title: Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy.
abstract: 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.
authors.affiliation: , Shanghai, China.|Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Chu
authors.affiliation: , Shanghai, China. yejun2314@163.com.|Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. yejun2314@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Ye
authors.affiliation: , Shanghai, China.|Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Zhang
authors.affiliation: , Shanghai, China.|Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lian-Shu
authors.initials: LS
authors.lastname: Han
authors.affiliation: , Shanghai, China.|Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wen-Juan
authors.initials: WJ
authors.lastname: Qiu
authors.affiliation: , Shanghai, China.|Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiao-Lan
authors.initials: XL
authors.lastname: Gao
authors.affiliation: , Shanghai, China.|Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xue-Fan
authors.initials: XF
authors.lastname: Gu
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012189:Retrospective Studies
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters
keywords: ABCD1 protein; adrenoleukodystrophy; adrenoleukodystrophy protein; missense variant; mutation