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Progression rate of myelopathy in X-linked adrenoleukodystrophy heterozygotes

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Abstract

X-linked adrenoleukodystrophy heterozygote women can present adult onset myeloneuropathy and little is known about its natural history. We aimed to describe the progression rate of the neurological impairment in the prospective follow-up of our cohort and to look for prognostic factors. The neurological scales Japanese Orthopaedic Association (JOA) and Severity Score System for Progressive Myelopathy (SSPROM) were applied at baseline in 29 symptomatic carriers and in follow-up visits. Age at onset, disease duration, X inactivation pattern, determination of the allele expressed, plasma levels of the very long chain fatty acids and of the neuron-specific enolase, and somato-sensory evoked potentials, were taken at baseline. The slope of the linear regression of both JOA and SSPROM versus disease duration since the first symptom was estimated using mixed modeling. JOA and SSPROM decreased 0.42 and 1.87 points per year, respectively (p < 0.001). None of the parameters under study influenced these rates. We estimated that the number of carriers per arm needed in a future 12 month trial with 80 % power and a 50 % reduction in disease progression would be 225 women for JOA and 750 for SSPROM. The progression rates of the studied neurological scales were small, did not depend on any modifier factor known, and reflected the characteristically slow worsening of symptoms in X-ALD heterozygotes. Better biomarkers are still necessary for future studies.

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Fig. 1

Abbreviations

ABCD1 :

Gene for the adenosine triphosphate (ATP)-binding cassette protein, subfamily D

cDNA:

Complementary DNA

HUMARA:

Human androgen-receptor locus

JOA:

Japanese Orthopaedic Association

NH:

Natural history

NSE:

Neuron-specific enolase

OMIM:

Online Mendelian Inheritance in Man

SSEP:

Somato-sensory evoked potentials

SSPROM:

Severity Score System for Progressive Myelopathy

VLCFA:

Very long chain fatty acids

X-ALD:

X-linked adrenoleukodystrophy

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Acknowledgments

We would like to thank the patients and their families for taking part in this study. We would also like to thank Raphael M. Castilhos and Deborah Blank for their technical assistance and contribution in early stages of this project; Karina C. Donis, André dos Anjos and Jonas Alex Saute for their contribution in recruiting some patients; and Ana Louzada for her technical assistance in the neurophysiological studies. This work was supported by Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA), Project 110308; and by Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCTEN), Porto Alegre, Brazil. Habekost CT and Pereira FS were funded by Instituto Nacional de Genética Médica Populacional (INAGEMP). Pereira FS, Matte U, Portela LV, Vargas CR and Jardim LB are funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Compliance with ethical standards

All the authors report no disclosures. The names of funding organizations were presented in the acknowledgements section. This study was approved by the Institutional Bioethics Commission (GPPG-HCPA-110308) and all subjects gave written consent to participate.

Authors’ contributions

CTH participated in the design of the study, carried out the recruitment, interviews and clinical studies, and helped to draft the manuscript. FSP carried out the molecular genetic studies, participated in the analysis, and helped to draft the manuscript. PS carried out the SSEP studies and participated in the analysis. PS and VTF carried out peripheral neurophysiology studies and participated in the analysis of the data. DMC performed VLCFA analyses and helped in the coordination of data. CRV performed VLCFA analyses and helped in the acquisition of funding. VT performed NSE analyses and participated in the analysis of data. LVP performed NSE studies and helped in the acquisition of funding. UM participated in the molecular analysis and in the coordination of data, and helped to draft the manuscript. VLT performed the statistical analyses, and helped to draft the manuscript. LBJ conceived the study, participated in the design and coordination of the study, helped to perform the statistical analysis, and drafted the manuscript. All authors read and approved the final manuscript.

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Author notes

    Authors and Affiliations

    1. Post-Graduation Programs in Genetics and Molecular Biology, Porto Alegre, Brazil

      Clarissa Troller Habekost, Ursula Matte & Laura Bannach Jardim

    2. Post-Graduation Programs in Genetics and Biochemistry, Porto Alegre, Brazil

      Carmen Regla Vargas, Vitor Torrez & Luis Valmor Portela

    3. Department of Biochemistry, Porto Alegre, Brazil

      Luis Valmor Portela

    4. Department of Analysis, Porto Alegre, Brazil

      Carmen Regla Vargas

    5. Department of Internal Medicine, Porto Alegre, Brazil

      Pedro Schestatsky & Laura Bannach Jardim

    6. Department of Statistics, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

      Vanessa Leotti Torman

    7. Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Rua Ramiro Barcelos 2350, 90.035-903, Porto Alegre, Brazil

      Carmen Regla Vargas, Daniella Moura Coelho & Laura Bannach Jardim

    8. Neurology Service, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil

      Pedro Schestatsky & Vitor Torres Felix

    9. Laboratory of Genetic Identification, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil

      Fernanda Santos Pereira & Laura Bannach Jardim

    10. Laboratory of Gene Therapy, Hospital de Clínicas de Porto Alegre, Rio Grande do Sul, Brazil

      Ursula Matte

    11. Laboratório de Neurociências Clínicas, Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas, Centro, Brazil

      Jean Pierre Oses

    12. Instituto Nacional de Genética Médica Populacional (INAGEMP), Porto Alegre, Brazil

      Clarissa Troller Habekost, Ursula Matte & Laura Bannach Jardim

    Authors
    1. Clarissa Troller Habekost
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    2. Fernanda Santos Pereira
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    3. Carmen Regla Vargas
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    4. Daniella Moura Coelho
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    7. Luis Valmor Portela
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    8. Pedro Schestatsky
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    9. Vitor Torres Felix
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    10. Ursula Matte
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    12. Laura Bannach Jardim
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    Corresponding author

    Correspondence to Laura Bannach Jardim.

    Additional information

    Clarissa Troller Habekost and Fernanda Santos Pereira contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplemental file 1

    The SSPROM scale (PDF 123 kb)

    Supplemental file 2

    Individual raw data obtained from SSPROM and JOA scales (XLS 35 kb)

    Supplemental Figure 1

    The progression rate of the clinical scales, described by their Growth Curves, according to VLCFA obtained at baseline. Figure 1a: the progression rate of JOA according to disease duration, in years, and according to the percentiles obtained for the VLCFA discriminant factor - the lower the VLCFA, the lower the JOA scores at the start of the symptoms. Figure 1b: the progression rate of SSPROM to disease duration, in years, and according to the percentiles obtained for the C26:0/C22:0 ratio - the lower the ratio, the lower the SSPROM scores at the start of the symptoms. (GIF 101 kb)

    High Resolution Image (TIFF 109 kb)

    Supplemental Figure 2

    The progression rate of SSPROM, described by a Growth Curve, to disease duration, in years, and according to the X chromosome inactivation patterns obtained at baseline. Figure 2A depicts the progression rate of SSPROM according to the median and to percentiles 25 and 75 for the inactivation ratios (p = 0.009). Figure 2B depicts the curves of the 4 more skewed against the remaining women (p = 0.008). (GIF 99 kb)

    High Resolution Image (TIFF 106 kb)

    Supplemental Figure 3

    Capillary electrophoresis of ABCD1 PCR from leukocyte DNA (upper panel) and cDNA (lower panel) in women with most skewed X-inactivation. Note that on DNA samples, peak height at heterozygote sites are roughly the same, whereas on cDNA peak height is markedly different showing preferential expression of the mutant alleles. (GIF 269 kb)

    High Resolution Image (TIFF 191 kb)

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    Habekost, C.T., Pereira, F.S., Vargas, C.R. et al. Progression rate of myelopathy in X-linked adrenoleukodystrophy heterozygotes. Metab Brain Dis 30, 1279–1284 (2015). https://doi.org/10.1007/s11011-015-9672-2

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    • DOI: https://doi.org/10.1007/s11011-015-9672-2

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