Potential Risks to Stable Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Children With Cerebral X-linked Adrenoleukodystrophy

Kühl, Jörn‐Sven; Kupper, Jana; Baqué, Hermann; Ebell, Wolfram; Gärtner, Jutta; Korenke, Christoph; Spors, Birgit; Steffen, Ingo G.; Strauß, Gabriele; Voigt, Sebastian; Weschke, Bernhard; Weddige, Almuth; Köhler, Wolfgang; Steinfeld, Robert

doi:10.1001/jamanetworkopen.2018.0769

Cited by 37 publications

(38 citation statements)

References 31 publications

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“…In the present single center analysis, all patients received grafts from matched donors after a busulfan‐based conditioning with reduced cyclophosphamide . Busulfan/cyclophosphamide is a well‐established regimen for boys with CCALD . Busulfan allows for replacement of defective microglia by bone marrow‐derived donor macrophages .…”

Section: Discussionmentioning

confidence: 99%

“…24 Busulfan/cyclophosphamide is a wellestablished regimen for boys with CCALD. [11][12][13] Busulfan allows for replacement of defective microglia by bone marrow-derived donor macrophages. 25 In addition, serotherapy with ATG was given to limit GVHD.…”

Section: Discussionmentioning

confidence: 99%

“…Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective long-term treatment method in boys with CCALD. [10][11][12][13][14] The replacement of defective microglia by long-lived bone marrow-derived donor macrophages in the brain is presumably the therapeutic principle of HSCT. [15][16][17] In contrast to children, studies in adult men with cerebral disease are still limited.…”

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confidence: 99%

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Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Waldhüter

Köhler

Hemmati

et al. 2019

J of Inher Metab Disea

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The adult cerebral form of X‐linked adrenoleukodystrophy (ACALD), an acute inflammatory demyelinating disease, results in a rapidly progressive neurodegeneration, typically leading to severe disability or death within a few years after onset. We have treated 15 men who had developed ACALD with allogeneic hematopoietic stem cell transplantation (HSCT) from matched donors after myeloablative conditioning with busulfan and cyclophosphamide. All patients engrafted and 11 survived (estimated survival 73 ± 11%), 8 with stable cognition and 7 of them with stable motor function (estimated event‐free survival 36 ± 17%). Death after transplantation occurred within the first year after HSCT and was caused either primarily by infection (N = 3) or due to disease progression triggered by infection (N = 1). Patients with minor myelopathic symptoms (N = 4) or with no or mild cerebral symptoms pre‐transplant (N = 7) had an excellent outcome. In contrast, no patient with major neurological symptoms associated with an extensive involvement of pyramidal tract fibres in the internal capsule (N = 5) survived without cognitive deterioration. Notably, early leukocyte recovery was associated with dismal outcome for yet unknown reasons. All 10 tested survivors showed a reduction of plasma hexacosanoic acid (C26:0) in the absence of Lorenzo's oil. Over time, the event‐free survival could be improved from 2 out of 8 patients (25%) before 2013 to 5 out of 7 patients (71%) thereafter. Therefore, allogeneic HSCT appears to be a suitable treatment option for carefully selected ACALD patients when transplanted from matched donors after myeloablative, busulfan‐based conditioning.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Waldhüter

Köhler

Hemmati

et al. 2019

J of Inher Metab Disea

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“…Another e ciency approach is hematopoietic stem cell transplantation (HSCT), especially in the early stage of the disease [23]. Transplantation with autologous bone marrow transfected in vitro with ABCD1gene modi cation has been performed [24][25]. Bone marrow transplant has been reported in CCALD therapy, most of the patients achieved improved prognosis.…”

Section: Discussionmentioning

confidence: 99%

Identification of two novel mutations of ABCD1 gene in pedigrees with X‐linked adrenoleukodystrophy

Dong¹,

Lv²,

Xu³

et al. 2020

Preprint

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Background: X-linked adrenoleukodysrophy (ALD) is an inherited peroxisomal metabolism disorder, results from the loss-of-function mutation of ATP-binding cassette protein subfamily D1 (ABCD1) gene. The dysfunction of ALD protein, a peroxisomal ATP-binding cassette transporter, results in the excessive saturated very long chain fatty acids (VLCFAs) accumulation in organs including brain, spine and adrenal cortex. X-ALD is characterized as the childhood, adolescent, adult cerebral ALD, adrenomyeloneuropathy (AMN), adrenal insufficiency, and asymptomatic phenotypes, exhibiting a high variety of clinical neurological manifestations with or without adrenocortical insufficiency. Results: In this study, we reported two cases of X-ALD, which were firstly diagnosed as adrenal insufficiency (Addison’s disease) and treated with adrenocortical supplement. However, both of the cases progressed as neurological symptoms and signs after decades. Elevated VLCFAs level, brain MRI scan and genetic analysis confirmed final diagnosis. In addition, we identified two novel mutations of ABCD1 gene, c.874_876delGAG (p.Glu292del) and c.96_97delCT (p.Tyr33Profs*161) in exon 1 of ABCD1 gene. Sanger sequencing confirmed that the proband’s mother of the first case was heterozygous carrying the same variant. Adrenal insufficiency-only type is very rare, however, it may be the starting performance of X-ALD. Conclusions: The early warning manifestations should be noticed, and the probability of X-ALD should be considered. This report could be beneficial for the early diagnosis and genetic counseling for patients with X-ALD.

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“…Patients younger than 4 years with no or only mild gross motor defects and minimal if any MRI changes when transplanted are likely to have the most benefit and the mildest course [95]. Patients with larger cerebral lesions at the time of transplant have worse clinical outcomes [96], and nontransplanted patients are most likely to die of disease progression [95]. Gene therapy for ADL using elivaldogene tavalentivec viral vector may provide an alternative to bone marrow transplant [97].…”

Section: Adrenoleukodystrophymentioning

confidence: 99%

Psychiatric Symptoms Associated with Inborn Errors of Metabolism

Turkel

Wong

Randolph

2020

SN Compr. Clin. Med.

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Inborn errors of metabolism (IEM) are individually rare but collectively common disorders, occurring in 1:800 to 1:1000 births. There are more than 1000 known inherited disorders characterized by disruption of metabolic pathways which may present with diverse symptoms affecting any organ at any age, including with psychiatric symptoms mimicking primary psychiatric disorders. This review is intended to help psychiatrists and other physicians suspect an inborn error of metabolism in a patient presenting with psychiatric symptoms. A comprehensive literature review was undertaken, using Index Medicus and resources at the University of Southern California Norris Medical Library to identify specific information for each individual disorder described. Those inborn errors of metabolism most likely to present with psychiatric symptoms primarily impact the brain, acting either directly on biochemical pathways in the central nervous system or indirectly reflecting dysfunction in other organs. Symptoms may occur episodically under stress when metabolic demands are highest or progressively evolve over time reflecting gradual neuropsychiatric deterioration. Cognitive impairment and psychosis appear to be the most frequently reported psychiatric problems. Noting age of onset, patterns of psychiatric presentation, and associated symptoms in other organ systems can increase suspicion and facilitate diagnosis of psychiatric symptoms due to an inborn error of metabolism. Psychiatric problems can be seen with multiple inborn errors of metabolism with associated systemic dysfunction or as isolated symptoms. It is important for physicians to be aware of clues that might increase suspicion of an underlying genetic disorder, and to recognize that consultation with a medical geneticist is recommended for diagnosis and to provide the patient optimal care in either situation.

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Potential Risks to Stable Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Children With Cerebral X-linked Adrenoleukodystrophy

Cited by 37 publications

References 31 publications

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Identification of two novel mutations of ABCD1 gene in pedigrees with X‐linked adrenoleukodystrophy

Psychiatric Symptoms Associated with Inborn Errors of Metabolism

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Potential Risks to Stable Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Children With Cerebral X-linked Adrenoleukodystrophy

Cited by 37 publications

References 31 publications

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning for adult cerebral X‐linked adrenoleukodystrophy

Identification of two novel mutations of&nbsp;ABCD1&nbsp;gene in pedigrees with X‐linked adrenoleukodystrophy

Psychiatric Symptoms Associated with Inborn Errors of Metabolism

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Identification of two novel mutations of ABCD1 gene in pedigrees with X‐linked adrenoleukodystrophy