A clinical and genetic study of a rare adrenoleukodystrophy kindred

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1 October 2013 Vol. 33 No. 10 * ALD ABCD1 4 4 ALD ALD ABCD1 ABCD1 8 c G > T ALD ABCD1 c G > T ABCD1 R A A clinical and genetic study of a rare adrenoleukodystrophy kindred ZHOU Pei-ran HU Ying-ying LU Lin LU Zhao-lin XIA Wei-bo XING Xiao-ping LI Mei * Dept. of Endocrinology Key Laboratory of Endocrinology of Ministry of Health PUMC Hospital PUMC & CAMS Beijing China Abstract Objective To analyse the clinical features of a kindred with adrenoleukodystrophy ALD and to detect the mutation of ABCD1 gene. Methods A Chinese ALD kindred with four affected males from four-generations was studied. ALD was diagnosed according to clinical manifestations cranial MRI image and serium level of very long chain fatty acid VLCFA. Mutation of ABCD1 was detected by direct DNA sequencing of polymerase chain reaction amplification product. Results Primary adrenocortical insufficiency and neurological dysfunction were the main manifestations of the patients. MRI image showed extensive cerebral white matter demyelination. Serum VLCFA level was significantly high. A novel missense substitution c C > T in exon 8 of ABCD1 was identified. All affected males were hemizygotes and female carriers were heterzygotes. Conclusions The typical manifestations of ALD are primary adrenocortical insufficiency and neurological dysfunction. A missense substitution c C > T in exon 8 of ABCD1 is a novel mutation firstly detected in this Chinese pedigree with ALD. Key words adrenoleukodystrophy ABCD1 gene mutation detection adrenoleukodystrophy X ALD OMIM # ABCD1 Xq * corresponding author limeilzh@ sina. com

2 ALDP ABCD1 ALDP 4 6 very long chain fatty acid VLCFA VLCFA C μmol /L ± C μmol /L ALD ± C26 0 /C ALD ± C24 0 /C ABCD ± F μg /L ~ Ⅲ Ⅲ ~ Ⅲ ABCD1 10 Oligo7 1 ABCD1 1 ~ Ⅳ ± C μmol /L ACTH > ng /L ~ MRI 2A ~ D - VLCFA 1 F 110 /80 mmhg 1 mmhg = kpa ACTH 66 / 1. 3 ABCD1 1 DNA Tiangen 5' 3' 8 ~ ~ 10 2 PCR 30 μl 1 ALD Fig 1 Pedigree of ALD patients

3 PCR Table 1 Sequence of PCR primers primers position sequence length bp annealing temperature / time of extension s ALD-1F exon1 5'-GCCTAAAGCGACAGTCTC-3' /90 ALD-1R 5'-TCGCAGCTCTAAGGCCAGGACAAC-3' ALD-2F exon2 5'-CCCCACCCAATCGTAACCTC-3' /90 ALD-2R 5'-CGAGCTCAACCTCTGAAAGCATC-3' ALD-3F exon3 5'-TTTCTCTTGTTGCTCATGCTTT-3' /90 ALD-3R 5'-GACAGCCTTACCTCGGAT-3' ALD-4F exon4 5'-CCCACCCTTGCCATCCTT-3' /90 ALD-4R 5'-CCCCTTGTTTTGAATGAATAATCCAG-3' ALD-5F exon5 5'-AAGACCTGGCTGTGTTCCCT-3' /90 ALD-5R 5'-TTCCTTGCTGTGGCCTTCCGA-3' ALD-6F exon6 5'-CACCATGTTCTCCAGGCGTGTC-3' /90 ALD-6R 5'-ACACACCCCACACAGATCCAA-3' ALD-7F exon7 5'-CTCCAAACCCGCCCGATCCAC-3' /90 ALD-7R 5'-CCTCTCGCACCACCAAGCCTT-3' ALD-8F exon8-10 5'-CTGGGGCTGCCATAAACCGCAGGGA-3' /105 ALD-10R 5'-GACTCGAGTCTCTGGAGGGAGG-3' Taq mix 15 μl 20 μmol /L 1 μl 0 ~ 46 CT MRI DNA 2 μl ddh 2 O 11 μl PCR 95 5 min s 30 s 2E ~ H CT min PCR C mg /L C mg /L C26 0 NM_ ABCD ABCD1 1 CT G MRI CT C ALD 1 VLCFA C mg /L ~ C mg /L ~ C mg /L 0 ~ 0. 5 C26 0 /C ~ C24 0 /C ABCD1 VLCFA 0 ~ F 7. 7 μg /L ~ ACTH 7. 0 ng /L VLCFA mg /L C26 0 /C C24 0 /C T c G > T 3A 617 p. R617L 3B Ⅰ1 3 ALD

4 T2-weight Flair image of patient 3 reveals symmetrical diffuse high signal intensity area in the white matter of the parietal lobes A and occipital lobes B T2-weight image reveals symmetrical diffuse high signal intensity area in the white matter of occipital lobes C T2-weight Flair image at the position of sagittalia reveals diffuse high signal intensity area in the white matter of the parietal and occipital lobes D T1-weight image of patient 1 reveals abnormal signal intensity area in the white matter of both lateral ventricle posterior horn side and corpus callosum splenium E T2-weight Flair image at the position of sagittalia reveals high signal intensity area in the white matter of lateral ventricle posterior horn side F Cranial CT reveals diffuse hypodense shadow in the white matter of the occipital G and parietal H lobes especially in the left side Fig 2 2 CT MRI Cranial CT and MRI imaging of patients A. sequence of patient hemizygote B. sequence of female carriers heterozygote C. normal sequence 3 ALD ABCD1 Fig 3 Mutation analysis of ABCD1 in this ALD family ALD 4 ~ 8 ALD 35% ALD % ~ 20% 1

5 1013 ABCD1 8 c G > T X G > A ALDP ABCD1 1 VLCFA 20% ~ % ABCD % 22% http / /www. x-adl. nl 47% 11 ALDP 34% ATP 4 X-ALD PubMed c G > T 1 ALD 3 ALD ATP 4 ALDP ALD ABCD c G > T ALD c. 1849delC 5 c C > T 5-7 c C > G 6 c C > A 8 c X 12 Fig 4 4 ALDP A hypothetical model of ALDP www. x-ald. nl 1 Barbier M Sabbagh A Kasper E et al. CD1 gene polymorphisms and phenotypic variability in X-linked adrenoleukodystrophy J. PLoS One e doi / journal. pone Matsukawa T Asheuer M Takahashi Y et al. Identification of novel SNPs of ABCD1 ABCD2 ABCD3 and AB- CD4 genes in patients with X-linked adrenoleukodystrophy ALD based on comprehensive resequencing and associa-

6 tion studies with ALD phenotypes J. Neurogenetics López-Erauskin J Galino J Bianchi P et al. Oxidative stress modulates mitochondrial failure and cyclophilin D function in X-linked adrenoleukodystrophy J. Brain Pereira Fdos S Matte U Habekost CT et al. Mutations clinical findings and survival estimates in South American patients with X-Linked adrenoleukodystrophy J. PLoS One e doi /journal. pone Coll MJ Palau N Camps C et al. X-linked adrenoleukodystrophy in Spain. Identification of 26 novel mutations in the ABCD1 gene in 80 patients. Improvement of genetic counseling in 162 relative females J. Clin Genet Lan F Wang Z Ke L et al. A rapid and sensitive protocol for prenatal molecular diagnosis of X-linked adrenoleukodystrophy J. Clin Chim Acta Shimozawa N Honda A Kajiwara N et al. X-linked adrenoleukodystrophy diagnostic and follow-up system in Japan J. J Hum Genet Kumar N Taneja KK Kumar A et al. Novel mutation in ATP-binding domain of ABCD1 gene in adrenoleukodystrophy J. J Genet Wang Y Busin R Reeves C et al. X-linked adrenoleukodystrophy ABCD1 de novo mutations and mosaicism J. Mol Genet Metab O'Neill BP Moser HW Saxena KM et al. Adrenoleukodystrophy clinical and biochemical manifestations in carriers J. Neurology Engelen M Kemp S de Visser M et al. X-linked adrenoleukodystrophy X-ALD clinical presentation and guidelines for diagnosis follow-up and management. J. Orphanet J Rare Dis doi / Salsano E Tabano S Sirchia SM et al. Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms J. Orphanet J Rare Dis doi / WebMD Mee Young Hong 70% d LDL HDL LDL 20% HDL 20% Hong Joe Vinson Vinson 2012

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