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Adult-onset autosomal dominant leukodystrophy without early autonomic dysfunctions linked to lamin B1 duplication: a phenotypic variant

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Abstract

The early presentation of autonomic dysfunctions at the disease onset has been considered the mandatory clinical feature in adult-onset autosomal dominant leukodystrophy, which is a rarely recognised leukodystrophy caused by duplication of the lamin B1 gene. We report the first family with adult-onset autosomal dominant leukodystrophy and lamin B1 duplication, without the distinguishing early-appearing autonomic dysfunctions. Subjects from three consecutive generations of a multi-generational Serbian family affected by adult-onset autosomal dominant leukodystrophy underwent clinical, biochemical, neurophysiological, neuroradiological, and genetic studies. The patients atypically exhibited late autonomic dysfunctions commencing at the disease end-stages in some. Genetic findings of lamin B1 duplication verified adult-onset autosomal dominant leukodystrophy, which was supported also by neuroimaging studies. Exclusively, proton magnetic spectroscopy of the brain revealed a possibility of neuro-axonal damage in the white matter lesions, while magnetic resonance imaging of the spinal cord excluded spinal myelin affection as a required finding in this leukodystrophy. The detection of lamin B1 duplication, even when autonomic dysfunctions do not precede the other symptoms of the disease, proves for the first time that lamin B1-duplicated adult-onset autosomal dominant leukodystrophy may have a phenotypic variant with delayed autonomic dysfunctions. Prior to this report, such a phenotype had been speculated to represent an entity different from lamin B1-duplicated leukodystrophy. Hereby we confirm the underlying role of lamin B1 duplication, regardless of the autonomic malfunction onset in this disorder. It is the only report on adult-onset autosomal dominant leukodystrophy from Southeastern Europe.

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Acknowledgments

This study was supported by grants from Telethon Foundation (GGP09301), the Italian Ministry of Health (RF-2009-1539841), and from the Ministry of Science of the Republic of Serbia (Grant No. 175022). The grants supported the genetic and neuroradiological investigations of the study. The authors thank the patients for participating in the study.

Conflicts of interest

On behalf of all the authors, the corresponding author states that there is no conflict of interest. Aleksandra M. Pavlovic, MD, PhD, receives grants from the following nonprofit funding agencies: Ministry of Science of the Republic of Serbia (Grant No. 175022). Dusko Kozic, MD, PhD, receives grants from the following nonprofit funding agencies: Ministry of Science of the Republic of Serbia (Grant No. 175022) and Provincial Secretariat of Science and Technological Development of Province of Vojvodina, Serbia (Scientific Project Grant 114-451-2255/2011). Jelena Ostojic, PhD, receives grants from the following nonprofit funding agencies: Ministry of Science of the Republic of Serbia (grant number 175022) and Provincial Secretariat of Science and Technological Development of Province of Vojvodina, Serbia (Scientific project grant 114-451-2255/2011). Nadezda Sternic, MD, PhD, receives grants from the following nonprofit funding agencies: Ministry of Science of the Republic of Serbia (Grant No. 175022). Franco Taroni, MD, receives grants from the following nonprofit funding agencies: Telethon Foundation (grant number GGP09301), Italian Ministry of Health (Grant No. RF-2009-1539841) and European Union E-Rare-2 JTC 2011 (grant Euro-SCAR). All the other authors (Dr. Ana Potic, Dr. Graziella Uziel, Dr. Attilio Rovelli, Dr. Mladen Bjelan, Elisa Sarto and Dr. Daniela Di Bella) declare no financial disclosures.

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All human studies must state that they have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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Authors and Affiliations

  1. Medical Faculty, Clinic for Child Neurology and Psychiatry, University of Belgrade, 6A Dr. Subotica Street, Belgrade, 11000, Serbia

    Ana Potic

  2. Medical Faculty, Clinic for Neurology, University of Belgrade, 6 Dr. Subotica Street, Belgrade, 11000, Serbia

    Aleksandra M. Pavlovic & Nadezda Sternic

  3. Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Via Celoria 11, Milan, 20133, Italy

    Graziella Uziel, Elisa Sarto, Daniela Di Bella & Franco Taroni

  4. Faculty of Medicine, Oncology Institute of Vojvodina, Diagnostic Imaging Center, University of Novi Sad, Institutski Put 4, Sremska Kamenica, 21204, Novi Sad, Serbia

    Dusko Kozic & Mladen Bjelan

  5. Faculty of Medicine, Clinical Center of Vojvodina, Center of Radiology, University of Novi Sad, 1-7 Hajduk Veljkova Street, Novi Sad, 21000, Serbia

    Jelena Ostojic

  6. Department of Pediatrics, Fondazione MBBM Ospedale San Gerardo, University of Milano-Bicocca, Via Pergolesi 33, Monza, 20900, Italy

    Attilio Rovelli

Authors
  1. Ana Potic
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  2. Aleksandra M. Pavlovic
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  3. Graziella Uziel
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  4. Dusko Kozic
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  5. Jelena Ostojic
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  6. Attilio Rovelli
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  7. Nadezda Sternic
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  8. Mladen Bjelan
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  9. Elisa Sarto
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  10. Daniela Di Bella
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  11. Franco Taroni
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Corresponding author

Correspondence to Ana Potic.

Additional information

A. Potic and A. M. Pavlovic equally contributed to the manuscript.

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Potic, A., Pavlovic, A.M., Uziel, G. et al. Adult-onset autosomal dominant leukodystrophy without early autonomic dysfunctions linked to lamin B1 duplication: a phenotypic variant. J Neurol 260, 2124–2129 (2013). https://doi.org/10.1007/s00415-013-6958-3

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  • DOI: https://doi.org/10.1007/s00415-013-6958-3

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