Adrenoleukodystrophy ; genetics ; therapy ; Humans ; Lovastatin ; pharmacology

OBJECTIVE: To analyze the clinical features and variants of ABCD1 gene in a Chinese pedigree affected with X-linked adrenoleukodystrophy. METHODS: Clinical data of the proband were collected and analyzed. Potential variant of the ABCD1 gene were analyzed by PCR and Sanger sequencing of the proband, his parents and 100 unrelated healthy individuals. RESULTS: The prominent features of the proband included cerebellar and brainstem lesions, along with increased serum level of very-long chain fatty acids. He was found to harbor a hemizygous c.1509delG (p.L504Sfs*54) variant of the ABCD1 gene, for which his mother was heterozygous. The same variant was not detected in his father and 100 healthy controls. CONCLUSION X-linked adrenoleukodystrophy has a variety of clinical manifestations. Discovery of the c.1509delG (p.L504Sfs*54), as a novel pathogenic variant of the ABCD1 gene, has enabled diagnosis and genetic counseling for this pedigree.
Adrenoleukodystrophy/genetics* ; Asians/genetics* ; China ; Female ; Genetic Testing ; Humans ; Male ; Mutation ; Pedigree

X-linked adrenoleukodystrophy (X-ALD) shows a wide range of phenotypic expression, but clinical presentation as an isolated lesion of the cerebellar white matter and dentate nuclei has not been reported. We report an unusual presentation of X-ALD only with an isolated lesion of the cerebellar white matter and dentate nuclei. The proband, a 37-year-old man presented with bladder incontinence, slurred speech, dysmetria in all limbs, difficulties in balancing, and gait ataxia. Brain magnetic resonance imaging showed an isolated signal change of white matter around the dentate nucleus in cerebellum. With high level of very long chain fatty acid, gene study showed a de novo mutation in exon 1 at nucleotide position c.277_296dup20 (p.Ala100Cysfs*10) of the adenosine triphosphate-binding cassette D1 gene. It is advised to consider X-ALD as a differential diagnosis in patients with isolated cerebellar degeneration symptoms.
ATP-Binding Cassette Transporters/*genetics ; Adrenoleukodystrophy/blood/*genetics ; Adult ; Cerebellar Diseases/blood/*genetics ; Fatty Acids/blood ; Humans ; Male ; Mutation

OBJECTIVETo investigate the association of the polymorphisms of methionine metabolism genes and the phenotype of X-linked adrenoleukodystrophy (X-ALD) and clinical severity.

METHODSThe clinical information of 120 X-ALD patients were analyzed and three genetic variants involved in the methionine metabolism, including cystathionine beta-synthase (CBS) c.844_855ins68, 5-methyltetrahydrofolate-homocysteine-S-methyltransferase (MTR) c.2756A to G, and transcobalamin 2 (TC2) c.776 C to G were analyzed by polymerase chain reaction and sequencing. The association between these polymorphisms and phenotype of X-ALD was studied.

RESULTSThe frequency of GG genotype of the TC2 c.776 C/G was higher in patients with central nervous system(CNS) demyelination than in controls (P= 0.012). However, the other two polymorphisms did not show any significant associations with the phenotypes.

CONCLUSIONThe GG genotype of TC2 c.776 C/G may contribute to X-ALD phenotype.

5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase ; genetics ; Adrenoleukodystrophy ; genetics ; Cystathionine beta-Synthase ; genetics ; Gene Frequency ; Genotype ; Humans ; Male ; Methionine ; metabolism ; Phenotype ; Polymorphism, Genetic ; Transcobalamins ; genetics

Adrenoleukodystrophy ; genetics ; therapy ; Animals ; Color Vision Defects ; genetics ; therapy ; Dependovirus ; Gene Transfer Techniques ; Genetic Therapy ; ethics ; trends ; Hematopoietic Stem Cell Transplantation ; Humans ; Leber Congenital Amaurosis ; genetics ; therapy ; Lentivirus

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.
ATP-Binding Cassette Transporters/genetics ; Adolescent ; Adrenoleukodystrophy/*diagnosis/*genetics ; Adult ; Brain/pathology ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Republic of Korea ; Young Adult

OBJECTIVETo identify the mutational genotype of three Chinese families with X-linked adrenoleukodystrophy (X-ALD: MIM#300100).

METHODSTotal RNA was extracted from the peripheral blood leukocytes of patients 1, 2 and the mother of patient 3, using RNA blood Mini kit (QIAGEN). After reverse transcription, cDNA was amplified in four overlapping segments. The PCR products were purified and directly sequenced. To confirm the mutations, the genomic DNA was isolated from the patients and their family members using DNA blood isolation kit (MO-BIO) and analyzed by PCR-restrictive digestion or amplification refractory mutation system.

RESULTSThree distinct mutations were detected in the ABCD1 gene of the three pedigrees. A mutation of CCC-->CGC was detected at codon 534 of the ABCD1 gene from patient 1, resulting in the arginine for proline substitution. A change of GGG-->AGG was found at codon 266 of the second patient's gene, accompanied with the replacement of glycine by arginine. A mutation of CGC-->GGC was found at codon 617 in one ABCD1 allele of the third patient's mother, leading to the glycine for arginine substitution. The three mutations were confirmed through restriction analysis or amplification refractory mutation system.

CONCLUSIONThree ABCD1 gene missense mutations were detected in three unrelated Chinese families with X-linked adrenoleukodystrophy, one of which, the mutation (P534R), is novel in Chinese with ALD, and the other two G266R and R617G mutations, have been reported outside China.

ATP Binding Cassette Transporter, Sub-Family D, Member 1 ; ATP-Binding Cassette Transporters ; genetics ; Adrenoleukodystrophy ; genetics ; Child ; Child, Preschool ; Humans ; Male ; Mutation ; Pedigree

OBJECTIVEX-linked adrenoleukodystrophy (X-ALD) is the most common inherited disorder of peroxisomal metabolism which is characterized by demyelination of central nervous system, impaired adrenal cortex and abnormal accumulation of very long chain fatty acids in body fluid and tissues. In this study, the clinical features and the genotype-phenotype relationship were investigated so as to help early diagnosis.

METHODSClinical data of 89 Chinese patients with X-ALD were analyzed and mutation spectrums in 53 of the patients were investigated by polymerase chain reaction and DNA sequencing.

RESULTSOf the 89 cases, 60 (67.4%) had childhood cerebral ALD (CCALD, mean age of onset was 6.5 years, range 2 - 10 years), 18 (20.2%) had adolescent cerebral ALD (ACALD, mean age of onset 12.1 years, range 11 - 19 years), 7 (7.9%) had adrenomyeloneuropathy (AMN, mean age of onset 23 years, range 6 - 39.5 years), and two cases were asymptomatic and another 2 had simple Addison's disease only. CCALD was the most common and severe phenotype, visual impairment was the most common initial symptom in CCALD and ACALD patients. Twenty four cases (63%) in whom hydrocortisone and ACTH were measured showed adrenal insufficiency. Forty five different mutations were identified in 53 patients. Missense mutations were the most common. No hotspot mutation was found in these patients and 1415delAG, the most frequent mutation found worldwide seemed not to be the real "hotspot" in these Chinese patients. The same phenotype may be due to diverse genomic mutations. A single mutation may result in different phenotypes even within a family.

CONCLUSIONThe phenotype distribution, initial symptom and gene mutation spectrum of Chinese patients may not be completely consistent with those in other countries. The clinical phenotype of the disease had no definite relationship with the nature of gene mutations.

Adolescent ; Adrenoleukodystrophy ; genetics ; Adult ; Age of Onset ; Asian Continental Ancestry Group ; genetics ; Child ; Child, Preschool ; DNA Mutational Analysis ; Female ; Genotype ; Humans ; Male ; Mutation, Missense ; Phenotype ; Young Adult

OBJECTIVETo investigate mutations of ABCD1 gene in X- linked adrenoleukodystrophy (ALD) patients in China.

METHODSPolymerase chain reaction and DNA direct sequencing were employed to analyze the 10 exons of ABCD1 gene in 25 ALD patients.

RESULTSSeventeen mutations in different exons (except exons 4, 9 and 10) were identified in 18 of 25 patients. Most of the mutations were missense mutations, including R182P, G266R, H283D, S404P, N509I, R518G, L520Q, Q556R, S606L and R617C, four (H283D, S40 4P, N509I, R518G) of 10 missense mutations were novel. Also identified were 3 nonsense mutations (W132X, W242X, W595X), 1 dinucleotides deletion mutation (1414 del AG) resulting in frameshift, and 1 base pair deletion at splice acceptor site (IVS5-6 del C). Two synonymous mutations (L516L and V349V) appeared simultaneously in 2 unrelated patients, and no other mutations could be found with them in all 10 exons screened.

CONCLUSIONThere were no hot spot mutations in ABCD1 gene in China. Mutations in gene were found over 70% of patients with ALD in China. The ABCD1 gene mutations identified revealed no obvious correlation between the type of mutation and phenotype.

ATP Binding Cassette Transporter, Sub-Family D, Member 1 ; ATP-Binding Cassette Transporters ; genetics ; Adrenoleukodystrophy ; genetics ; pathology ; Age of Onset ; Base Sequence ; China ; Codon, Nonsense ; DNA ; chemistry ; genetics ; DNA Mutational Analysis ; Humans ; Male ; Mutation ; Mutation, Missense

OBJECTIVETo detect the mutations in exon 6 of ABCD1 gene encoding adrenoleukodystrophy protein(ALDP) in Chinese X-linked adrenoleukodystrophy (ALD MIM 300100) patients.

METHODSGenomic DNA from 14 unrelated patients and two patients' parents with X-linked ALD was extracted using standard procedures from the peripheral blood leukocytes. Polymerase chain reaction (PCR) and DNA direct sequencing were employed to analyze exon 6 of ABCD1 gene.

RESULTSThree mutations in exon 6 were identified in 3 of 14 patients. One mutation was deleted 1 base pair at splice acceptor-site (1489-6 del C). It was not clear what the effect of this mutation is on the ALD protein, maybe induce splicing error. One missense mutation: T1559A(L520Q). These two patients' mothers were heterozygous. The third patient had a mutation: G1548A (L516 L), which is a known polymorphism. It was not a disease causing mutation, so there should be another mutation in this patient.

CONCLUSIONFor the first time, mutations in ABCD1 are identified in Chinese ALD patients in the mainland of China. No major gene deletion or rearrangement is detected in exon 6. Despite many mutations having been identified in patients with these clinical phenotypes, the genotype-phenotype correlations have not been clarified, suggesting that other genetic or environmental factors may also be involved in determining phenotypic expression in ALD. Two carriers are also confirmed.

ATP Binding Cassette Transporter, Sub-Family D, Member 1 ; ATP-Binding Cassette Transporters ; genetics ; Adolescent ; Adrenoleukodystrophy ; genetics ; pathology ; Base Sequence ; Child ; Child, Preschool ; China ; DNA ; chemistry ; genetics ; DNA Mutational Analysis ; Humans ; Mutation