Metabolic Brain Disease

, Volume 33, Issue 3, pp 805–812 | Cite as

Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations

  • Irene Toldo
  • Margherita Nosadini
  • Chiara Boscardin
  • Giacomo Talenti
  • Renzo Manara
  • Eleonora Lamantea
  • Andrea Legati
  • Daniele Ghezzi
  • Giorgio Perilongo
  • Stefano Sartori
Original Article

Abstract

A homoallelic missense founder mutation of the iron-sulfur cluster assembly 2 (ISCA2) gene has been recently reported in six cases affected by an autosomal recessive infantile neurodegenerative mitochondrial disorder. We documented a case of a 2-month-old girl presenting with severe hypotonia and nystagmus, who rapidly deteriorated and died at the age of three months. Increased cerebral spinal fluid level of lactate, documented also at the brain spectroscopy, involvement of the cortex, restricted diffusion of white and gray matter abnormalities, sparing of the corpus callosum and extensive involvement of the spinal cord were observed. Her clinical presenting features and course as well as some neuroradiological findings mimicked those of early-onset leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate (LBSL). The analysis of the mitochondrial respiratory chain function showed a reduced activity of complexes II and IV. The girl harboured two heterozygous mutations in the ISCA2 gene. A comprehensive review of the literature and a comparison with the cases of early onset LBSL enabled us to highlight significant differences in the clinical, biochemical and neuroradiological phenotype between the two conditions, which also emerged from the comparison with the other 6 reported cases of ISCA2 gene mutation previously reported. In summary, this represents the second report ever published associating ISCA2 gene mutation with a mitochondrial leukoencephalopathy, with a different genetic mechanism to the previous cases. Molecular analysis of ISCA2 should be included in the genetic panel for the diagnosis of early onset mitochondrial leukoencephalopathies.

Keywords

ISCA2 gene Leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate Early-onset LBSL Mitochondrial disorder DARS2 gene 

Notes

Acknowledgements

The Authors thank the parents of the child and Dr. Isabella Mammi for their kind co-operation.

Funding

The work of EL, AL and DG is supported by Pierfranco and Luisa Mariani Foundation (CM23).

Supplementary material

11011_2017_181_MOESM1_ESM.doc (36 kb)
ESM 1 (DOC 36 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Irene Toldo
    • 1
  • Margherita Nosadini
    • 1
  • Chiara Boscardin
    • 1
  • Giacomo Talenti
    • 2
  • Renzo Manara
    • 3
  • Eleonora Lamantea
    • 4
  • Andrea Legati
    • 4
  • Daniele Ghezzi
    • 4
    • 5
  • Giorgio Perilongo
    • 1
  • Stefano Sartori
    • 1
  1. 1.Pediatric Neurology Unit, Department of Women’s and Children’s HealthUniversity Hospital of PaduaPaduaItaly
  2. 2.Neuroradiology Unit, Department of Neurological SciencesUniversity Hospital of PaduaPaduaItaly
  3. 3.NeuroradiologyUniversity of SalernoSalernoItaly
  4. 4.Unit of Molecular NeurogeneticsFoundation IRCCS Institute of Neurology ‘Carlo Besta’MilanItaly
  5. 5.Department of Pathophysiology and TransplantationUniversity of MilanMilanItaly

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