Further delineation of the phenotypic spectrum of ISCA2 defect: A report of ten new cases

Eur J Paediatr Neurol. 2018 Jan;22(1):46-55. doi: 10.1016/j.ejpn.2017.10.003. Epub 2017 Oct 16.


Iron-Sulfur Cluster (ISC) biogenesis is a vital cellular process required to produce various ISC-containing proteins. These ISC proteins are responsible for essential functions such as glycine cleavage and the formation of lipoic acid, an essential cofactor of respiratory chain complexes. Defects in ISC biogenesis lead to multiple mitochondrial dysfunction syndromes including: ISCA2 with infantile onset leukodystrophy. Recently, a founder mutation, c.229G > A, p.Gly77Ser in ISCA2 was reported to cause Multiple Mitochondrial Dysfunction Syndrome type 4. In a retrospective review of children diagnosed with the ISCA2 defect, we were able to identify ten new patients who were not reported previously with the identical founder mutation. High CSF glycine levels and elevated glycine peaks on MR spectroscopy were demonstrated in all tested probands. All patients were between 3 and 7 months of age with a triad of neurodevelopmental regression, nystagmus and optic atrophy and leukodystrophy. MRI findings were typical in the patients with diffuse, abnormal white matter signal in the cerebrum, cerebellum, brain stem and spinal cord. The patients ended up in a vegetative state, and often premature death due to respiratory infections. We alert clinicians to consider the ISCA2 defect as a differential diagnosis of infantile onset leukodystrophies affecting the brain as well as the spinal cord, especially in the presence of elevated CSF glycine or elevated glycine peaks in MR spectroscopy.

Keywords: Hypotonia; ISCA2; Mitochondrial disease; Neurodevelopmental regression; White matter.

MeSH terms

  • Brain / pathology*
  • Female
  • Humans
  • Infant
  • Iron-Sulfur Proteins / genetics*
  • Leukodystrophy, Metachromatic / genetics
  • Leukodystrophy, Metachromatic / pathology
  • Magnetic Resonance Imaging
  • Male
  • Mitochondrial Diseases / genetics
  • Mitochondrial Diseases / pathology*
  • Phenotype
  • Retrospective Studies
  • Spinal Cord / pathology*
  • White Matter / pathology*


  • Iron-Sulfur Proteins

Supplementary concepts

  • Multiple Mitochondrial Dysfunctions Syndrome