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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)805-812
Number of pages8
JournalMetabolic Brain Disease
Volume33
Issue number3
DOIs
Publication statusPublished - Jun 1 2018

Fingerprint

Leukoencephalopathies
Sulfur
Lactic Acid
Brain
Iron
Genes
Phenotype
Mutation
Spinal Cord
Mitochondrial Diseases
Muscle Hypotonia
Eye movements
Corpus Callosum
Missense Mutation
Electron Transport
Neurodegenerative Diseases
Brain Stem
Spectrum Analysis
Spectroscopy
Fluids

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate : expanding the phenotype of ISCA2 gene mutations. / Toldo, Irene; Nosadini, Margherita; Boscardin, Chiara; Talenti, Giacomo; Manara, Renzo; Lamantea, Eleonora; Legati, Andrea; Ghezzi, Daniele; Perilongo, Giorgio; Sartori, Stefano.

In: Metabolic Brain Disease, Vol. 33, No. 3, 01.06.2018, p. 805-812.

Research output: Contribution to journalArticle

Toldo, Irene ; Nosadini, Margherita ; Boscardin, Chiara ; Talenti, Giacomo ; Manara, Renzo ; Lamantea, Eleonora ; Legati, Andrea ; Ghezzi, Daniele ; Perilongo, Giorgio ; Sartori, Stefano. / Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate : expanding the phenotype of ISCA2 gene mutations. In: Metabolic Brain Disease. 2018 ; Vol. 33, No. 3. pp. 805-812.
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AU - Manara, Renzo

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AU - Perilongo, Giorgio

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AB - 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.

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