Clinical and genetic characteristics of adult cerebral adrenoleukodystrophy

doi:10.3969/j.issn.1674-8115.2023.05.009

Abstract

Abstract:

Objective ·To summarize and analyze the clinical and genetic characteristics of adult cerebral adrenoleukodystrophy(ACALD ). Methods ·The data of eight patients with ACALD who attended the Shanghai Sixth People′s Hospital, Shanghai Jiao Tong University School of Medicine from June 2018 to September 2022 were collected and comprehensively analyzed. Clinical data included age at onset, duration of disease, family history, present history and physical examination. Imaging examinations included magnetic resonance imaging (MRI) of the cranial, cervical spine and thoracic spine. Laboratory tests included serum very-long-chain fatty acids (VLCFA), adrenal cortical function and genetic test. Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (Moca) were used to assess patients′ cognitive function. Results ·A total of 8 male patients with ACALD were included in this study. Ageat onset ranged from 23 to 40 years old with an average age of (32.75±5.80) years, and the disease duration ranged from 4 to 59 months. Patients′ first symptoms were highly variable. Three patients showed memory loss and cognitive dysfunction, two showed irritability and personality change, one showed mental and behavioral abnormalities, one showed dysarthria and ataxia, and one showed persistent dizziness, occipital numbness and insomnia. All the patients had multiple white matter demyelination lesions, and white matter demyelination in parietal occipital lobe and posterior corpus callosum was the most common. Enhancement MRI showed patchy Gd-enhancement of partial lesions in three cases. In two patients, magnetic resonance spectroscopy showed that choline (Cho) peak increased and N-acetyl-aspartate (NAA) peak decreased. Serum VLCFA levels of C26, C24/C22 and C26/C22 were elevated in six patients who underwent serum VLCFA examination. Seven patients underwent adrenal cortical function testing, of which six experienced adrenal cortical dysfunction. Six patients were cognitively impaired, four of whom had decreased MMSE and MoCA scores, and two of whom were unable to cooperate with the assessment due to severe cognitive impairment. Eight different ABCD1 gene mutations were identified, among which c.1750delC (p.H584Tfs*52) and c.160_170delACGCAGGAGGC (p.T54Lfs*137) were novel mutations. Conclusion ·The initial symptoms of ACALD vary, among which memory loss and cognitive dysfunction are the most common. White matter demyelination lesions in the parietal and corpus callosum pressure are the most common, and imaging abnormalities precede neurological symptoms. The clinical features of the disease are hair thinning and skin pigmentation, and the biochemical features are elevated serum VLCFA and adrenal insufficiency. Missense mutations are more common in the ABCD1 gene, and exons 1 and 6 are the hot mutant exons in Chinese.

Key words: adrenoleukodystrophy(ACALD), genetic diseases, X-linked, cognition disorders, demyelinating diseases, adrenal insufficiency

CLC Number:

R742.3

LIU Taotao, LIU Xiaoli, WU Jingying, NI Ruilong, ZHANG Mengyuan, JI Duxin, ZHANG Mei, CAO Li. Clinical and genetic characteristics of adult cerebral adrenoleukodystrophy[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(5): 592-599.

Figures/Tables 4

TrendMD

References 47

1	MOSSER J, LUTZ Y, ELISABETH STOECKEL M, et al. The gene responsible for adrenoleukodystrophy encodes a peroxisomal membrane protein[J]. Hum Mol Genet, 1994, 3(2): 265-271.
2	JANGOUK P, ZACKOWSKI K M, NAIDU S, et al. Adrenoleukodystrophy in female heterozygotes: underrecognized and undertreated[J]. Mol Genet Metab, 2012, 105(2): 180-185.
3	平莉莉, 包新华, 王爱花, 等. X连锁肾上腺脑白质营养不良89例临床特征及基因型/表型关系[J]. 中华儿科杂志, 2007, 45(3): 203-207.
	PING L L, BAO X H, WANG A H, et al. Clinical features and genotype-phenotype studies of 89 Chinese patients with X-linked adrenoleukodystrophy[J]. Chinese Journal of Pediatrics, 2007, 45(3):203-207.
4	LI J, WANG H, HE Z, et al. Clinical, neuroimaging, biochemical, and genetic features in six Chinese patients with Adrenomyeloneuropathy[J]. BMC Neurol, 2019, 19(1): 227.
5	WATKINS P A, GOULD S J, SMITH M A, et al. Altered expression of ALDP in X-linked adrenoleukodystrophy[J]. Am J Hum Genet, 1995, 57(2): 292-301.
6	MATTESON J, SCIORTINO S, FEUCHTBAUM L, et al. Adrenoleukodystrophy newborn screening in California since 2016: programmatic outcomes and follow-up[J]. Int J Neonatal Screen, 2021, 7(2): 22.
7	LIBERATO A P, MALLACK E J, AZIZ-BOSE R, et al. MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy[J]. Neurology, 2019, 92(15): e1698-e1708.
8	GUIMARÃES C P, LEMOS M, SÁ-MIRANDA C, et al. Molecular characterization of 21 X-ALD Portuguese families: identification of eight novel mutations in the ABCD1 gene[J]. Mol Genet Metab, 2002, 76(1): 62-67.
9	ASHEUER M, BIECHE I, LAURENDEAU I, et al. Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy[J]. Hum Mol Genet, 2005, 14(10): 1293-1303.
10	CHEN Y H, LEE Y C, TSAI Y S, et al. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia[J]. PLoS One, 2017, 12(5): e0177296.
11	OLGAC A, KASAPKARA Ç S, DERINKUYU B, et al. Retrospective evaluation of patients with X-linked adrenoleukodystrophy with a wide range of clinical presentations: a single center experience[J]. J Pediatr Endocrinol Metab, 2021, 34(9): 1169-1179.
12	GÄRTNER J, BRAUN A, HOLZINGER A, et al. Clinical and genetic aspects of X-linked adrenoleukodystrophy[J]. Neuropediatrics, 1998, 29(1): 3-13.
13	OZDEMIR KUTBAY N, OZBEK M N, SARER YUREKLI B, et al. A distinct clinical phenotype in two siblings with X-linked adrenoleukodystrophy[J]. Neuro Endocrinol Lett, 2019, 40(1): 36-40.
14	MAIER E M, KAMMERER S, MUNTAU A C, et al. Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation[J]. Ann Neurol, 2002, 52(5): 683-688.
15	HSU S L, CHEN Y H, CHOU C T, et al. Investigating ABCD1 mutations in a Taiwanese cohort with hereditary spastic paraplegia phenotype[J]. Parkinsonism Relat Disord, 2021, 92: 7-12.
16	CHU S S, YE J, ZHANG H W, et al. Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy[J]. World J Pediatr, 2015, 11(4): 366-373.
17	CAPALBO D, MORACAS C, CAPPA M, et al. Primary adrenal insufficiency in childhood: data from a large nationwide cohort[J]. J Clin Endocrinol Metab, 2021, 106(3): 762-773.
18	SALSANO E, TABANO S, SIRCHIA S M, et al. Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms[J]. Orphanet J Rare Dis, 2012, 7: 10.
19	KEMP S, HUFFNAGEL I C, LINTHORST G E, et al. Adrenoleukodystrophy-neuroendocrine pathogenesis and redefinition of natural history[J]. Nat Rev Endocrinol, 2016, 12(10): 606-615.
20	JIA M R, WU W Z, LI C M, et al. Clinical characteristics and phenotype distribution in 10 Chinese patients with X-linked adrenoleukodystrophy[J]. Exp Ther Med, 2019, 18(3): 1945-1952.
21	罗晓妹, 刘丽英, 邹丽萍, 等. X-连锁肾上腺脑白质营养不良表型及基因型研究[J]. 中华神经科杂志, 2021, 54(7): 686-692.
	LUO X M, LIU L Y, ZOU L P, et al. Study on the phenotype and genotype of X-linked adrenoleukodystrophy[J]. Chinese Journal of Neurology, 2021, 54(7): 686-692.
22	GARSIDE S, ROSEBUSH P I, LEVINSON A J, et al. Late-onset adrenoleukodystrophy associated with long-standing psychiatric symptoms[J]. J Clin Psychiatry, 1999, 60(7): 460-468.
23	FURUHASHI Y, ISHIKAWA M. Adult-onset adrenoleukodystrophy heralded by auditory hallucinations and delusions[J]. Psychosomatics, 2011, 52(5): 492-493.
24	BOUQUET F, DEHAIS C, SANSON M, et al. Dramatic worsening of adult-onset X-linked adrenoleukodystrophy after head trauma[J]. Neurology, 2015, 85(22): 1991-1993.
25	BUDHRAM A, PANDEY S K. Activation of cerebral X-linked adrenoleukodystrophy after head trauma[J]. Can J Neurol Sci, 2017, 44(5): 597-598.
26	MOSER H W, MOSER A B, SMITH K D, et al. Adrenoleukodystrophy: phenotypic variability and implications for therapy[J]. J Inherit Metab Dis, 1992, 15(4): 645-664.
27	OGAKI K, KOGA S, AOKI N, et al. Adult-onset cerebello-brainstem dominant form of X-linked adrenoleukodystrophy presenting as multiple system atrophy: case report and literature review[J]. Neuropathology, 2016, 36(1): 64-76.
28	MATSUKAWA T, YAMAMOTO T, HONDA A, et al. Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy[J]. Brain Commun, 2020, 2(1): fcz048.
29	YAN F, WANG W, YING H, et al. S149R, a novel mutation in the ABCD1 gene causing X-linked adrenoleukodystrophy[J]. Oncotarget, 2017, 8(50): 87529-87538.
30	梁凯, 梁建华, 马红玲. 以小脑脑干为突出表现的成人型X-连锁肾上腺脑白质营养不良症一例[J]. 中华神经科杂志, 2018, 51(9):738-742.
	LIANG K, LIANG J H, MA H L. One case of adult X-linked adrenoleukodystrophy characterized by cerebellar symptoms.[J]. Chinese Journal of Neurology, 2018, 51(9): 738-742.
31	LI J Y, HSU C C, TSAI C R. Spinocerebellar variant of adrenoleukodystrophy with a novel ABCD1 gene mutation[J]. J Neurol Sci, 2010, 290(1/2): 163-165.
32	王梦文, 伍楚君, 张在强. 成年肾上腺脑白质营养不良患者临床及遗传分析[J]. 罕见病研究, 2022(2): 130-136.
	WANG M W, WU C J, ZHANG Z Q. Clinical and genetic analysis of adrenoleukodystrophy in adults[J]. Journal of Rare Diseases, 2022(2): 130-136.
33	SCHIFFMANN R, VAN DER KNAAP M S. Invited article: an MRI-based approach to the diagnosis of white matter disorders[J]. Neurology, 2009, 72(8): 750-759.
34	BUERMANS N J M L, VAN DEN BOSCH S J G, HUFFNAGEL I C, et al. Overall intact cognitive function in male X-linked adrenoleukodystrophy adults with normal MRI[J]. Orphanet J Rare Dis, 2019, 14(1): 217.
35	KIM J H, KIM H J. Childhood X-linked adrenoleukodystrophy: clinical-pathologic overview and MR imaging manifestations at initial evaluation and follow-up[J]. Radiographics, 2005, 25(3): 619-631.
36	VAN DE STADT S I W, SCHRANTEE A, HUFFNAGEL I C, et al. Magnetic resonance spectroscopy as marker for neurodegeneration in X-linked adrenoleukodystrophy[J]. Neuroimage Clin, 2021, 32: 102793.
37	STRADOMSKA T J, BACHAŃSKI M, PAWŁOWSKA J, et al. The impact of a ketogenic diet and liver dysfunction on serum very long-chain fatty acids levels[J]. Lipids, 2013, 48(4): 405-409.
38	YU J, CHEN T, GUO X, et al. The role of oxidative stress and inflammation in X-link adrenoleukodystrophy[J]. Front Nutr, 2022, 9: 864358.
39	HUFFNAGEL I C, LAHEJI F K, AZIZ-BOSE R, et al. The natural history of adrenal insufficiency in X-linked adrenoleukodystrophy: an international collaboration[J]. J Clin Endocrinol Metab, 2019, 104(1): 118-126.
40	DONG B, LV W, XU L, et al. Identification of two novel mutations of ABCD1 gene in pedigrees with X-linked adrenoleukodystrophy and review of the literature[J]. Int J Endocrinol, 2022, 2022: 5479781.
41	VAN ROERMUND C W, VISSER W F, IJLST L, et al. The human peroxisomal ABC half transporter ALDP functions as a homodimer and accepts acyl-CoA esters[J]. FASEB J, 2008, 22(12): 4201-4208.
42	PEREIRA FDOS S, MATTE U, HABEKOST C T, et al. Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy[J]. PLoS One, 2012, 7(3): e34195.
43	SHIMOZAWA N, HONDA A, KAJIWARA N, et al. X-linked adrenoleukodystrophy: diagnostic and follow-up system in Japan[J]. J Hum Genet, 2011, 56(2): 106-109.
44	NIU Y F, NI W, WU Z Y. ABCD1 mutations and phenotype distribution in Chinese patients with X-linked adrenoleukodystrophy [J]. Gene, 2013, 522(1): 117-120.
45	KORENKE G C, FUCHS S, KRASEMANN E, et al. Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype[J]. Ann Neurol, 1996, 40(2): 254-257.
46	KÜHL J S, SUAREZ F, GILLETT G T, et al. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy[J]. Brain, 2017, 140(4): 953-966.
47	WALDHüTER N, KöHLER W, HEMMATI PG, et al. Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X-linked adrenoleukodystrophy [J]. J Inherit Metab Dis, 2019, 42(2):313-324.

Items	P1	P2	P3	P4	P5	P6	P7	P8
Age of onset/Years	27	23	40	37	34	30	33	38
Disease duration/Months	12	4	59	31	5	4	8	16
First symptoms	Memory and cognitive decline	Dizziness with occipital numbness, insomnia	Mental and behavioral abnormalities	Dysarthria and ataxia	Bad temper, personality change	Memory and cognitive decline	Memory decline	Bad temper, personality change
MMSE/MoCA	21/17	ND	NA	ND	21/16	14/9	23/16	NA
VLCFA
C26(≤1.30 nmol/mL)	5.71	ND	3.94	ND	3.77	3.03	3.28	3.38
C24/C22(≤1.39)	1.89	ND	1.50	ND	1.46	1.77	1.76	1.95
C26/C22(≤0.023)	0.132	ND	0.065	ND	0.077	0.068	0.070	0.073
Adrenal insufficiency
Cortisol levels	↓	ND	↓	↓	N	N	↓	↓
ACTH	↑	ND	↑	↑	N	↑	↑	↑
Protein content in cerebrospinal fluid	1.00 g/L	N	0.47 g/L	0.47 g/L	N	ND	ND	ND
Mutation information
Exon	8	10	6	7	1	1	6	3
Nucleotide mutations	c.1817C>T	c.2135G>A	c.1559T>C	c.1750delC	c.323C>T	c.160_170delACGCAGGAGGC	c.1534G>A	c.1202G>A
Amino acid variants	S606L	R712H	L520P	H584Tfs*52	S108L	T54Lfs*137	G512S	R401Q
ACMG	Pathogenic	VUS	VUS	Pathogenic	Pathogenic	Pathogenic	Pathogenic	Pathogenic
Reported phenotypes	CCALD^[3],AMN^[4],AO^[5]	NB^[6]	NB^[6]	‒	CCALD^[7],AO^[8], AMN^[9], Olivo-ponto-cerebellar^[10]	‒	CCALD^[11],AMN^[12],ACALD^[11],AO^[13],Female^[14]	CCALD^[7],AMN^[15],ACALD^[16],NB^[6]AO^[17], Female carrier^[18]

Items	P1	P2	P3	P4	P5	P6	P7	P8
Age of onset/Years	27	23	40	37	34	30	33	38
Disease duration/Months	12	4	59	31	5	4	8	16
First symptoms	Memory and cognitive decline	Dizziness with occipital numbness, insomnia	Mental and behavioral abnormalities	Dysarthria and ataxia	Bad temper, personality change	Memory and cognitive decline	Memory decline	Bad temper, personality change
MMSE/MoCA	21/17	ND	NA	ND	21/16	14/9	23/16	NA
VLCFA
C26(≤1.30 nmol/mL)	5.71	ND	3.94	ND	3.77	3.03	3.28	3.38
C24/C22(≤1.39)	1.89	ND	1.50	ND	1.46	1.77	1.76	1.95
C26/C22(≤0.023)	0.132	ND	0.065	ND	0.077	0.068	0.070	0.073
Adrenal insufficiency
Cortisol levels	↓	ND	↓	↓	N	N	↓	↓
ACTH	↑	ND	↑	↑	N	↑	↑	↑
Protein content in cerebrospinal fluid	1.00 g/L	N	0.47 g/L	0.47 g/L	N	ND	ND	ND
Mutation information
Exon	8	10	6	7	1	1	6	3
Nucleotide mutations	c.1817C>T	c.2135G>A	c.1559T>C	c.1750delC	c.323C>T	c.160_170delACGCAGGAGGC	c.1534G>A	c.1202G>A
Amino acid variants	S606L	R712H	L520P	H584Tfs*52	S108L	T54Lfs*137	G512S	R401Q
ACMG	Pathogenic	VUS	VUS	Pathogenic	Pathogenic	Pathogenic	Pathogenic	Pathogenic
Reported phenotypes	CCALD^[3],AMN^[4],AO^[5]	NB^[6]	NB^[6]	‒	CCALD^[7],AO^[8], AMN^[9], Olivo-ponto-cerebellar^[10]	‒	CCALD^[11],AMN^[12],ACALD^[11],AO^[13],Female^[14]	CCALD^[7],AMN^[15],ACALD^[16],NB^[6]AO^[17], Female carrier^[18]

[1]	LI Yahui, WANG Yiwen, XIE Lijuan. A case of neonatal MIRAGE syndrome caused by novel mutation of SAMD9 gene [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(11): 1644-1648.
[2]	Tong TONG, Xing QIN, Fei XIE, Ying-ying JIANG, Jian-bo SHI, Jian-jun ZHANG. USP47 induces cisplatin resistance in head and neck squamous cell carcinoma by up-regulation of anti-apoptotic proteins [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(4): 434-441.
[3]	CHEN Jun-jue, TIAN Lin-lu, WEI Yan, KANG Xiao-li. Clinical characteristics of X-linked infantile nystagmus in a Chinese family [J]. , 2018, 38(11): 1355-.
[4]	GU Ben-hong, ZHU Xiao-bin, ZHU Zi-jue, TIAN Ru-hui, LI Peng, ZHI Er-lei, YAO Chen-cheng, WANG Hong, CHEN Hui-xing, WAN Zhong, HUANG Yuhua, HE Zu-ping, LI Zheng . Novel EDA gene splicing mutation in a X-linked hypohidrotic ectodermal dysplasia family [J]. , 2017, 37(3): 288-.
[5]	CHANG Guo-ying, DONG Zhi-ya, WANG Wei, et al. Analysis of clinical manifestations and gene mutations in children with primary adrenal insufficiency [J]. , 2011, 31(6): 782-.
[6]	ZHU Li-ming, TU Shui-ping, DAI Qiang, et al. Study on X-linked inhibitor of apoptosis associated factor-1 suppressing xenograft growth in nude mice with hepatocellular carcinoma [J]. , 2009, 29(12): 1419-.