain, fatty acids, because of altered peroxisomal beta-oxidation that concomitantly leads to demyelination in the central and peripheral nervous systems. ALD shows a highly variable phenotypic expression and extensive mutation analysis in ALD patients has failed to establish a genotype-phenotype correlation, even in the presence of the same ALD-gene defect. Therefore, we have looked for a relationship between the molecular lesion and the age of onset in 19 patients with a well-classified clinical course of AMN. The nearly complete novel spectrum of ALD gene mutations identified has revealed no obvious correlation between the type of mutation and age of AMN onset in this small series. However, intrafamiliar concordance could be observed with respect to the occurrence of adrenocortical insufficiency. This supports the idea of one (or more) additional gene(s) contributing to the phenotypic expression of ALD.

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45 Mutations affecting amino acid residues T105 and R401 have been observed previously in patients with "Addison-only" symptoms (T105I; Feigenbaum et al. 1996) and childhood cerebral ALD or AMN (R401Q; Fuchs et al. 1994; Watkins et al. 1995; Krasemann et al. 1996), respectively, but, in these cases, are associated with different nucleotide substitutions. Login to comment

[hide] Homo- and heterodimerization of peroxisomal ATP-bi... J Biol Chem. 1999 Nov 12;274(46):32738-43. Liu LX, Janvier K, Berteaux-Lecellier V, Cartier N, Benarous R, Aubourg P
Homo- and heterodimerization of peroxisomal ATP-binding cassette half-transporters.
J Biol Chem. 1999 Nov 12;274(46):32738-43., [PMID:10551832]

Abstract [show]
Mammalian peroxisomal proteins adrenoleukodystrophy protein (ALDP), adrenoleukodystrophy-related protein (ALDRP), and 70-kDa peroxisomal protein (PMP70) belong to the superfamily of ATP-binding cassette (ABC) transporters. Unlike many ABC transporters that are single functional proteins with two related halves, ALDP, ALDRP, and PMP70 have the structure of ABC half-transporters. The dysfunction of ALDP is responsible for X-linked adrenoleukodystrophy (X-ALD), a neurodegenerative disorder in which saturated very long-chain fatty acids accumulate because of their impaired peroxisomal beta-oxidation. No disease has so far been associated with mutations of adrenoleukodystrophy-related or PMP70 genes. It has been proposed that peroxisomal ABC transporters need to dimerize to exert import functions. Using the yeast two-hybrid system, we show that homo- as well as heterodimerization occur between the carboxyl-terminal halves of ALDP, ALDRP, and PMP70. Two X-ALD disease mutations located in the carboxyl-terminal half of ALDP affect both homo- and heterodimerization of ALDP. Co-immunoprecipitation demonstrated the homodimerization of ALDP, the heterodimerization of ALDP with PMP70 or ALDRP, and the heterodimerization of ALDRP with PMP70. These results provide the first evidence of both homo- and heterodimerization of mammalian ABC half-transporters and suggest that the loss of ALDP dimerization plays a role in X-ALD pathogenesis.

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47 ALD point mutations (R389H, R401Q, P484R, and R591Q) were individually introduced into pGBT- and pLEX-hALDPc by site-directed mutagenesis using "overlap extension PCR" with Pfu polymerase (Stratagene) and appropriate primers (25). Login to comment
90 B and C, interactions of wild type and mutated (R389H, R401Q, P484R, and R591Q) ALDPc with mALDRPc and hPMP70c. Login to comment
95 A, HF7c yeast strains expressing wild type or mutated (R389H, R401Q, P484R, and R591Q) ALDPc fused to Gal4-BD were analyzed for histidine auxotrophy (left panel, medium with histidine; right panel, medium without histidine). Login to comment
46 ALD point mutations (R389H, R401Q, P484R, and R591Q) were individually introduced into pGBT- and pLEX-hALDPc by site-directed mutagenesis using "overlap extension PCR" with Pfu polymerase (Stratagene) and appropriate primers (25). Login to comment
89 B and C, interactions of wild type and mutated (R389H, R401Q, P484R, and R591Q) ALDPc with mALDRPc and hPMP70c. Login to comment
94 A, HF7c yeast strains expressing wild type or mutated (R389H, R401Q, P484R, and R591Q) ALDPc fused to Gal4-BD were analyzed for histidine auxotrophy (left panel, medium with histidine; right panel, medium without histidine). Login to comment
45 ALD point mutations (R389H, R401Q, P484R, and R591Q) were individually introduced into pGBT- and pLEX-hALDPc by site-directed mutagenesis using "overlap extension PCR" with Pfu polymerase (Stratagene) and appropriate primers (25). Login to comment
88 B and C, interactions of wild type and mutated (R389H, R401Q, P484R, and R591Q) ALDPc with mALDRPc and hPMP70c. Login to comment
93 A, HF7c yeast strains expressing wild type or mutated (R389H, R401Q, P484R, and R591Q) ALDPc fused to Gal4-BD were analyzed for histidine auxotrophy (left panel, medium with histidine; right panel, medium without histidine). Login to comment

[hide] Molecular analysis of ABCD1 gene in Indian patient... Clin Chim Acta. 2011 Nov 20;412(23-24):2289-95. Epub 2011 Aug 26. Shukla P, Gupta N, Gulati S, Ghosh M, Vasisht S, Sharma R, Gupta AK, Kalra V, Kabra M
Molecular analysis of ABCD1 gene in Indian patients with X-linked adrenoleukodystrophy.
Clin Chim Acta. 2011 Nov 20;412(23-24):2289-95. Epub 2011 Aug 26., [PMID:21889498]

Abstract [show]
BACKGROUND: X-linked Adrenoleukodystrophy (X-ALD), with an incidence of 1:14,000 is the most frequent monogenic demyelinating disorder worldwide. The principal biochemical abnormality in X-ALD is the increased levels of saturated, unbranched very long chain fatty acids (VLCFA). It is caused by mutations in ABCD1 gene. No molecular data on X-ALD is available in India and mutational spectrum in Indian patients is not known. METHODS: We standardized conformation sensitive gel electrophoresis (CSGE) method to detect mutations in ABCD1 gene in twenty Indian patients with X-ALD. The results were confirmed by sequencing. Genotype-phenotype correlation was also attempted. Prenatal diagnosis (PND) in one family was done using chorionic villi (CV) sample at 12 weeks of gestation. RESULTS: Out of twenty, causative mutations could be identified in twelve patients (60%). Six reported and four novel mutations were identified. Three polymorphisms were also observed. No hot spot was found. No significant genotype-phenotype correlation could be established. CONCLUSIONS: The study identified the mutation spectrum of Indian X-ALD patients, which enabled us to offer accurate genetic counseling, carrier detection and prenatal diagnosis where needed.

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55 Prenatal diagnosis Prenatal diagnosis was done in one family having an affected child with c.1202 GNA (p.Arg401Gln) mutation in exon 3 of ABCD1 gene by CV sample taken at 12 weeks of gestation. CSGE was done for exon 3 of ABCD1 gene followed by sequencing to confirm the results. Login to comment
68 Six reported mutations, c.1202 GNA (p.Arg401Gln), c.1679 CNT (p.Pro560Leu), c.1816 TNC (p.Ser606Pro), 1547 TNC (p. Leu516Pro), c.1780+2 TNG (p.Gly593fs), c.1979 GNA (p.Arg660Gln) were found in eight patients (Fig. 1a, b, c and d). Login to comment
75 Prenatal diagnosis of X-ALD Prenatal diagnosis was done in one family having an affected child with c.1202 GNA (p.Arg401Gln) mutation in exon 3 of ABCD1 gene by CV sample taken at 12 weeks of gestation. CSGE analysis of exon 3 of CV sample showed no mobility shift, suggesting that the CV sample was negative for c.1202 GNA (p.Arg401Gln) change (Fig. 2a). Login to comment
90 Missense mutation, c.1202 GNA (p.Arg401Gln) is located in "hinge" region between the transmembrane and ATP binding domains, which is a conserved region and thus supposed to be pathogenic. Login to comment
123 Patients Age of onset (Years) Age at diagnosis (Years) Clinical features Phenotype Mutation/polymorphisma PolyPhen results PSIC score difference A1 8 8 Neuroregression, seizures, deterioration of hearing, behavior problem, cognitive decline, frequent falls CCER c.1202 GNA (p.Arg401Gln) in exon 3 3.071 Probably damaging A2b 7.7 8 Neuroregression, deterioration of hearing, deterioration of school performance, behavior problem, cognitive decline, speech problem, abnormal gait CCER No A3b 26 27 Hyperactivity, behavior problem, abnormal gait AMN c.1679 CNT (p.Pro560Leu) in exon 7 3.379 Probably damaging A4 3 6 Neuroregression, deterioration of vision, deterioration of school performance, can't ambulate. Login to comment
131 a. CSGE gel showing shift in exon 3 in patint A1 and electropherogram showing c.1202 GNA (p.Arg401Gln) mutation. Login to comment
159 In our study, c.1202 GNA (p.Arg401Gln) mutation was found in the affected child having childhood cerebral phenotype while others reported them in patients with AMN and CCER phenotype [7,14]. Login to comment
166 This phenotype was found in patients with splice site mutation, insertion and nonsense mutation as well as patients having missense mutations, c.1202 GNA (p.Arg401Gln), c.1816 TNC (p.Ser606Pro) and c.1979 GNA (p.Arg660Gln) (Table 4). Login to comment
170 A1 is sample of affected child showing shift in exon 3 for the c.1202 GNA (p.Arg401Gln) of ABCD1 gene. Login to comment
173 Electropherogram showing CV DNA normal for c.1202 GNA (p.Arg401Gln) mutation in exon 3 of ABCD1 gene. Login to comment
175 Electropherogram showing heterozygous mutation, c.1202 GNA (p.Arg401Gln) in exon 3 of ABCD1 gene in mother of patient A1. Login to comment

[hide] X-linked adrenoleukodystrophy: diagnostic and foll... J Hum Genet. 2011 Feb;56(2):106-9. Epub 2010 Nov 11. Shimozawa N, Honda A, Kajiwara N, Kozawa S, Nagase T, Takemoto Y, Suzuki Y
X-linked adrenoleukodystrophy: diagnostic and follow-up system in Japan.
J Hum Genet. 2011 Feb;56(2):106-9. Epub 2010 Nov 11., [PMID:21068741]

Abstract [show]
X-linked adrenoleukodystrophy (ALD) is an intractable neurodegenerative disease associated with the accumulation of very long-chain saturated fatty acids (VLCFA) in tissues and body fluids. We have established a Japanese referral center for the diagnosis of ALD, using VLCFA measurements and mutation analysis of the ABCD1 gene, and have identified 60 kinds of mutations in 69 Japanese ALD families, which included 38 missense mutations, 6 nonsense mutations, 8 frame-shift mutations, 3 amino acid deletions, 2 exon-skip mutations and 3 large deletions. A total of 24 kinds of mutations (40%) were identified only in Japanese patients by referring to the current worldwide ALD mutation database. There was no clear correlation between these mutations and phenotypes of 81 male patients in these 69 families. About 12% of the individuals with ALD had de novo mutations by mutation analysis in the male probands and their mothers, which should be helpful data for genetic counseling. The only effective therapy for the cerebral form of ALD should be hematopoietic stem cell transplantation at the early stages of the cerebral symptoms, therefore, we performed presymptomatic diagnosis of ALD by extended familial screening of the probands with careful genetic counseling, and established a long follow-up system for these patients to prevent the progression of brain involvement and to monitor the adrenocortical insufficiency. Further elucidation of pathology in ALD, especially concerning the mechanisms of the onset of brain involvement, is expected.

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21 Although most probands with ALD identified by us had a unique gene mutation, 6 missense mutations (p.Gly266Arg, p.Arg401Gln, p.Gly512Ser, p.Ser514Ile, p.Arg617His and p.Arg660Trp) and 1 frame-shift mutation (p.Gln472fs) were detected in two or three families (* in Figure 2). Login to comment

[hide] Altered expression of ALDP in X-linked adrenoleuko... Am J Hum Genet. 1995 Aug;57(2):292-301. Watkins PA, Gould SJ, Smith MA, Braiterman LT, Wei HM, Kok F, Moser AB, Moser HW, Smith KD
Altered expression of ALDP in X-linked adrenoleukodystrophy.
Am J Hum Genet. 1995 Aug;57(2):292-301., [PMID:7668254]

Abstract [show]
X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder with variable phenotypic expression that is characterized by elevated plasma and tissue levels of very long-chain fatty acids. However, the product of the gene defective in ALD (ALDP) is a membrane transporter of the ATP-binding cassette family of proteins and is not related to enzymes known to activate or oxidize fatty acids. We generated an antibody that specifically recognizes the C-terminal 18 amino acids of ALDP and can detect ALDP by indirect immunofluorescence. To better understand the mechanism by which mutations in ALDP lead to disease, we used this antibody to examine the subcellular distribution and relative abundance of ALDP in skin fibroblasts from normal individuals and ALD patients. Punctate immunoreactive material typical of fibroblast peroxisomes was observed in cells from seven normal controls and eight non-ALD patients. Of 35 ALD patients tested, 17 had the childhood-onset cerebral form of the disease, 13 had the milder adult phenotype adrenomyeloneuropathy, 3 had adrenal insufficiency only, and 2 were affected fetuses. More than two-thirds (69%) of all patients studied showed no punctate immunoreactive material. There was no correlation between the immunofluorescence pattern and clinical phenotype. We determined the mutation in the ALD gene in 15 of these patients. Patients with either a deletion or frameshift mutation lacked ALDP immunoreactivity, as expected. Four of 11 patients with missense mutations were also immunonegative, indicating that these mutations affected the stability or localization of ALDP. In the seven immunopositive patients with missense mutations, correlation of the location and nature of the amino acid substitution may provide new insights into the function of this peroxisomal membrane protein. Furthermore, the study of female relatives of immunonegative ALD probands may aid in the assessment of heterozygote status.

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176 In 11 patients, missense mutations that occurred throughout the protein were found: within the transmembrane domains (patients 1, 3, and 4), within the ATP-binding domain (patients 8-12), and on either side of the ATP-binding Table 3 Mutational Analysis of the ALD Gene in IS Unrelated Patients ALDP Patient Phenotype Mutation Consequence Immunoreactivity 1 .................. CALD 825 A-GG K276E + 2.................. AMN 870-2AGAGE291,& 3 .................. CALD 872 G-C E291D 4 .................. AMN 1023 T-IC S342P+ 5 .................. AMN 1166 G-C R389H + 6 .................. CALD 1201 G-AA R401Q + 7 ........ CALD 1415-6 AAG FS@472 8 ........ AMN 1771 G-AA R591Q + 9 ........ Addison 1817 C-T S606L + 10 ................ AMN 1850 G-AA R617H 11 ................ CALD 1876 G-AA A626T 12 ................ Fetus 1884 G-C D629H + 13 ................ CALD 1932 C-UT Q645X 14 ................ AMN 1978 C-OT R660W 15 ........ AMN AExon7-10 Null Mutations in the ALD gene were determined, as described in Methods, in 15 of the ALD patients reported in table 2. Login to comment
178 In 11 patients, missense mutations that occurred throughout the protein were found: within the transmembrane domains (patients 1, 3, and 4), within the ATP-binding domain (patients 8-12), and on either side of the ATP-binding Table 3 Mutational Analysis of the ALD Gene in IS Unrelated Patients ALDP Patient Phenotype Mutation Consequence Immunoreactivity 1 .................. CALD 825 A-GG K276E + 2 .................. AMN 870-2 AGAG E291,& 3 .................. CALD 872 G-C E291D 4 .................. AMN 1023 T-IC S342P + 5 .................. AMN 1166 G-C R389H + 6 .................. CALD 1201 G-AA R401Q + 7 ........ CALD 1415-6 AAG FS@472 8 ........ AMN 1771 G-AA R591Q + 9 ........ Addison 1817 C-T S606L + 10 ................ AMN 1850 G-AA R617H 11 ................ CALD 1876 G-AA A626T 12 ................ Fetus 1884 G-C D629H + 13 ................ CALD 1932 C-UT Q645X 14 ................ AMN 1978 C-OT R660W 15 ........ AMN AExon7-10 Null Mutations in the ALD gene were determined, as described in Methods, in 15 of the ALD patients reported in table 2. Login to comment

[hide] Missense mutations are frequent in the gene for X-... Hum Mol Genet. 1994 Oct;3(10):1903-5. Fuchs S, Sarde CO, Wedemann H, Schwinger E, Mandel JL, Gal A
Missense mutations are frequent in the gene for X-chromosomal adrenoleukodystrophy (ALD).
Hum Mol Genet. 1994 Oct;3(10):1903-5., [PMID:7849723]

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39 (C) Detection of G1588A (R401Q) in exon 3. Login to comment
42 Mutations identified in the ALD gene of 9 unrelated ALD patients/families Amino acid |Codon |Exon |ALDP-PMP70 | Restriction site Asnl48Ser Tyrl74Asp Gly266Arg Arg401Gln Arg418Trp Gln472-frameshift Glu477ter Ser515Phe AAC->AGC TAC->GAC GGG-»AGG CGG->CAG CGG->TGG delAG GAG-+TAG TCC-»TTC I I I III IV V V VI conserved conserved conserved conserved conserved conserved none +TaqI none none - Smal none none -Sad that are conserved between the ALD protein and PMP70. Login to comment
43 These missense mutations are (positions of nucleotides and amino acids according to the ALD cDNA sequence in ref. 4) A829G (N148S), T906G (Y174D), Gl 182A (G266R), G1588A (R401Q), C1638T (R418W), and C1930T (S515F). Login to comment
45 For R401Q and R418W the families •e« M 1 2 3 4 5 B R418W C S515F r 1 2 3 4 5 6 M bp Figure 3. Identification of ALD mutations by restriction enzyme digestion. Login to comment

[hide] Genomic profiling identifies novel mutations and S... PLoS One. 2011;6(9):e25094. Epub 2011 Sep 22. Kumar N, Taneja KK, Kalra V, Behari M, Aneja S, Bansal SK
Genomic profiling identifies novel mutations and SNPs in ABCD1 gene: a molecular, biochemical and clinical analysis of X-ALD cases in India.
PLoS One. 2011;6(9):e25094. Epub 2011 Sep 22., [PMID:21966424]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and adrenal cortex secondary to mutations in the ABCD1 gene that encode the peroxisomal membrane protein. We conducted a genomic and protein expression study of susceptibility gene with its clinical and biochemical analysis. To the best of our knowledge this is the first preliminary comprehensive study in Indian population that identified novel mutations and SNPs in a relatively large group. We screened 17 Indian indigenous X-linked adrenoleukodystrophy cases and 70 controls for mutations and SNPs in the exonic regions (including flanking regions) of ABCD1 gene by direct sequencing with ABI automated sequencer along with Western blot analysis of its endogenous protein, ALDP, levels in peripheral blood mononuclear cells. Single germ line mutation was identified in each index case in ABCD1 gene. We detected 4 novel mutations (2 missense and 2 deletion/insertion) and 3 novel single nucleotide polymorphisms. We observed a variable protein expression in different patients. These findings were further extended to biochemical and clinical observations as it occurs with great clinical expression variability. This is the first major study in this population that presents a different molecular genetic spectrum as compared to Caucasian population due to geographical distributions of ethnicity of patients. It enhances our knowledge of the causative mutations of X-ALD that grants holistic base to develop effective medicine against X-ALD.

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103 Of the 10 non-recurrent mutations in our study group i.e a frameshift mutation c.110_117del8 (Val36fs) in exon 1 was identified in an asymptomatic heterozygous female and 5 missense mutations, c.904G.A (Glu302Lys) in exon 2, c.1202G.A (Arg401Gln) in exon 3, c.1771C.T (Arg591Trp) in exon 7, c.1816T.C (Ser606Pro) and c.1825G.A (Glu609Lys) in exon 8 were present in 5 different patients. Login to comment
156 Patients Phenotype1 Age(Year) Sex Exon/IVS Mutation Type Mutations Protein Localization ALDP PSIC Score5 P01* ccALD 4 M 9 Inframe del/ins c.1903_04delinsCCA/Val635delinsAlaMet NBF + + - P02* ccALD 5 M 9 Missense c.1979G.A/Arg660Gln - - 2.409 P03 ccALD 3 M IVS84 Frameshift g.1866-10G.A/Arg622fs Walker B3 - - P04 ccALD 4.5 M 1 Missense c.796G.A/Gly266Arg TMD + ++ 2.539 P05 ccALD 6 M 9 Frameshift c.1939_40insGG/Ala646fs NBF n.d - P06 ccALD 7 M 2 Missense c.904G.A/Glu302Lys TMD + + 2.194 P07 ccALD 8 M 3 Missense c.1202G.A/Arg401Gln - + ++ 2.396 P08* ccALD 8 M 10 Inframe del/ins c.1993_95delinsGAG/Lys665delinsGlu - + + - P09 AdolCALD 11 M 1 Missense c.796G.A/Gly266Arg TMD + ++ 2.539 P10 AdolCALD 11 M 8 Missense c.1816T.C/Ser606Pro C sequence - 2.499 P11 AdolCALD 15 M IVS8 Frameshift g.1866-10G.A/Arg622fs Walker B + - P12 ACALD 42 M 8 Missense c.1825G.A/Glu609Lys C sequence3 - 2.075 P13* ACALD 46 M 7 Missense c.1673T.C/Ile558Thr NBF3 + ++ 1.211 P14 AMN 26 M 9 Frameshift c.1939_40insGG/Ala646fs - - - P15 AMN 35 M 1 Missense c.796G.A/Gly266Arg TMD2 + ++ 2.539 P16 Asymptomatic 18 F 7 Missense c.1771C.T/Arg591Trp NBF + ++ 2.818 P17 Asymptomatic 26 F 1 Frameshift c.110_17del8/Val36fs - + + - *Novel Mutations, 1 ccALD-Childhood Adrenoleukodystrophy, AMN-Adrenomyeloneuropathy, ACALD-Adult Cerebral Adrenoleukodystrophy, AdolCALD- Adolescent cerebral Adrenoleukodystrophy. Login to comment
168 Lane 1 and 10 (Control by symbol ''C``), Lane 2 (P01, ccALD, V635delins A & M), Lane 3 (P02, ccALD, R660Q), Lane 4 (P03, ccALD, R622fs), Lane 5 (P04, ccALD, G266R), Lane 6 (P06, ccALD, E302K), Lane 7 (P07, ccALD, R401Q), Lane 8 (P08, ccALD, K665delinsE), Lane 9 (P09, AdolCALD, G266R), Lane 11 (P10, AdolCALD, S606P), Lane 12 (P11, AdolCALD, R622fs), Lane 13 (P12, ACALD, E609K), Lane 14 (P13, ACALD, I558T), Lane 15 (P14, AMN, A646fs), Lane 16 (P15, AMN, G266R), Lane 17 (P16, asymptomatic female, R591W) and Lane 18 (P17, asymptomatic female,). Login to comment
198 Supporting Information Supporting Information S1 Frequently occurring mutations in (a) intervening sequence 8 (g.1866-10G.A/Arg622fs, shown as C.T in antisense strand) in P03 and P11, (b) exon 1 (c.796G.A/ Gly266Arg, shown as C.T in antisense strand) in P04, P09 and P15, (c) exon 9 (c.1939_40insGG/Ala646fs, shown as CC in antisense strand) in P05 and P14, (d) exon 2 (c.904G.A/ Glu302Lys) in P06, (e) exon 3 (c.1202G.A/Arg401Gln) in P07, (f) exon 8 (c.1816T.C/Ser606Pro) in P10, (g) exon 8 (c.1825G.A/ Glu609Lys) in P12, (h) exon 7 (c.1771C.T/Arg591Trp) in P16 and (i) exon 1 (c.110_17del8/Val36fs) in P17. Login to comment
102 Of the 10 non-recurrent mutations in our study group i.e a frameshift mutation c.110_117del8 (Val36fs) in exon 1 was identified in an asymptomatic heterozygous female and 5 missense mutations, c.904G.A (Glu302Lys) in exon 2, c.1202G.A (Arg401Gln) in exon 3, c.1771C.T (Arg591Trp) in exon 7, c.1816T.C (Ser606Pro) and c.1825G.A (Glu609Lys) in exon 8 were present in 5 different patients. Login to comment
155 Patients Phenotype1 Age(Year) Sex Exon/IVS Mutation Type Mutations Protein Localization ALDP PSIC Score5 P01* ccALD 4 M 9 Inframe del/ins c.1903_04delinsCCA/Val635delinsAlaMet NBF + + - P02* ccALD 5 M 9 Missense c.1979G.A/Arg660Gln - - 2.409 P03 ccALD 3 M IVS84 Frameshift g.1866-10G.A/Arg622fs Walker B3 - - P04 ccALD 4.5 M 1 Missense c.796G.A/Gly266Arg TMD + ++ 2.539 P05 ccALD 6 M 9 Frameshift c.1939_40insGG/Ala646fs NBF n.d - P06 ccALD 7 M 2 Missense c.904G.A/Glu302Lys TMD + + 2.194 P07 ccALD 8 M 3 Missense c.1202G.A/Arg401Gln - + ++ 2.396 P08* ccALD 8 M 10 Inframe del/ins c.1993_95delinsGAG/Lys665delinsGlu - + + - P09 AdolCALD 11 M 1 Missense c.796G.A/Gly266Arg TMD + ++ 2.539 P10 AdolCALD 11 M 8 Missense c.1816T.C/Ser606Pro C sequence - 2.499 P11 AdolCALD 15 M IVS8 Frameshift g.1866-10G.A/Arg622fs Walker B + - P12 ACALD 42 M 8 Missense c.1825G.A/Glu609Lys C sequence3 - 2.075 P13* ACALD 46 M 7 Missense c.1673T.C/Ile558Thr NBF3 + ++ 1.211 P14 AMN 26 M 9 Frameshift c.1939_40insGG/Ala646fs - - - P15 AMN 35 M 1 Missense c.796G.A/Gly266Arg TMD2 + ++ 2.539 P16 Asymptomatic 18 F 7 Missense c.1771C.T/Arg591Trp NBF + ++ 2.818 P17 Asymptomatic 26 F 1 Frameshift c.110_17del8/Val36fs - + + - *Novel Mutations, 1 ccALD-Childhood Adrenoleukodystrophy, AMN-Adrenomyeloneuropathy, ACALD-Adult Cerebral Adrenoleukodystrophy, AdolCALD- Adolescent cerebral Adrenoleukodystrophy. Login to comment
167 Lane 1 and 10 (Control by symbol ''C``), Lane 2 (P01, ccALD, V635delins A & M), Lane 3 (P02, ccALD, R660Q), Lane 4 (P03, ccALD, R622fs), Lane 5 (P04, ccALD, G266R), Lane 6 (P06, ccALD, E302K), Lane 7 (P07, ccALD, R401Q), Lane 8 (P08, ccALD, K665delinsE), Lane 9 (P09, AdolCALD, G266R), Lane 11 (P10, AdolCALD, S606P), Lane 12 (P11, AdolCALD, R622fs), Lane 13 (P12, ACALD, E609K), Lane 14 (P13, ACALD, I558T), Lane 15 (P14, AMN, A646fs), Lane 16 (P15, AMN, G266R), Lane 17 (P16, asymptomatic female, R591W) and Lane 18 (P17, asymptomatic female,). Login to comment
197 Supporting Information Supporting Information S1 Frequently occurring mutations in (a) intervening sequence 8 (g.1866-10G.A/Arg622fs, shown as C.T in antisense strand) in P03 and P11, (b) exon 1 (c.796G.A/ Gly266Arg, shown as C.T in antisense strand) in P04, P09 and P15, (c) exon 9 (c.1939_40insGG/Ala646fs, shown as CC in antisense strand) in P05 and P14, (d) exon 2 (c.904G.A/ Glu302Lys) in P06, (e) exon 3 (c.1202G.A/Arg401Gln) in P07, (f) exon 8 (c.1816T.C/Ser606Pro) in P10, (g) exon 8 (c.1825G.A/ Glu609Lys) in P12, (h) exon 7 (c.1771C.T/Arg591Trp) in P16 and (i) exon 1 (c.110_17del8/Val36fs) in P17. Login to comment

[hide] Molecular diagnosis of X-linked adrenoleukodystrop... Clin Chim Acta. 2011 May 12;412(11-12):970-4. Epub 2011 Feb 12. Lan F, Wang Z, Xie H, Huang L, Ke L, Yang B, Zhu Z
Molecular diagnosis of X-linked adrenoleukodystrophy: experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations.
Clin Chim Acta. 2011 May 12;412(11-12):970-4. Epub 2011 Feb 12., [PMID:21300044]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by progressive demyelination of the nervous system, adrenocortical insufficiency and increase of very long chain fatty acids (VLCFAs) in the plasma and tissues. METHODS: A total of 131 individuals from 30 Chinese pedigrees were involved in this study, including 42 symptomatic patients, 44 female carriers, and 15 high-risk fetuses from 13 families. The mutation was first pinpointed through long distance RT-PCR-based RNA approach and confirmed through peripheral blood DNA approach. RESULTS: A total of 28 mutations were identified, of which 19 were missense, 3 nonsense and 6 frame-shift mutations. Thirteen mutations were novel, i.e. p.R280L, p.P580L, p.G343V, p.S108X, p.R259W, p.P534R, p.fs A246, p.L576P, p.K602X, p.A314P, p.N148D, p.H283R, and p.fs R89. Two mutations occurred de novo, for they were not found in somatic cells of their parents. Three females from the same family developed AMN-like symptoms and they were heterozygous for the p.H283R mutation. Four asymptomatic boys were diagnosed as X-ALD patients and prenatal molecular diagnosis were provided for 13 X-ALD-stricken families. CONCLUSIONS: Our work extended the spectrum of mutations in X-ALD and benefited genetic counseling through reliable identification of heterozygous females and asymptomatic males.

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52 Of 19 missense mutations, 18 were distributed in the transmembrane domain (amino acid residues 51-350) or ATP binding domain (amino acid residues 501-651), only one mutation (p.R401Q) was located in the region between the above two domains, which is in accordance with previous notion that most missense mutations concentrated in transmembrane and ATP binding domains [10]. Login to comment
59 The mutation p.fs E471, or c.1415_1416delAG, was pinpointed in 3 families (1/10), p.R401Q was found in 2 families (1/15), and the rest were private. Login to comment
84 Only two mutations (p.fs E471 and p.R401Q) were shared by more than one families, with p.fs E471 being shared by 3 families (3/30, or 10%) and p.R401Q by 2 families (2/30, or 6.7%). Login to comment
99 Pedigree Number of patient Number of carriere Phenotype of patient Base change Amino acid change Position of mutation Feature of mutation Prenatal diagnosis 1 1 2 AdolCALD 1225GNT R280L Exon 1 Missense 2 1 1 CCALD 1909CNT P508L Exon 6 Missense 3 4 3 CCALD 1987CNG P534R Exon 6 Missense Y 4 1 1 CCALD 1182GNA G266R Exon 1 Missense 5 1a +1b 1 CCALD 2235CNG R617G Exon 8 Missense Y 6 1+1a +1c 1 CCALD 1414GNT G343V Exon 2 Missense 7 1 1 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift 8 1+1b 1 CCALD 2235CNT R617C Exon 8 Missense Yh 9 1 1 CCALD 2065CNT P560L Exon 7 Y 10 1+1a 2+1b CCALD [709 NA; 1161CNT] [S108X; R259W] Exon 1 Nonsense; Missense Y 11 1 1 CCALD 1126ins GCCATCG fs I246 Exon 1 Frameshift 12 1 1 CCALD 2113TNC L576P Exon 7 Missense 13 1a +2c 3 CCALD 807GNA A141T Exon 1 Missense 14 1 1 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift Y 15 1 1+1b CCALD 915CNA Q177X Exon 1 Nonsense Yh 16 1+1a 1 CCALD 1588GNA R401Q Exon 3 Missense 17 1 1 CCALD 1212 ANG K276E Exon 1 Missense Y 18 1 1 CCALD 907 ANG Y174C Exon 1 Missense 19 1 2 CCALD 2190 ANT K602X Exon 8 Nonsense 20 1 1 CCALD 1326GNC A314P Exon 2 Missense 21 1 1 CCALD 828 ANG N148D Exon 1 Missense Y 22 1 1 CCALD 1588GNA R401Q Exon 3 Missense Y 23 1 0f CCALD 2278GNA C631Y Exon 9 Missense 24 1a 1 CCALD 1008insG fs S207 Exon 1 Frameshift Y 25 1 0f CCALD 1920GNA G512S Exon 6 Missense 26 1+1c 3 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift Y 27 1+1b 1 CCALD [1035ANG; 1853GNA] [K217E; V489V] Exon 1 Missense; same sense Y 28 1+3d 4 AMNg 1234ANG H283R Exon 1 Missense 29 1+2a 3 CCALD 1233CNG H283D Exon 1 Missense 30 2 3 AMN; CCALD 656_57 delGA fs R89 Exon 1 Frameshift a patient or proband died at the time of referral; b fetus by prenatal diagnosis; c presymptomatic at the time of referral; d female heterozygote patient; e determined by molecular ananlysis or deduced by the fact that the carrier was the daughter of an X-ALD, or the mother of at least one X-ALD patients; f de novo mutation; g including three heterozygote female patients; h twice for two pregnancies. Login to comment

[hide] A rapid and sensitive protocol for prenatal molecu... Clin Chim Acta. 2010 Dec 14;411(23-24):1992-7. Epub 2010 Aug 26. Lan F, Wang Z, Ke L, Xie H, Huang L, Huang H, Tu X, Zheng D, Zeng J, Li H, Xin N, Yang B
A rapid and sensitive protocol for prenatal molecular diagnosis of X-linked adrenoleukodystrophy.
Clin Chim Acta. 2010 Dec 14;411(23-24):1992-7. Epub 2010 Aug 26., [PMID:20800589]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative genetic disease characterized by progressive demylination of the brain, adrenal insufficiency and elevated VLCFA level. ABCD1gene is the disease gene and more than 500 unique mutations in the ABCD1gene have been recorded in the database, approximately 60% of which are noncurrent ones. Although great progress has been made in the treatment of X-ALD, prenatal diagnosis is still badly needed by X-ALD-stricken families. METHODS: Twelve high-risk fetuses entered this study. Amniotic fluid (AF) was divided into two parts, with one part being used directly to isolate genomic DNA and debris from the other part for amniotic fluid cells (AFC) culturing. STR profiling was performed to evaluate maternal contamination of AFC genomic DNA. Two different molecular approaches, be they any two of direct sequencing, PCR-RFLP, ARMS, dot hybridization and DHPLC, were applied to determine whether the mutation identified in the index patient was found in the fetus. RESULTS: The genotypes of all 12 fetuses were determined, among which 2 were diagnosed as ALD males, 5 unaffected males, 1 heterozygote, and 4 normal unaffected females. A total of 9 families sent samples of umbilical blood at the time of delivery, and results of molecular checking of these samples agreed with those of prenatal diagnosis. Up until now, no ALD-related abnormalities were reported postnatally. CONCLUSION: An in-house protocol for the prenatal molecular diagnosis of X-ALD was established, and this protocol would provide accurate and rapid prenatal genetic service to X-ALD-stricken families.

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74 Family Origin (province) Genotype of proband Age (years) of carrier at amniocentesis Weeks of pregnancy at amniocentesis 1 Guangdong p.Arg617Gly 39 28 2 Shandong p.Pro534Arg 25 21 3 Fujian p.Arg617Cys 33(34)a 16(17)a 4 Hebei 1415_1416delAG (p.Glu471fs) 29 26 5 Fujian [p.Ser108X; p.Arg259Trp] 33 19 6 Shandong p.Pro560Leu 35 18 7 Anhui p.Gln177X 33 20 8 Shandong p.Lys276Glu 33 16 9 Hubei p.Asn148Asp 35 18 10 Jilin c.622_623insG (p.Ser207fs) 35 16 11 Guangxi p.Arg401Gln 32 16 a Figures in parentheses represent those data of second-time prenatal diagnosis for another fetus from family 3. Login to comment
117 Fetus 12: The PCR products of 302 bp, spanning the site of p. Arg401Gln mutation, from the AFC's DNA of fetus 12 as well as the genomic DNA of its parents and elder brother (proband of the family) were digested with the restriction enzyme Mbi I. Login to comment
118 In normal cases, this enzyme has one cutting site on this product, producing two fragments (226 bp and 76 bp) upon its action. When there exists the p. Arg401Gln mutation, the cutting site disappears. Login to comment

[hide] Preferential expression of mutant ABCD1 allele is ... Orphanet J Rare Dis. 2012 Jan 26;7:10. doi: 10.1186/1750-1172-7-10. Salsano E, Tabano S, Sirchia SM, Colapietro P, Castellotti B, Gellera C, Rimoldi M, Pensato V, Mariotti C, Pareyson D, Miozzo M, Uziel G
Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms.
Orphanet J Rare Dis. 2012 Jan 26;7:10. doi: 10.1186/1750-1172-7-10., [PMID:22280810]

Abstract [show]
BACKGROUND: Approximately 20% of adrenoleukodystrophy (X-ALD) female carriers may develop clinical manifestations, typically consisting of progressive spastic gait, sensory deficits and bladder dysfunctions. A skewing in X Chromosome Inactivation (XCI), leading to the preferential expression of the X chromosome carrying the mutant ABCD1 allele, has been proposed as a mechanism influencing X-linked adrenoleukodystrophy (X-ALD) carrier phenotype, but reported data so far are conflicting. METHODS: To shed light into this topic we assessed the XCI pattern in peripheral blood mononuclear cells (PBMCs) of 30 X-ALD carriers. Since a frequent problem with XCI studies is the underestimation of skewing due to an incomplete sample digestion by restriction enzymes, leading to variable results, we developed a pyrosequencing assay to identify samples completely digested, on which to perform the XCI assay. Pyrosequencing was also used to quantify ABCD1 allele-specific expression. Moreover, very long-chain fatty acid (VLCFA) levels were determined in the same patients. RESULTS: We found severely (>/=90:10) or moderately (>/=75:25) skewed XCI in 23 out of 30 (77%) X-ALD carriers and proved that preferential XCI is mainly associated with the preferential expression of the mutant ABCD1 allele, irrespective of the manifestation of symptoms. The expression of mutant ABCD1 allele also correlates with plasma VLCFA concentrations. CONCLUSIONS: Our results indicate that preferential XCI leads to the favored expression of the mutant ABCD1 allele. This emerges as a general phenomenon in X-ALD carriers not related to the presence of symptoms. Our data support the postulated growth advantage of cells with the preferential expression of the mutant ABCD1 allele, but argue against the use of XCI pattern, ABCD1 allele-specific expression pattern and VLCFA plasma concentration as biomarkers to predict the development of symptoms in X-ALD carriers.

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53 All samples were tested in Table 1 Clinical Findings, Genotype, X-Chromosome Inactivation (XCI), ABCD1 Allele-Specific Expression (ASE) and Biochemical Findings (VLCFA plasma levels) of X-ALD carriers Nr of family, consultants Age (yrs) Presence of symptoms (age at onset, yrs) Mutations XCI pattern ABCD1 ASE (mut:wt) C26 (nv) C26/C22 (nv) C24/C22 (nv) F1 II-3 67 Yes (45) 410G > A W137X 97:03 84:16 1,09 (<0,75) 48 (<17) 1644 (<1100) F1 III-2 34 No 410G > A W137X 91:09 nd 0,58 (<0,75) 47 (<17) 1482 (<1100) F2 I-2 61 Yes (59) 427C > G P143A 71:29 93:07 0,85 (<0,75) 18 (<17) 1222 (<1100) F2 II-1 38 No 427C > G P143A 85:15 83:17 nd nd nd F2 II-2 35 No 427C > G P143A 76:24 77:23 nd nd nd F3 II-2 73 Yes (45) 428C > A P143H 60:40 38:62 1,45 (<1,50) 28 (<40) 700 (<820) F3 III.1 46 No 428C > A P143H 84:16 84:16 1,53 (<1,50) 40 (<40) 860 (<820) F3 III-2 50 No 428C > A P143H 83:17 75:25 1,75 (<1,50) 37 (<40) 733 (<820) F4 II-3 75 Yes (50) 652C > T; 664G > T P218S; V222L 81:19 82:18 1,57 (<0,75) 19 (<17) 1680 (<1100) F4 III-1 44 No 652C > T; 664G > T P218S; V222L 83:17 81:19 2,38 (<1,50) 53 (<40) 1424 (<820) F4 III-3 45 Yes (29) 652C > T; 664G > T P218S; V222L 89:11 82:18 1,00 (<0,75) 36 (<17) 1611 (<1100) F5 II-1 55 Yes (54) 1202G > A R401Q 98:02 82:18 1,96 (<1,50) 38 (<40) 1031 (<820) F6 II-1 76 Yes (58) 1727T > C L576P 73:27 76:24 2,10 (<0,75) 21 (<17) 1039 (<1100) F7 I-2 72 No 1772G > A R591Q n/a n/a 1,23 (<1,5) 16 (<40) 798 (<820) F7 II-1 44 Yes (34) 1772G > A R591Q 96:04 97:03 2,7 (<1,50) 56 (<40) 957 (<820) F8 II-1 62 Yes (40) 1992G > A W664X 83:17 82:18 3,08 (<1,50) 56 (<40) 1132 (<820) F9 II-1 63 No 293C > T S98L 83:17 93:07 1,82 (<1,50) 37 (<40) 888 (<820) F9 II-3 57 No 293C > T S98L 79:21 75:25 1,99 (<1,50) 42 (<40) 913 (<820) F9 III-2 20 No 293C > T S98L 75:25 61:39 2,65 (<1,50) 46 (<40) 1149 (<820) F10 I-2 63 No 443A > G N148S 86:14 42:58 2,16 (<1,50) 42 (<40) 788 (<820) F10 II-2 40 No 443A > G N148S 96:04 84:16 2,17 (<1,50) 43 (<40) 757 (<820) F11 III-1 67 No 1165C > T R389C 52:48 72:28 0,7 (<1,50) 13 (<40) 572 (<820) F11 III-3 64 No 1165C > T R389C 78:22 34:66 1,1 (<1,50) 16 (<40) 823 (<820) F11 III-5 49 No 1165C > T R389C 98:02 20:80 1,05 (<1,50) 16 (<40) 848 (<820) F11 III-6 46 No 1165C > T R389C 71:29 74:26 1,30 (<1,50) 18 (<40) 1000 (<820) F11 V-1 26 No 1165C > T R389C 57:43 58:42 0,68 (<1,50) 14 (<40) 663 (<820) F12 I-2 53 No 1211C > A S404X 95:05 09:91 nd nd nd F13 I-2 60 No del. ex8-10 n/a 76:24 nd nd nd nd duplicate and one male DNA sample was included in each experiment as a control for enzymatic digestion. 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] X-linked adrenoleukodystrophy in a 6-year-old boy ... Turk J Pediatr. 2014 Nov-Dec;56(6):651-3. Incecik F, Herguner MO, Mert G, Onenli-Mungan N, Ceylaner S, Kor D, Altunbasak S
X-linked adrenoleukodystrophy in a 6-year-old boy initially presenting with psychiatric symptoms.
Turk J Pediatr. 2014 Nov-Dec;56(6):651-3., [PMID:26388597]

Abstract [show]
X-linked adrenoleukodystrophy (ALD) leads to demyelination of the nervous system, adrenal insufficiency and accumulation of long-chain fatty acids. Most young patients with X-linked ALD develop seizures and progressive neurologic deficits, and die within the first two decades of life. We present the case of a 6-year-old with childhood-onset ALD, first presenting with psychiatric symptoms and progressive gait difficulties, slurred speech and cognitive impairment. Genetic testing was performed and a p.R401Q (c.1202G>A) mutation detected in the ABCD1 gene. ALD should be considered in the differential diagnosis of patients presenting with behavior changes and white matter disease in neuroimaging.

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8 Genetic testing was performed and a p.R401Q (c.1202G>A) mutation detected in the ABCD1 gene. Login to comment
41 To confirm the diagnosis of X-linked ALD, we analyzed the ABCD1 gene sequencing in the patient, revealing a p.R401Q (c.1202G>A) mutation. Login to comment

[hide] Eight novel mutations in the ABCD1 gene and clinic... World J Pediatr. 2015 Nov;11(4):366-73. doi: 10.1007/s12519-015-0044-0. Epub 2015 Oct 11. Chu SS, Ye J, Zhang HW, Han LS, Qiu WJ, Gao XL, Gu XF
Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy.
World J Pediatr. 2015 Nov;11(4):366-73. doi: 10.1007/s12519-015-0044-0. Epub 2015 Oct 11., [PMID:26454440]

Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the adenosine triphosphate-binding cassette D1 (ABCD1) gene. This study aimed to retrospectively investigate the clinical characteristics of 25 patients with X-ALD including members of large pedigrees, to analyze ABCD1 gene mutations, the effect of gene novel variants on ALD protein (ALDP) structure and function, and to expand gene mutation spectrum of Chinese patients. METHODS: Twenty-five male patients diagnosed with X-ALD were enrolled in this study. The clinical characteristics of the patients were retrospectively summarized by reviewing medical records or telephone consultation. ABCD1 gene mutations were analyzed. The pathogenicity of novel missense variants was analyzed using cobalt constraint-based multiple protein alignment tool, polymorphism phenotyping, sorting intolerant from tolerant, Align-Grantham variation and Grantham deviation, and Swiss-Program Database Viewer 4.04 software, respectively. RESULTS: Childhood cerebral form ALD (CCALD) is the most common phenotype (64%) in the 25 patients with X-ALD. The progressive deterioration of neurological and cognitive functions is the main clinical feature. The demyelination of the brain white matter and elevated plasma very long chain fatty acids (VLCFAs) were found in all patients. Different phenotypes were also presented within family members of the patients. Twenty-two different mutations including 8 novel mutations in the ABCD1 gene were identified in the 25 patients. Of the mutations, 63.6% were missense mutations and 34.8% located in exon 1. The amino acid residues of three novel missense mutations in eight species were highly conserved, and were predicted to be "probably" damaging to ALDP function. The other five novel mutations were splice, nonsense, deletion or duplication mutations. CONCLUSIONS: CCALD is the most common phenotype (64%) in our patients with X-ALD. Eight novel mutations in the ABCD1 gene identified are disease-causing mutations. Brain magnetic resonance imaging and plasma VLCFA determination should be performed for the patients who present with progressive deterioration of neurological development.

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111 However, some X-ALD males remain asymptomatic and one-third of heterozygous women remain free of clinical symptoms during their Patient number Exon Nucleotide change Amino acid change Protein localization References P1 2 c.1017G>T p.Trp339Cys TMD Novel P2 8 c.1850G>A p.Arg617His NBD Fanen et al, 1994[12] P4 1 c.892G>C p.Gly298Arg TMD Novel P5, P6 5 c.1415_16delAG p.Gln472Argfs*83 TMD to NBD Barcelo et al, 1994[13] P7 1 c.532C>T p.Gln178* TMD Novel P8 1 c.473T>C p.Leu158Pro TMD The peroxisomal diseases laboratory (unpublished) P10 6 c.1552C>T p.Arg518Trp NBD Fanen et al, 1994[12] P11 3 c.1202G>A p.Arg401Gln TMD to NBD Fuchs et al, 1994[14] P12 1 c.887A>G p.Tyr296Cys TMD Takano et al, 1999[15] P13 1 c.893G>A p.Gly298Asp TMD Lachtermacher et al, 2000[16] P14 1 c.310C>T p.Arg104Cys TMD Kok et al, 1995[17] P15 IVS 8 c.1866-10G>A p.Pro623fs* NBD Kemp et al, 1995[18] P16 5 c.1428C>A p.Cys476* NBD Novel P17 5 c.1421T>C p.Ile474Thr NBD Shimozawa et al, 2011[19] P18 6 c.1538A>G p.Lys513Arg NBD Piti&#e9;-Salp&#e9;tri&#e8;re Hospital (unpublished) P19 1 c.310C>T p.Arg104Cys TMD Kok et al, 1995[17] P20 6 c.1544C>A p.Ser515Tyr NBD Novel P21 2 c.901-1G>A p.Val301fs* TMD Kemp et al, 2001[20] P22 2 c.974T>C p.Leu325Pro TMD The peroxisomal diseases laboratory (unpublished) P23 3 c.1182delG p.Ala395Leufs*15 TMD to NBD Novel P24 1 c.424delC p.Leu142Serfs*56 TMD Novel P25 7 c.1759_1761dup p.Ile588His NBD Novel Table 2. Login to comment