ABCMdb

ABCD1 p.Pro560Leu

ClinVar:	c.1679C>T , p.Pro560Leu D , Pathogenic
Predicted by SNAP2:	A: D (91%), C: D (91%), 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%), Q: D (95%), R: 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, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] Mutational and protein analysis of patients and he... Am J Hum Genet. 1996 Jun;58(6):1135-44. Feigenbaum V, Lombard-Platet G, Guidoux S, Sarde CO, Mandel JL, Aubourg P
Mutational and protein analysis of patients and heterozygous women with X-linked adrenoleukodystrophy.
Am J Hum Genet. 1996 Jun;58(6):1135-44., [PMID:8651290]

Abstract [show]
X-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder associated with impaired beta-oxidation of very-long-chain fatty acids (VLCFA), is due to mutations in a gene encoding a peroxisomal ATP-binding cassette (ABC) transporter (ALD protein [ALDP]). We analyzed the open reading frame of the ALD gene in 44 French ALD kindred by using SSCP or denaturing gradient-gel electrophoresis and studied the effect of mutations on ALDP by immunocytofluorescence and western blotting of fibroblasts and/or white blood cells. Mutations were detected in 37 of 44 kindreds and were distributed over the whole protein-coding region, with the exception of the C terminus encoded in exon 10. Except for two mutations (delAG1801 and P560L) observed four times each, nearly every ALD family has a different mutation. Twenty-four of 37 mutations were missense mutations leading to amino acid changes located in or close to putative transmembrane segments (TMS 2, 3, 4, and 5), in the EAA-like motif and in the nucleotide fold of the ATP-binding domain of ALDP. Of 38 ALD patients tested, 27 (71%) lacked ALDP immunoreactivity in their fibroblasts and/or white blood cells. More than half of missense mutations studied (11 of 21) resulted in a complete lack of ALDP immunoreactivity, and six missense mutations resulted in decreased ALDP expression. The fibroblasts and/or white blood cells of 15 of 15 heterozygous carrier from ALD kindred with no ALDP showed a mixture of positive- and negative-ALDP immunoreactivity due to X-inactivation. Since 5%-15% of heterozygous women have normal VLCFA levels, the immunodetection of ALDP in white blood cells can be applicable in a majority of ALD kindred, to identify heterozygous women, particularly when the ALD gene mutation has not yet been identified.

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4 Except for two mutations (delAG1801 and P560L) observed four times each, nearly every ALD family has a different mutation. Login to comment
59 Twenty-nine different mutations were found, and five of them were present in more than one family (S98L, R518W, and R660W in two families, and 1801 delAG and P560L in four families each). Login to comment
76 58:1135-1144, 1996 Table 2 Mutations in the ALD Gene in Studied Patients AMINO ACID MUTATIONSb HOMOLOGUE INd KINDRED CLINICAL LOCALIZATION AMINO ACID ALDP BY NUMBER PHENOTYPEa DNA CpG Exon IN PROTEINC ALTERATION h/m ALDRP hPMP70 IF/WB' CALD, AMN CALD CALD CALD, AS AD CALD, AMN CALC AD AD AD ALMD CALD CALD, AMN CALD CALD, AMN, AD AMN ALMD CALD ALMD CALD AMN ALD AD, AMN, AS CALD, AS CALD CALD AD CALD AMN, ALMD CALD CALD AMN, ALMD CALD CALD, AMN, ALMD CALD CALD, ALMD, AS ALMD CALD AMN CALD, AMN AD AD AMN CALD G416A Ins T524 C679T C679T C700T C709G G732A A829G C840T Del TA927-28 A928G A985T A1048G DeIGC1080-81 C1174T G1266A ins C1521 1636delC DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 ins TGG 1848 G 1920 A C1938T C1938T G1950A C2065T C2065T C2065T C2065T C2065G G 2166+1 A T2202C DelGC 2335 C2364T C2364T No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found 1 1 + 1 + 1 1 1 + 1 1 + 1 1 1 1 1 1 1 + 1 3 4 S 5 S S S 6 + 6 + 6 6 + 7 + 7 + 7 + 7 + 7 + 7 8 9 9 9 W10 X Frameshift at L46 TMS2 S98L TMS2 S98L T1OSI S108W G116R TMS3 N148S TMS3 R152C Frameshift at Y180 Y181C TMS4 D200V TMS4 D221G Frameshift at R231 P263L EAA-like A294T Frameshift at V378 Frameshift at T416 Frameshift at E471 Frameshift at E471 Frameshift at E471 Frameshift at E471 ins val 491 Walker A G512S Walker A R518W Walker A R518W G 522 W P560L P560L P560L P560L P56OR Splice at G593 Walker B S606P Frameshift at D649 R660W R660W Absent Not done S A Present S A Present T T Absent S D Decreased G T Absent N N Present R K Present Absent Y Y Not done D D Not done D D Absent Absent P R Decreased A A Not done Absent Absent Absent Absent Absent Absent Absent G G Absent R R Absent R R Decreased G E Absent P P Decreased P P Decreased P P Decreased P P Absent P P Absent Not done S S Absent Absent R R Absent R R Absent Not done Absent Absent Absent Present Absent Absent a CALD = cerebral ALD (5-15 years); AMN = adrenomyeloneuropathy; ALMD = adrenomyeloneuropathy with cerebral involvement; AD = Addison disease; AS = Asymptomatic. Login to comment
88 C, ALD fibroblasts (R152C mutation) immunostained with mAb2B4, showing normal ALDP immunoreactivity. Login to comment
89 D, ALD fibroblasts (P560L mutation), showing weakly positive immunoreactivity with mAb 2B4 (and 1D6, not shown). Login to comment
102 Variation in the immunoreactivity of the ALD mutant protein was observed for two mutations, P560L and R518W: immunoreactivity of mutant protein P560L was markedly decreased in fibroblasts and peripheral white blood cells from patients 69, 5, and 37 and was completely absent in patient 13. Login to comment
131 Lane 1, protein markers; lane 2, control; lane 3, patient 18 (S108W); lane 4, patient 32 (P263L); lane 5, patient 5 (P560L); lane 6, patient 4 (G116R); lane 7, patient 19 (D221G); lane 8, patient 33 (S98L); lane 9, patient 78 (S606P); lane 10, patient 3 (no mutation found); lane 11, patient 37 (P560L); lane 12, patient 22 (R660W); lane 13, control; lane 14, patient 39 (T1051); lane 15, patient 4 (G116R); lane 16, patient 43 (frameshift at Y180); lane 17, patient 5 (P560L); lane 18, patient 59 (G512S); lane 19, patient 29 (frameshift at D649); lane 20, patient 69 (P560L); lane 21, patient 19 (D221G); lane 22, patient 64 (W1OX); lane 23, patient 63 (frameshift at R231); lane 24, patient 52 (no mutation found); lane 25, patient 61 (frameshift at E471); and lane 26, patient 83 (G522W). Login to comment
134 Exceptions are a dinucleotide deletion (del 1801-1802) and P560L missense mutation, which were both observed in four kindreds, and S98L, R518W, and R660W missense mutations, which were each observed in two kindreds. Login to comment
135 As shown in ALD Dutch families (Kemp et al. 1994), there is no indication that the French ALD families in whom the dinucleotide deletion (del 1801-1802) or the P560L mutation was observed were related. Login to comment
140 In all cases, only one alteration was found, and except for the S98L, R518W, P560L, and R660W mutations, these alterations differed from each other. Login to comment
142 The R518W mutation occurred as a de novo mutation in one ALD patient, and the R518W and P560L mutations were not observed in 100 normal X chromosomes. Login to comment
173 Four missense mutations (S108W, P263L, R518W, and P560L) resulted in decreased ALDP immunoreactivity reflecting likely instability and/or partial deficiency in the peroxisomal targeting of ALDP. Login to comment
174 Three missense mutations (S98L, N148S, and R152C) resulted in the synthesis of a stable but presumably nonfunctioning protein. Login to comment
58 Twenty-nine different mutations were found, and five of them were present in more than one family (S98L, R518W, and R660W in two families, and 1801 delAG and P560L in four families each). Login to comment
75 58:1135-1144, 1996 Table 2 Mutations in the ALD Gene in Studied Patients AMINO ACID MUTATIONSb HOMOLOGUE INd KINDRED CLINICAL LOCALIZATION AMINO ACID ALDP BY NUMBER PHENOTYPEa DNA CpG Exon IN PROTEINC ALTERATION h/m ALDRP hPMP70 IF/WB' CALD, AMN CALD CALD CALD, AS AD CALD, AMN CALC AD AD AD ALMD CALD CALD, AMN CALD CALD, AMN, AD AMN ALMD CALD ALMD CALD AMN ALD AD, AMN, AS CALD, AS CALD CALD AD CALD AMN, ALMD CALD CALD AMN, ALMD CALD CALD, AMN, ALMD CALD CALD, ALMD, AS ALMD CALD AMN CALD, AMN AD AD AMN CALD G416A Ins T524 C679T C679T C700T C709G G732A A829G C840T Del TA927-28 A928G A985T A1048G DeIGC1080-81 C1174T G1266A ins C1521 1636delC DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 DelAG 1801-02 ins TGG 1848 G 1920 A C1938T C1938T G1950A C2065T C2065T C2065T C2065T C2065G G 2166+1 A T2202C DelGC 2335 C2364T C2364T No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found No mutation found 1 1 + 1 + 1 1 1 + 1 1 + 1 1 1 1 1 1 1 + 1 3 4 S 5 S S S 6 + 6 + 6 6 + 7 + 7 + 7 + 7 + 7 + 7 8 9 9 9 W10 X Frameshift at L46 TMS2 S98L TMS2 S98L T1OSI S108W G116R TMS3 N148S TMS3 R152C Frameshift at Y180 Y181C TMS4 D200V TMS4 D221G Frameshift at R231 P263L EAA-like A294T Frameshift at V378 Frameshift at T416 Frameshift at E471 Frameshift at E471 Frameshift at E471 Frameshift at E471 ins val 491 Walker A G512S Walker A R518W Walker A R518W G 522 W P560L P560L P560L P560L P56OR Splice at G593 Walker B S606P Frameshift at D649 R660W R660W Absent Not done S A Present S A Present T T Absent S D Decreased G T Absent N N Present R K Present Absent Y Y Not done D D Not done D D Absent Absent P R Decreased A A Not done Absent Absent Absent Absent Absent Absent Absent G G Absent R R Absent R R Decreased G E Absent P P Decreased P P Decreased P P Decreased P P Absent P P Absent Not done S S Absent Absent R R Absent R R Absent Not done Absent Absent Absent Present Absent Absent a CALD = cerebral ALD (5-15 years); AMN = adrenomyeloneuropathy; ALMD = adrenomyeloneuropathy with cerebral involvement; AD = Addison disease; AS = Asymptomatic. 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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174 P560S 7 1678C>T n.d. # P560L 7 1679C>T Reduced P560L 7 1679C>T Reduced fs I588 7 1765delC n.d. # R591P 7 1772G>C Absent S606L 8 1817C>T Present E609K 8 1825G>A Absent E609K 8 1825G>A Absent R617C 8 1849C>T Absent R617H 8 1850G>A Absent R617H 8 1850G>A Absent A626T 9 1876G>A Absent A626T 9 1876G>A Absent A626D 9 1877C>A n.d. # E630G 9 1889A>G n.d. # C631Y 9 1892G>A n.d. # T632I 9 1895C>T n.d. # V635M 9 1903G>A n.d. # L654P 9 1961T>C Absent # R660W 9 1978C>T Absent fs L663 9 1988insT n.d. # fs L663 IVS 9 IVS9+1g>a n.d. # fs L663 IVS 9 IVS9-1g>a n.d. # H667D 10 1999C>G Absent # T668I 10 2003C>T Absent # T693M 10 2078C>T Present # exon1-5del 1-5 n.d. # The 47 mutations marked with a # are novel unique mutations reported for the first time in this paper. 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] 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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152 In contrast, the R591Q disease mutation, which alters the dimerization of ALDP in the yeast two-hybrid assays, does not lead to ALDP unstability in vivo. Login to comment
154 This is supported by the observation that several ALDP missense mutations (in particular R518W and P560L) can lead to either a normal, decreased level or absence of ALDP in ALD fibroblasts.4 The specific carboxyl-terminal subdomain region of ALDP responsible for dimerization could not be defined. Login to comment
153 This is supported by the observation that several ALDP missense mutations (in particular R518W and P560L) can lead to either a normal, decreased level or absence of ALDP in ALD fibroblasts.4 The specific carboxyl-terminal subdomain region of ALDP responsible for dimerization could not be defined. 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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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
69 All mutations were unique except two, c.1679 CNT (p.Pro560Leu) and c.1979 GNA (p. Arg660Gln) which were found in two unrelated families. Login to comment
73 Data analysis Results of data analysis done by PolyPhen tool for the missense mutations found in X-ALD patients showed all missense changes, c.1202 GNA (p.Arg401Gln), c.1679 CNT (p.Pro560Leu), c.1816 TNC (p.Ser606Pro), c.1547 TNC (p.Leu516Pro) c.1979 GNA (p.Arg660Gln) as probably damaging (Table 3). Login to comment
93 Another missense mutation c.1679 CNT (p.Pro560Leu), lies between Walker A and B# motifs of ALDP protein, which are the conserved regions of the protein [7]. 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
124 CCER No A5b 34 39 Neuroregression, behavior problem, speech problem, abnormal gait, urinary incontinence AMN c.1679 CNT (p.Pro560Leu) in exon7/c.420 CNA (p.Ile140Ile) (unreported) in exon 1 A6 13 15 Hyperactivity, slurred speech, spastic gait, deterioration of vision AMN No A7b 22 26 Neuroregression, deterioration of vision, cognitive decline, aggressive behavior, spastic gait, urinary incontinence Adult Cerebral c.1938_1939dupGG (p.Ala647fs) in exon 9 A8 4 4.5 Deterioration of vision and hearing, delayed micturition CCER No A9 6 6 Neuroregression, deterioration of vision and hearing, behavior problem, slurred speech, abnormal gait CCER c.1816 TNC (p.Ser606Pro) in exon 8 2.499 Probably damaging A10b 8 8 Neroregression, deterioration of vision, cognitive decline, speech problem, spastic gait CCER c.1394-2ANG in intron 4 A11 15 22 Neuroregression, seizures, deterioration of vision, cognitive decline, speech problem, spastic gait Adolescent c.67_83del17 (p.Ala23fs) in exon 1 A12b 20 21 Neuroregression, speech problem, abnormal gait, urinary incontinence AMN c.1547 TNC (p.Leu516Pro) in exon 6 2.482 Probably damaging A13 45.5 46 Neuroregression, spastic paraparesis, deterioration of vision and hearing, memory decine, behavior problem, cognitive decline, impotence, urinary incontinence Adult cerebral c.1780+2 TNG in exon 7 A14 11 11 Neuroregression, deterioration of hearing, deterioration of school performance, behavior problem, gait abnormaility Adolescent No A15 9 12 Loss of vision and hearing, low volume speech CCER c.395 GNA (p.Trp132X) in exon 1 A16 1 14 Neuroregression, seizures, deterioration of school performance, behavioral problem CCER c.1979 GNA (p.Arg660Gln) in exon 9/p.Ala650Ala, p. Ser633Ser in exon 9 2.409 Probably damaging A17b 0.3 9 Seizures, weakness of right limbs, speech problem, abnormal gait CCER No A18 0.9 15 Neuroregression, deterioration of vision and hearing, behavioral problem, cognitive decline, speech problem, abnormal gait CCER c.1979 GNA (p.Arg660Gln) in exon 9/p.Ala650Ala, p. Ser633Ser in exon 9 2.409 Probably damaging A19 0.6 14 Loss of vision and hearing, speech problem CCER No/p.Ser633Ser in exon 9 A20 12 14 Spastic quadriparaparesis, mild cognitive decline, delayed puberty AMN No CCER: Childhood Cerebral. Login to comment
133 c. CSGE gel showing shift in exon 7 in patients A3 and A5 and electropherogram showing c.1679 CNT (p.Pro560Leu) mutation. Login to comment
142 Most of the mutations found in our study were unique to the kindreds except two missense mutations, c.1679 CNT (p.Pro560Leu) in exon 7 (found A3 and A5) and c.1979 GNA (p.Arg660Gln) in exon 9 (found in A16 and A18) of the ABCD1 gene. Login to comment
160 Similarly the mutation c.1679 CNT (p.Pro560Leu) was observed in AMN patient in our study, but Takano et al. reported this mutation in childhood cerebral phenotype and Feigenbaum and coworkers reported it in four patients, three having childhood cerebral phenotype and one having AMN phenotype with cerebral involvement [7,8]. Login to comment
176 Although the mild phenotype, adrenomyeloneuropathy was present in second group of missense mutations, but in a patient with AMN (A3) phenotype having the mutation, c.1679 CNT (p.Pro560Leu) had two sibs who had early onset of same illness with visual loss, seizures, stiffness, paraparesis and had expired at an early age of 8 years. Login to comment

[hide] Peroxisomal localization of the proopiomelanocorti... Endocrinology. 2010 Oct;151(10):4801-10. Epub 2010 Sep 1. Hoftberger R, Kunze M, Voigtlander T, Unterberger U, Regelsberger G, Bauer J, Aboul-Enein F, Garzuly F, Forss-Petter S, Bernheimer H, Berger J, Budka H
Peroxisomal localization of the proopiomelanocortin-derived peptides beta-lipotropin and beta-endorphin.
Endocrinology. 2010 Oct;151(10):4801-10. Epub 2010 Sep 1., [PMID:20810565]

Abstract [show]
The peptide hormones ACTH, MSHs, beta-lipotropin (beta-LPH), and beta-endorphin are all derived from the precursor molecule proopiomelanocortin (POMC). Using confocal laser microscopy and immunoelectron microscopy in human pituitary gland, we demonstrate a peroxisomal localization of beta-endorphin and beta-LPH in cells expressing the peroxisomal ATP-binding cassette-transporter adrenoleukodystrophy protein (ALDP). The peroxisomal localization of beta-LPH and beta-endorphin was not restricted to the pituitary gland but was additionally found in other human tissues that express high levels of ALDP, such as dorsal root ganglia, adrenal cortex, distal tubules of kidney, and skin. In contrast to the peptide hormones beta-LPH and beta-endorphin, which are derived from the C terminus of POMC, the N-terminal peptides ACTH, alpha-MSH, and gamma-MSH were never detected in peroxisomes. This novel peroxisomal localization of beta-endorphin and beta-LPH in ALDP-positive cells was confirmed by costaining with ALDP and the peroxisomal marker catalase. Moreover, peroxisomal sorting of beta-LPH could be modeled in HeLa cells by ectopic expression of a POMC variant, modified to allow cleavage and release of beta-LPH within the secretory pathway. Although beta-LPH and beta-endorphin were only associated with peroxisomes in cells that normally express ALDP, the transporter activity of ALDP is not necessary for the peroxisomal localization, as demonstrated in tissues of X-linked adrenoleukodystrophy patients lacking functional ALDP. It remains to be elucidated whether and how the peroxisomal localization of POMC-derived hormones has a role in the endocrine dysfunction of peroxisomal disease.

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25 Both patients were diagnosed by elevated VLCFA in plasma; in addition, genetic analysis was performed in one patient (ALD-7 1679, CϾT, P560L). Login to comment

[hide] X-linked adrenoleukodystrophy: ABCD1 de novo mutat... Mol Genet Metab. 2011 Sep-Oct;104(1-2):160-6. Epub 2011 Jun 22. Wang Y, Busin R, Reeves C, Bezman L, Raymond G, Toomer CJ, Watkins PA, Snowden A, Moser A, Naidu S, Bibat G, Hewson S, Tam K, Clarke JT, Charnas L, Stetten G, Karczeski B, Cutting G, Steinberg S
X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism.
Mol Genet Metab. 2011 Sep-Oct;104(1-2):160-6. Epub 2011 Jun 22., [PMID:21700483]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection. Amongst 489 X-ALD families tested at Kennedy Krieger Institute, we identified 20 cases in which the ABCD1 mutation was de novo in the index case, indicating that the mutation arose in the maternal germ line and supporting a new mutation rate of at least 4.1% for this group. In addition, we identified 10 cases in which a de novo mutation arose in the mother or the grandmother of the index case. In two of these cases studies indicated that the mothers were low level gonosomal mosaics. In a third case biochemical, molecular and pedigree analysis indicated the mother was a gonadal mosaic. To the best of our knowledge mosaicism has not been previously reported in X-ALD. In addition, we identified one pedigree in which the maternal grandfather was mosaic for the familial ABCD1 mutation. Less than 1% of our patient population had evidence of gonadal or gonosomal mosaicism, suggesting it is a rare occurrence for this gene and its associated disorders. However, the residual maternal risk for having additional ovum carrying the mutant allele identified in an index case that appears to have a de novo mutation is at least 13%.

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90 Previously reported (Yes/No) Number of pedigrees reporteda CpG (Yes/No) 25 c.124delC ND No 1 N/A 5 c.279_280ins12bp (p.Leu93_Leu94insGluThrGlyLeu) ND No 1 No 6 c.410G>A (p.Trp137X) ND No 1 No 7 c.412_414delCTC (p.Leu139del) ND Yes 2 No 26 c.476del24 ND No 1 N/A 4 c.593C>G (p.Thr198Met) N/A No 1 Yes 8 c.695_696insG (p.Ala233fsX67) ND No 1 Yes 2 c.725G>A (p.Trp242X) Gonosomal No 1 No c.796G>A (p.Gly266Arg) ND Yes 23 Yes 27 c.797G>A (p.Gly266Gln) ND No 1 No 12 c.944C>A (p.Ser315X) ND No 1 Yes 13 c.1201C>T (p.Arg401Trp) ND Yes 12 Yes 14 c.1225-2A>G (splice defect) ND No 1 No 15 c.1390C>T (p.Arg464X) ND Yes 11 Yes 16 c.1553G>A (p.Arg518 Gln) ND Yes 20 Yes 17 c.1567C>T (p.Leu523Phe) ND No 1 No 18 c.1609C>T (p.Gln537X) ND No 1 No 28 c.1619T>G (p.Phe540Cys) ND No 1 No 19 c.1679C>T (p.Pro560Leu) ND Yes 20 Yes 29 c.1679C>T (p.Pro560Leu) ND Yes 20 Yes 20 exon3 to exon10 deletion ND Yesb 9 N/A 30 c.1781-1G>A ND No 1 No 21 c.1816T>C (p.Ser606Pro) ND Yes 3 No 31 c.1850G>A (p.Arg617His) ND Yes 20 Yes 22 c.1876G>A (p.Ala626Thr) ND Yes 10 Yes 23 c.1894A>C (p.Thr632Pro) ND No 2 No 1 c.1899C>A (p.Ser633Arg) Gonosomal Yes 2 Yes 24 c.1918 G>A (p.Glu640Lys) ND No 2 No 3 c.2030G>A (p.Gly677Asp) Gonadal No 1 Yes de novo mutation in male index case with childhood cerebral X-ALD;somatic and/or gonadal mosaicisim; de novo mutationND = none detected; N/A = not applicable; Color codes: in female carrier. Login to comment

[hide] Functional characterization of the adrenoleukodyst... Endocr Res. 2002 Nov;28(4):741-8. Gartner J, Dehmel T, Klusmann A, Roerig P
Functional characterization of the adrenoleukodystrophy protein (ALDP) and disease pathogenesis.
Endocr Res. 2002 Nov;28(4):741-8., [PMID:12530690]

Abstract [show]
X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by abnormal accumulation of saturated very long chain fatty acids in tissues and body fluids with predominance in brain white matter and adrenal cortex. The clinical phenotype is highly variable ranging from the severe childhood cerebral form to asymptomatic persons. The responsible ALD gene encodes the adrenoleukodystrophy protein (ALDP), a peroxisomal integral membrane protein that is a member of the ATP-binding cassette (ABC) transporter protein family. The patient gene mutations are heterogeneously distributed over the functional domains of ALDP. The extreme variability in clinical phenotype, even within one affected family, indicates that besides the ALD gene mutations other factors strongly influence the clinical phenotype. To understand the cell biology and function of mammalian peroxisomal ABC transporters and to determine their role in the pathogenesis of X-ALD we developed a system for expressing functional ABC protein domains in fusion with the maltose binding protein. Wild type and mutant fusion proteins of the nucleotide-binding fold were overexpressed, purified, and characterized by photoaffinity labeling with 8-azido ATP or 8-azido GTP and a coupled ATP regenerating enzyme assay for ATPase activity. Our studies provide evidence that peroxisomal ABC transporters utilize ATP to become a functional transporter and that ALD gene mutations alter peroxisomal transport function. The established disease model will be used further to study the influence of possible disease modifier proteins on ALDP function.

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41 The mutant constructs included missense mutations of patients with X-ALD in the nucleotide binding fold regions Walker A and 19mer (ALDP-NBF-G512S, ALDP-NBF-Q544R, ALDP-NBF-P560L, ALDP-NBF-R591Q, ALDP-NBF-S606L, and ALDP-NBF-D629H) and corresponding mutations in another ABC transporter in the peroxisome membrane, the 70 kDa peroxisomal membrane protein (PMP70; PMP70-NBF-G478R, PMP70- NBF-S572I). Login to comment

[hide] Mutations in the gene for X-linked adrenoleukodyst... Am J Hum Genet. 1995 Apr;56(4):854-61. Braun A, Ambach H, Kammerer S, Rolinski B, Stockler S, Rabl W, Gartner J, Zierz S, Roscher AA
Mutations in the gene for X-linked adrenoleukodystrophy in patients with different clinical phenotypes.
Am J Hum Genet. 1995 Apr;56(4):854-61., [PMID:7717396]

Abstract [show]
Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expression of X-ALD and in their female relatives; these clinical expressions were cerebral childhood ALD, adrenomyeloneuropathy (AMN), and "Addison disease only" (ADO) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5' portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis.

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79 Deletion of 38 bp (nt 660-697) Frameshift 1 Mother, heterozygous CALD-002 ......... C2065T P560L (missenseb) 7 Mother, heterozygous Sister, wild type CALD-003 ......... Login to comment
88 Patient CALD-002 had a C-to-T transition at nucleotide position 2065, a transition that leads to substitution ofproline by leucine in the ATP-binding domain at position 560 (P560L) at a conserved residue in the ALDP/ PMP70 comparison. The mutation erases a restriction site for MspI in fragment BP-6; the mother of CALD-002 is heterozygous for this mutation, and the sister does not carry the disease allele (fig. 3). Login to comment
113 Examination of 108 unrelated X chromosomes did not show this sequence variation, and therefore this result is compatible with the hypothesis that P560L is a true mutation leading to ALD and is not only a simple polymorphism. Login to comment
132 In the ATP-binding domain of the ALD protein lie the mutations G528 or G529 (03-sheet B) and P560L (loop 2). Login to comment
80 Deletion of 38 bp (nt 660-697) Frameshift 1 Mother, heterozygous CALD-002 ......... C2065T P560L (missenseb) 7 Mother, heterozygous Sister, wild type CALD-003 ......... Login to comment
89 Patient CALD-002 had a C-to-T transition at nucleotide position 2065, a transition that leads to substitution ofproline by leucine in the ATP-binding domain at position 560 (P560L) at a conserved residue in the ALDP/ PMP70 comparison. The mutation erases a restriction site for MspI in fragment BP-6; the mother of CALD-002 is heterozygous for this mutation, and the sister does not carry the disease allele (fig. 3). Login to comment
114 Examination of 108 unrelated X chromosomes did not show this sequence variation, and therefore this result is compatible with the hypothesis that P560L is a true mutation leading to ALD and is not only a simple polymorphism. Login to comment
133 In the ATP-binding domain of the ALD protein lie the mutations G528 or G529 (03-sheet B) and P560L (loop 2). Login to comment
78 Deletion of 38 bp (nt 660-697) Frameshift 1 Mother, heterozygous CALD-002 ......... C2065T P560L (missenseb) 7 Mother, heterozygous Sister, wild type CALD-003 ......... Login to comment
87 Patient CALD-002 had a C-to-T transition at nucleotide position 2065, a transition that leads to substitution ofproline by leucine in the ATP-binding domain at position 560 (P560L) at a conserved residue in the ALDP/ PMP70 comparison. The mutation erases a restriction site for MspI in fragment BP-6; the mother of CALD-002 is heterozygous for this mutation, and the sister does not carry the disease allele (fig. 3). Login to comment
112 Examination of 108 unrelated X chromosomes did not show this sequence variation, and therefore this result is compatible with the hypothesis that P560L is a true mutation leading to ALD and is not only a simple polymorphism. Login to comment
131 In the ATP-binding domain of the ALD protein lie the mutations G528 or G529 (03-sheet B) and P560L (loop 2). 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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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
99 Fetus 7: The PCR products of 799 bp, spanning the site of p. Pro560Leu mutation, from the AFC's DNA of fetus 7 as well as the genomic DNA of its parents and elder brother (proband of the family) were digested with the restriction enzyme Bcn I. Login to comment
100 In normal cases, this enzyme has one cutting site on this product and produces two fragments (595 bp and 204 bp) upon its action. When there exists the P560L mutation, the cutting site disappears. 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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55 NBF ND Northern Brazil 52/Male CALD p.Arg401Gly # E3 Missense c.1201C.G CGG.GGG - Inherited Southern Brazil 54/Female CALD p.Ser358fsX42 # E2 Frameshift+stop codon c.1074_1075insA Truncated TMD ND Northern Brazil 55/Female AMN p.Gly510Ser (http://www.x-ald.nl) E6 Missense c.1528G.A GGC.AGC NBF ND Northern Brazil 56/Male CALD p.Asp200Asn (Takano H et al., 1999) E1C Missense c.528G.A GAC.AAC TMD Inherited Northern Brazil 57/Male CALD p. Pro560Leu (Braun A et al., 1995) E7 Missense c.1679C.T CCG.CTG NBF Inherited Northern Brazil The number of family: the registration number in records of our lab. AMN: adrenomyeloneuropaty; AO: Addison only; #: new mutations identified in this study; NBF: nucleotide-binding fold; TMD: Transmembrane Domin; ND: not determined. 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] An under-recognised cause of spastic paraparesis i... Pract Neurol. 2014 Jun;14(3):182-4. doi: 10.1136/practneurol-2013-000662. Epub 2013 Oct 23. Bargiela D, Eglon G, Horvath R, Chinnery PF
An under-recognised cause of spastic paraparesis in middle-aged women.
Pract Neurol. 2014 Jun;14(3):182-4. doi: 10.1136/practneurol-2013-000662. Epub 2013 Oct 23., [PMID:24154795]

Abstract [show]
Having excluded common structural, inflammatory and vascular causes of a spastic paraparesis, the diagnostic yield of further clinical investigations is low. Here, we show that testing for rare metabolic and genetic causes can have important implications for both the patient and their family.

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18 Subsequent DNA sequencing indicated a heterozygous c1679C>T (p.Pro560Leu) mutation in exon 7 of the ABCD1 gene. Login to comment

[hide] Clinical and genetic aspects in twelve Korean pati... Yonsei Med J. 2014 May;55(3):676-82. doi: 10.3349/ymj.2014.55.3.676. Epub 2014 Apr 1. Park HJ, Shin HY, Kang HC, Choi BO, Suh BC, Kim HJ, Choi YC, Lee PH, Kim SM
Clinical and genetic aspects in twelve Korean patients with adrenomyeloneuropathy.
Yonsei Med J. 2014 May;55(3):676-82. doi: 10.3349/ymj.2014.55.3.676. Epub 2014 Apr 1., [PMID:24719134]

Abstract [show]
PURPOSE: This study was designed to investigate the characteristics of Korean adrenomyeloneuropathy (AMN) patients. MATERIALS AND METHODS: We retrospectively selected 12 Korean AMN patients diagnosed by clinical analysis and increased plasma content of very long chain fatty acids. RESULTS: All 12 patients were men. Patient ages at symptom onset ranged from 18 to 55 years. Family history was positive in two patients. The phenotype distributions consisted of AMN without cerebral involvement in seven patients, AMN with cerebral involvement in two patients, and the spinocerebellar phenotype in three patients. Nerve conduction studies revealed abnormalities in four patients and visual evoked tests revealed abnormalities in three patients. Somatosensory evoked potential tests revealed central conduction defects in all of the tested patients. Spinal MRI showed diffuse cord atrophy or subtle signal changes in all 12 patients. Brain MRI findings were abnormal in six of the nine tested patients. These brain abnormalities reflected the clinical phenotypes. Mutational analysis identified nine different ABCD1 mutations in 10 of 11 tested patients. Among them, nine have been previously reported and shown to be associated with various phenotypes; one was a novel mutation. CONCLUSION: In conclusion, the present study is the first to report on the clinical and mutational spectrum of Korean AMN patients, and confirms various clinical presentations and the usefulness of brain MRI scan.

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89 The Mutational Analysis of Korean Patients with Adrenomyeloneuropathy Exon Mutation Allele Type Reference Adrenomyeloneuropathy without cerebral involvement 1 1 c.479T>C p.Leu160Pro Missense Sutovsk&#fd;, et al.13 2 3 c.1166G>A p.Arg389His Missense Kok, et al.14 3 9 c.1970_72del p.Ile657del In-frame deletion Ligtenberg, et al.15 4 1 c.421G>A p.Ala141Thr Missense Kok, et al.14 5 Not found 6 7 c.1679C>T p.Pro560Leu Missense Kemp, et al.6 7 Not available Adrenomyeloneuropathy with cerebral involvement 8 7 c.1679C>T p.Pro560Leu Missense Kemp, et al.6 9 1 c.225_242del p.Trp77_Leu82del Deletion Lee, et al.9 Spinocerebellar phenotype 10 1 c.277_296dup20 p.Leu93fs Frameshift Novel 11 7 c.1661G>A p.Arg554His Missense Kemp, et al.6 12 IVS1 c.901-1G>A p.Val301fs Frameshift Kemp, et al.6 IVS, intervening sequence. Login to comment