Quantitative Proton Magnetic Resonance Spectroscopy of Children with Adrenoleukodystrophy Before and After Hematopoietic Stem Cell Transplantation

Abstract

About 35-40 % of boys with X-linked adrenoleukodystrophy (ALD) develop a rapidly progressive cerebral form which leads to severe neurologic disability and death within 3-5 years after onset of clinical symptoms. Because previous proton magnetic resonance spectroscopy (MRS) studies of ALD identified metabolite patterns characteristic of demyelination, gliosis, and neuroaxonal loss, this work tested the hypothesis that MRS--apart from indicating disease progression--provides criteria for the outcome after hematopoietic stem cell transplantation (HSCT) which has been promising at an early stage of the active disease. Follow-up quantitative proton MRS was performed in frontal and occipital white matter of ALD patients (n = 12) before and up to 5 years after HSCT. The observed metabolite alterations were retrospectively correlated with the clinical outcome representing either a stable condition (n = 5), a further deterioration (n = 5), or death (n = 2). While disease progression of patients before HSCT was mainly characterized by a further increase of elevated choline-containing compounds (Cho) as an indicator of active demyelination, a positive outcome after HSCT was correlated with high N-acetylaspartate (tNAA) levels in affected white matter before HSCT yielding positive and negative predictive values for tNAA of 80 %. Although to be confirmed in a larger cohort of patients, the present findings suggest the preservation of neuroaxonal integrity as a prerequisite for an arrested course. Conversely, the combination of increased Cho with markedly reduced tNAA before HSCT apparently reflects a degree of tissue degeneration which precludes a successful therapeutic intervention.

Modeling and rescue of defective blood–brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients

“…ccALD, the most rapidly progressing phenotype, occurs in boys ages 2–12 and is characterized by sudden inflammatory demyelination in the brain and death within a few years [ 13 , 14 ]. ccALD affects about 40% of males with an ABCD1 mutation [ 15 , 16 ]. MRI observation of gadolinium enhancement in the brain remains the only method to detect this progression [ 17 – 21 ].…”

Economic impact of screening for X-linked Adrenoleukodystrophy within a newborn blood spot screening programme

“…The review identified 26 studies on either the natural history or outcome following transplantation [ 6 , 9 – 11 , 35 , 40 – 62 ]. For patients with CCALD, there is no direct comparative evidence on survival with and without HSCT.…”

“…For patients with CCALD, there is no direct comparative evidence on survival with and without HSCT. Survival and time to progression without transplantation were estimated from the Mahmood et al study [ 11 ], selected from the 26 studies [ 6 , 9 – 11 , 35 , 40 – 62 ] as it presented data on a large cohort, 283 patients, with follow-up of up to 30 years. The model assumed that CCALD patients start off with mild to moderate disease before progressing to severe CCALD indicated by developing two or more neurological deficits with a mean time to progression of 1.6 years.…”

“…For those undergoing HSCT the Peters et al [ 10 ] study was selected from the 26 studies identified [ 6 , 9 – 11 , 35 , 40 – 62 ] as it provided detailed outcomes following HSCT, including the ALD-Disability rating scale (ALD-DRS) and provided survival and outcomes data based on the severity of the disease at transplant. The model assumed that only patients with a Loes score of < 10 undergo HSCT and that those who survive and have a good outcome following HSCT have a normal life expectancy as no deaths occurred post 1.5 years for those undergoing early HSCT [ 9 , 10 ].…”

Therapy for X-linked adrenoleukodystrophy

“…The rationale of the HCT relies on the hypothesis that fully functional, donated bone marrow cells can cross the blood brain barrier of the recipient and exert beneficial effects on the mechanisms leading to CNS demyelination. The first report about a favorable effect of HCT in a CCALD patient was published in 1990 [95] and several subsequent reports in small patients series showed positive results [96][97][98][99][100]. Follow-up studies demonstrated that the beneficial effect is maintained for 5-10 years [101,102].…”