ABCD1 p.Thr254Met
| Predicted by SNAP2: | A: D (85%), C: D (85%), D: D (95%), E: D (95%), F: D (95%), G: D (91%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (91%), P: D (95%), Q: D (95%), R: D (95%), S: D (75%), V: D (91%), 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, R: D, S: D, V: D, W: D, Y: D, |
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[hide] Mutational analysis and genotype-phenotype correla... Arch Neurol. 1999 Mar;56(3):295-300. Takano H, Koike R, Onodera O, Sasaki R, Tsuji S
Mutational analysis and genotype-phenotype correlation of 29 unrelated Japanese patients with X-linked adrenoleukodystrophy.
Arch Neurol. 1999 Mar;56(3):295-300., [PMID:10190819]
Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (ALD) is an inherited disease characterized by progressive neurologic dysfunction, occasionally associated with adrenal insufficiency. The classic form of ALD usually has onset in childhood (childhood cerebral ALD), with rapid neurologic deterioration leading to a vegetative state. Adult-onset cerebral ALD also presents with rapidly progressive neurologic dysfunction. Milder phenotypes such as adrenomyeloneuropathy and Addison disease only also have been recognized. Despite discovery of the causative gene, a molecular basis for the diverse clinical presentations remains to be elucidated. OBJECTIVES: To conduct mutational analyses in 29 Japanese patients with ALD from 29 unrelated families, to obtain knowledge of the spectrum of mutations in this gene, and to study genotype-phenotype correlations in Japanese patients. METHODS: The 29 patients comprised 13 patients with childhood cerebral ALD, 11 patients with adult-onset cerebral ALD, and 5 patients with adrenomyeloneuropathy. We conducted detailed mutational analyses of 29 unrelated Japanese patients with ALD by genomic Southern blot analysis and direct nucleotide sequence analysis of reverse transcriptase-polymerase chain reaction products derived from total RNA that was extracted from cultured skin fibroblasts, lymphoblastoid cells, or peripheral blood leukocytes. RESULTS: Three patients with adult-onset cerebral ALD were identified as having large genomic rearrangements. The remaining 26 patients were identified as having 21 independent mutations, including 12 novel mutations resulting in small nucleotide alterations in the ALD gene. Eighteen (69%) of 26 mutations were missense mutations. Most missense mutations involved amino acids conserved in homologous gene products, including PMP70, mALDRP, and Pxa1p. The AG dinucleotide deletion at position 1081-1082, which has been reported previously to be the most common mutation in white patients (12%-17%), was also identified as the most common mutation in Japanese patients (12%). All phenotypes were associated with mutations resulting in protein truncation or subtle amino acid changes. There were no differences in phenotypic expressions between missense mutations involving conserved amino acids and those involving nonconserved amino acids. CONCLUSIONS: There are no obvious correlations between the phenotypes of patients with ALD and their genotypes, suggesting that other genetic or environmental factors modify the phenotypic expressions of ALD.
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No. Sentence Comment
87 Review of previous publications indicated that 14 missense mutations are associated exclu- sivelywithAMNorAddisondiseaseonly,includingC696T (R104C),33,34 G697A(R104H),42 C700T(T105I),45 G832A (S149N),35 C918G(Q178E),42 T1045C(L220P),35 C1137T (T254M),37 G1266A(A294T),45 C1551G(R389G),37 G1552A (R389H),33,35 C1638T (R418W),37 C1930T (S515F),38 T2084A(M566K),33 andG2211A(E606K).35,37 Analysisof these mutations may provide important insights into the mechanisms involved in variable phenotypic expressions in ALD.
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ABCD1 p.Thr254Met 10190819:87:244
status: NEW[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.
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ABCD1 p.Thr254Met 23419472:145:233
status: NEW[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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No. Sentence Comment
50 Genetic testing showed a heterozygous c.761C>T (p.Thr254Met) mutation of the ABCD1 gene.
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ABCD1 p.Thr254Met 24154795:50:50
status: NEW