五例X-连锁肾上腺脑白质营养不良的临床分析
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摘要
目的分析X-连锁肾上腺脑白质营养不良(X-ALD)的临床表现、实验室检查和神经影像学特点。方法回顾性分析5例临床确诊的X-ALD患者临床表现、血浆极长链脂肪酸(VLCFA)水平、肾上腺功能、ABCD1基因突变、影像特征、治疗和随访的结果。结果 5例X-ALD患者均为男童,发病年龄分别为3岁、5岁、6岁、13岁、14岁,其中儿童脑型(childhood cerebral ALD,CCALD;<10岁)3例,青春期脑型(adolescent cerebral ALD,AdolCALD;10～21岁)2例,病程分别为3.0、2.0、1.0、1.0、0.5年。5例均有不同程度的智力障碍和肢体活动障碍,其中1例伴听力下降,1例伴视力下降,1例伴抽搐发作,1例伴发育迟缓、皮肤色素沉着。3例检测VLCFA水平,血浆二十六酸(C26:0)水平(分别为1.1、1.4、1.5μg/mL)、二十四酸(C24:0)与二十二酸(C22:0)的比值(C24:0/C22:0;分别为1.52、1.55、2.10)、C26:0与C22:0的比值(C26:0/C22:0;分别为0.1、0.07、0.09)均增高。3例肾上腺功能减退,表现为血皮质醇(8Am)降低(分别为122、52、130 nmol/L)、ACTH (8Am)升高(分别为112、121、72 ng/L)。3例显示基因突变,分别为c.1780+2T>G、c.871G>A(p.Glu291Lys)、c.1849C>T(p.Arg617Cys),均支持X-ALD诊断。5例患者头颅MRI均显示顶枕叶白质区对称性蝶翼状长T1及长T2信号,2例增强扫描示病灶周边环状强化。3例给予氢化可的松激素替代治疗,1例给予抗癫痫治疗,5例均行肢体功能康复训练,疗效不佳。本组患者出院后均随访1～6年,1例患儿死亡,其余4例病情仍在加重。结论本组X-ALD患者均为男性儿童和青春期脑型。临床特征为进行性听力和视力下降、肢体活动障碍和癫痫发作,均有智力减退。血浆VLCFA水平升高和MRI特征改变是诊断的重要依据,基因检测可确诊。
Objective To analyze the clinical characteristics, laboratory examination results and neuroimaging manifestations of X-linked adrenoleukodystrophy(X-ALD). Methods The clinical manifestations, level of plasma very long chain fatty acid(VLCFA), adrenal function tests ABCD1 gene mutation analysis, imaging features, treatment and follow-up of 5 patients with X-ALD admitted to our hospital were retrospectively analyzed.Results All the patients were boys. The ages of onset were 3,5,6,13,14 years old.There were 3 Childhood cases,and 2 adolescent 2 cases.The disease durations were 3, 2, 1, 1 and 0.5 year. 5 patiens had different degrees of intelligent impairment and limb movement disorder associated with auditory disorder, visual disorder, seizures, developmental retardation and skin pigmentation. The level of VLCFA in 3 patients were increased,C26:0 1.1,1.4,1.5 μg/mL; C24:0/C22:0 1.52, 1.55, 2.10; C26:0/C22:0 0.1, 0.07, 0.09. Adrenal insufficiency were found in 3 patints, characterized by blood cortisol(8 Am) decrease and ACTH(8 Am)increase. 3 cases showed genetic mutations, namely c.1780 2 T>G, c.871 G>A(p.Glu291 Lys), c.1849 C>T(p.Arg617 Cys), supporting the diagnosis of X-ALD. cranial MRI of 5 patients showed the characteristic pattern of symmetrical long Tl and long T2 signal in the parieto-occipital region, even involving the splenium of the corpus callosum, with symmetric linear enhancement in postcontrast T1-weighted imaginge in 2 patients. 3 patients were given cortisol replacement therapy. 1 patient was given antiepileptic therapy. 5 patients underwent limb function rehabilitation training. 1 patient died and 4 patients' symptoms aggravated during the 1-6 years followed-up.Conclusions This group of X-ALD patients were CCALD and AdolCALD. Clinical features included progressive auditory and vision impairment, physical activity disorders, and seizures; all the patients had mental retardation. The elevated level of plasma VLCFA and the characteristic changes of MRI were important basis for diagnosis, and gene detection could help to confirm the diagnosis.
Objective To analyze the clinical characteristics, laboratory examination results and neuroimaging manifestations of X-linked adrenoleukodystrophy(X-ALD). Methods The clinical manifestations, level of plasma very long chain fatty acid(VLCFA), adrenal function tests ABCD1 gene mutation analysis, imaging features, treatment and follow-up of 5 patients with X-ALD admitted to our hospital were retrospectively analyzed.Results All the patients were boys. The ages of onset were 3,5,6,13,14 years old.There were 3 Childhood cases,and 2 adolescent 2 cases.The disease durations were 3, 2, 1, 1 and 0.5 year. 5 patiens had different degrees of intelligent impairment and limb movement disorder associated with auditory disorder, visual disorder, seizures, developmental retardation and skin pigmentation. The level of VLCFA in 3 patients were increased,C26:0 1.1,1.4,1.5 μg/mL; C24:0/C22:0 1.52, 1.55, 2.10; C26:0/C22:0 0.1, 0.07, 0.09. Adrenal insufficiency were found in 3 patints, characterized by blood cortisol(8 Am) decrease and ACTH(8 Am)increase. 3 cases showed genetic mutations, namely c.1780 2 T>G, c.871 G>A(p.Glu291 Lys), c.1849 C>T(p.Arg617 Cys), supporting the diagnosis of X-ALD. cranial MRI of 5 patients showed the characteristic pattern of symmetrical long Tl and long T2 signal in the parieto-occipital region, even involving the splenium of the corpus callosum, with symmetric linear enhancement in postcontrast T1-weighted imaginge in 2 patients. 3 patients were given cortisol replacement therapy. 1 patient was given antiepileptic therapy. 5 patients underwent limb function rehabilitation training. 1 patient died and 4 patients' symptoms aggravated during the 1-6 years followed-up.Conclusions This group of X-ALD patients were CCALD and AdolCALD. Clinical features included progressive auditory and vision impairment, physical activity disorders, and seizures; all the patients had mental retardation. The elevated level of plasma VLCFA and the characteristic changes of MRI were important basis for diagnosis, and gene detection could help to confirm the diagnosis.
引文
[1] Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy:new approaches to a neurodegenerative disease[J]. JAMA, 2005, 294(24) :3131-3134.
[2] Cappa M, Bizzarri C, Vollono C,et al. Adrenoleukodystrophy[J]. Endocr Dev,2011,20:149-160.
[3] Wiesinger C, Eichler FS, Berger J. The genetic landscape of X-linked adrenoleukodystrophy:inheritance, mutations, modifier genes, and diagnosis[J]. Appl Clin Genet, 2015,8:109-121.
[4] Engelen M, Kemp S, Poll-The BT. X-linked adrenoleukodystrophy:pathogenesis and treatment[J]. Curr Neurol Neurosci Rep, 2014, 14(10):486-493.
[5] López-Erauskin J, Galino J, Ruiz M, et al. Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy[J]. Hum Mol Gene, 2013, 22(16):3296-3305.
[6] Chluter A, Espinosa L, Fourcade S, et a1. Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy[J].Hum Mol Genet,2012,21(5):1062-1077.
[7] Engelen M, Kemp S, Visser M,et a1.X-linked adrenoleukodystrophy (X-ALD):clinical presentation and guidelines for diagnosis, follow-up and management[J]. Orphanet J Rare Dis, 2012, 7:51-64.
[8] Burtman E, Regelmann MO. Endocrine Dysfunction in X-Linked Adrenoleuko-dystrophy[J]. Endocrinol Metab Clin North Am, 2016, 45(2) :295-309.
[9] Karimzadeh P. Approach to Neurometabolic Diseases from a Pediatric Neurological Point of View[J]. Iran J Child Neurol, 2015, 9(1):1-16.
[10] Miller WP, Mantovani LF, Muzic J, et al. Intensity of MRI gadolinium enhancement in cerebral adrenoleukodystrophy:a biomarker for inflammation and predictor of outcome following transplantation in higher risk patients[J]. AJNR Am J Neuroradiol, 2016, 37:367-372.
[11] Castellano A, Papinutto N, Cadioli M, et al. Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy:in vivo assessment of structural changes[J]. Brain, 2016, 139(Pt 6):1735-1746.
[12] http://www.x-ald.nl,Last modified 2018-02-21.
[13] 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.
[14] Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, et al. A two-year trial of oleic and erucic acids ("Lorenzo's oil") as treatment for adrenomyeloneuropathy[J]. N Engl J Med,1993, 329:745.
[15] Engelen M, Ofman R, Dijkgraaf MG, et al. Lovastatin in X-linked adrenoleukodystrophy[J]. N Engl J Med, 2010, 362:276-277.
[16] Mahmood A, Raymond GV, Dubey P, et al. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy:a comparison study[J]. Lancet Neurol, 2007, 6(8):687-692.
[17] Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy:the largest single-institution cohort report[J]. Blood, 2011, 118(7):1971-1978.
[18] Kühl JS, Suarez F, Gillett GT, et al. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy[J].Brain, 2017, 140(4):953-966.
[19] Eichler F, Duncan C, Musolino PL, et al. Hematopoietic Stem-Cell Gene therapy for Cerebral Adrenoleukodystrophy[J]. N Engl J Med,2017,377(17):1630-1638.
[20] Kemp S, Huffnagel IC, Linthorst GE, et al. Adrenoleukodystrophy neuroendocrine pathogenesis and redefinition of natural history[J]. Nat Rev Endocrinol 2016; 12(10):606-615.
[2] Cappa M, Bizzarri C, Vollono C,et al. Adrenoleukodystrophy[J]. Endocr Dev,2011,20:149-160.
[3] Wiesinger C, Eichler FS, Berger J. The genetic landscape of X-linked adrenoleukodystrophy:inheritance, mutations, modifier genes, and diagnosis[J]. Appl Clin Genet, 2015,8:109-121.
[4] Engelen M, Kemp S, Poll-The BT. X-linked adrenoleukodystrophy:pathogenesis and treatment[J]. Curr Neurol Neurosci Rep, 2014, 14(10):486-493.
[5] López-Erauskin J, Galino J, Ruiz M, et al. Impaired mitochondrial oxidative phosphorylation in the peroxisomal disease X-linked adrenoleukodystrophy[J]. Hum Mol Gene, 2013, 22(16):3296-3305.
[6] Chluter A, Espinosa L, Fourcade S, et a1. Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy[J].Hum Mol Genet,2012,21(5):1062-1077.
[7] Engelen M, Kemp S, Visser M,et a1.X-linked adrenoleukodystrophy (X-ALD):clinical presentation and guidelines for diagnosis, follow-up and management[J]. Orphanet J Rare Dis, 2012, 7:51-64.
[8] Burtman E, Regelmann MO. Endocrine Dysfunction in X-Linked Adrenoleuko-dystrophy[J]. Endocrinol Metab Clin North Am, 2016, 45(2) :295-309.
[9] Karimzadeh P. Approach to Neurometabolic Diseases from a Pediatric Neurological Point of View[J]. Iran J Child Neurol, 2015, 9(1):1-16.
[10] Miller WP, Mantovani LF, Muzic J, et al. Intensity of MRI gadolinium enhancement in cerebral adrenoleukodystrophy:a biomarker for inflammation and predictor of outcome following transplantation in higher risk patients[J]. AJNR Am J Neuroradiol, 2016, 37:367-372.
[11] Castellano A, Papinutto N, Cadioli M, et al. Quantitative MRI of the spinal cord and brain in adrenomyeloneuropathy:in vivo assessment of structural changes[J]. Brain, 2016, 139(Pt 6):1735-1746.
[12] http://www.x-ald.nl,Last modified 2018-02-21.
[13] 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.
[14] Aubourg P, Adamsbaum C, Lavallard-Rousseau MC, et al. A two-year trial of oleic and erucic acids ("Lorenzo's oil") as treatment for adrenomyeloneuropathy[J]. N Engl J Med,1993, 329:745.
[15] Engelen M, Ofman R, Dijkgraaf MG, et al. Lovastatin in X-linked adrenoleukodystrophy[J]. N Engl J Med, 2010, 362:276-277.
[16] Mahmood A, Raymond GV, Dubey P, et al. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy:a comparison study[J]. Lancet Neurol, 2007, 6(8):687-692.
[17] Miller WP, Rothman SM, Nascene D, et al. Outcomes after allogeneic hematopoietic cell transplantation for childhood cerebral adrenoleukodystrophy:the largest single-institution cohort report[J]. Blood, 2011, 118(7):1971-1978.
[18] Kühl JS, Suarez F, Gillett GT, et al. Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy[J].Brain, 2017, 140(4):953-966.
[19] Eichler F, Duncan C, Musolino PL, et al. Hematopoietic Stem-Cell Gene therapy for Cerebral Adrenoleukodystrophy[J]. N Engl J Med,2017,377(17):1630-1638.
[20] Kemp S, Huffnagel IC, Linthorst GE, et al. Adrenoleukodystrophy neuroendocrine pathogenesis and redefinition of natural history[J]. Nat Rev Endocrinol 2016; 12(10):606-615.