ABCD1 p.Trp595*
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[hide] Efferent and afferent evoked potentials in patient... Clin Neurol Neurosurg. 2010 Feb;112(2):131-6. Epub 2009 Dec 5. Matsumoto H, Hanajima R, Terao Y, Hamada M, Yugeta A, Shirota Y, Yuasa K, Sato F, Matsukawa T, Takahashi Y, Goto J, Tsuji S, Ugawa Y
Efferent and afferent evoked potentials in patients with adrenomyeloneuropathy.
Clin Neurol Neurosurg. 2010 Feb;112(2):131-6. Epub 2009 Dec 5., [PMID:19963315]
Abstract [show]
OBJECTIVE: This paper investigates efferent and afferent conductions of the central nervous system by various evoked potentials in patients with adrenomyeloneuropathy (AMN). PATIENTS AND METHODS: Ten pure AMN patients without cerebral involvement were studied. Motor evoked potentials (MEPs), somatosensory evoked potentials (SEPs), auditory brainstem response (ABR), and pattern reversal full-field visual evoked potentials (VEPs) were recorded. For MEP recording, single-pulse or double-pulse magnetic brainstem stimulation (BST) was also performed. RESULTS: Abnormal MEP was observed in all ten patients, abnormal SEP in all ten, abnormal ABR in nine, and abnormal VEP in only one. Brainstem latency was measured in three of the seven patients with central motor conduction time (CMCT) prolongation. The cortical-brainstem conduction time was severely prolonged along the normal or mildly delayed brainstem-cervical conduction time in those three patients. CONCLUSIONS: The pattern of normal VEP and abnormal MEP, SEP, ABR is a clinically useful electrophysiological feature for the diagnosis. BST techniques are helpful to detect, functionally, intracranial corticospinal tract involvement, probably demyelination, in pure AMN patients.
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35 Case Age ABCD1 mutation Disease duration (years) Main symptom(s) Brain MRI Loes score Spinal MRI 1 32 Missense (H667N) 1 Spastic gait, pigmentation Normal 0 Normal 2 44 Nonsense (W595X) 1 Spastic gait, sensory disturbance (leg) Normal 0 Atrophy 3 61 N.E. 4 Spastic gait, muscular weakness (leg), sensory disturbance (leg) Normal 0 Normal 4 30 Missense (S290W) 5 Spastic gait, sensory disturbance (leg), dysuria, dyschezia, impotence P, V 2.5 Normal 5 31 Missense (F540S) 5 Spastic gait V 0.5 Normal 6 24 Missense (A616D) 6 Spastic gait, sensory disturbance (leg), dysuria, impotence Normal 0 Normal 7 31 Frameshift (Y281) 8 Spastic gait, sensory disturbance (leg), dyschezia C 0.5 Normal 8 33 Missense (G277R) 8 Spastic gait, dysuria, dyschezia impotence P 2 Atrophy 9 58 N.E. 18 Spastic gait, dysuria Normal 0 Atrophy 10 58 N.E. 19 Spastic gait, impotence Normal 0 Normal MRI: magnetic resonance image, P: pyramidal system, V: visual pathway, C: cerebellum, N.E.: not examined.
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ABCD1 p.Trp595* 19963315:35:179
status: NEW33 Case Age ABCD1 mutation Disease duration (years) Main symptom(s) Brain MRI Loes score Spinal MRI 1 32 Missense (H667N) 1 Spastic gait, pigmentation Normal 0 Normal 2 44 Nonsense (W595X) 1 Spastic gait, sensory disturbance (leg) Normal 0 Atrophy 3 61 N.E. 4 Spastic gait, muscular weakness (leg), sensory disturbance (leg) Normal 0 Normal 4 30 Missense (S290W) 5 Spastic gait, sensory disturbance (leg), dysuria, dyschezia, impotence P, V 2.5 Normal 5 31 Missense (F540S) 5 Spastic gait V 0.5 Normal 6 24 Missense (A616D) 6 Spastic gait, sensory disturbance (leg), dysuria, impotence Normal 0 Normal 7 31 Frameshift (Y281) 8 Spastic gait, sensory disturbance (leg), dyschezia C 0.5 Normal 8 33 Missense (G277R) 8 Spastic gait, dysuria, dyschezia impotence P 2 Atrophy 9 58 N.E. 18 Spastic gait, dysuria Normal 0 Atrophy 10 58 N.E. 19 Spastic gait, impotence Normal 0 Normal MRI: magnetic resonance image, P: pyramidal system, V: visual pathway, C: cerebellum, N.E.: not examined.
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ABCD1 p.Trp595* 19963315:33:179
status: NEW[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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74 The five known SNPs (rs17782508, rs2301345, rs4148077, rs4148078, and rs3742801) were in complete Table 1 Identified ABCD1 mutations: mutations of ABCD1 that result in devastating effects (frame shifts or nonsense mutations) on adrenoleukodystrophy protein (ALDP) Patient number Phenotype Mutation of ABCD1 Effect of mutation of ABCD1 1 CCALD 488C>AT Frameshift at P34 2 CCALD 2171G>A W595X 3 CCALD 5'UTR-Ex2 1.4-kb deletiona Disruption of gene structure 4 AdultCer Del. 986Ca Frameshift at D200 5 AdultCer Del. 1801-1802AGa Frameshift at Q472 6 AMN-Cer Del. 2251 GGTG ins. TGTTCTa Frameshift at R622 7 AMN Ins. 1237Ta Frameshift at Y281 8 AMN Del. 1801-1802AGa Frameshift at Q472 9 AMN 2171G>A W595X 10 AMN Del. 2251 GGTG ins. TGTTCTa Frameshift at R622 11 Unknown Del. 1541Ca Frameshift at F385 12 Unknown Ex8-10 0.3-kb deletiona Disruption of gene structure Amino acid residue numbers in ALDP are based on Mosser et al. [1].
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ABCD1 p.Trp595* 20661612:74:385
status: NEWX
ABCD1 p.Trp595* 20661612:74:695
status: NEW[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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39 Mutations in the ALD Gene That Result in Devastating Effects (Truncation) on ALDP* Patient No. Phenotype Mutation† Exon Effect of Mutation‡ Position of Mutation§ Family Data Large Genomic Rearrangement G4001(s) ACALD 0.5-kb deletion 1 Disruption of gene structure Exon 1 No family history G4002(s) ACALD 7-kb deletion 7-9 Disruption of gene structure Exons 7-8 No family history G4003(s) ACALD 10.6-kb deletion 6-10 Disruption of gene structure Exons 6-10 No family history Frameshift Mutation G4004 CCALD C488AT 1 Frameshift at P34 TM1 Symptomatic carrier G4005 ACALD ins.977T 1 Frameshift at L197 Between TM3 and TM4 Not available G4006 AMN del.1801-1802 5 Frameshift at E471 Between TM6 and Walker A Not available G4007(s) ACALD del.1801-1802 5 Frameshift at E471 Between TM6 and Walker A No family history G4008 CCALD del.1801-1802 5 Frameshift at E471 Between TM6 and Walker A Not available Nonsense Mutation G4009 CCALD G2171A 8 W595X Between Walker A and B CCALD *ALD indicates adrenoleukodystrophy; ALDP, ALD protein; ACALD, adult-onset cerebral ALD; CCALD, childhood cerebral ALD; AMN, adrenomyeloneuropathy; (s), apparently sporadic patients; ins., insert; and del., delete.
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ABCD1 p.Trp595* 10190819:39:954
status: NEWX
ABCD1 p.Trp595* 10190819:39:975
status: NEW