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Expanding the genotype-phenotype spectrum of ISCA2-related multiple mitochondrial dysfunction syndrome-cavitating
Tamar Gur Hartman1,2, Keren Yosovich3, Hila Gur Michaeli3
1Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel.
Abstract:
Iron-sulfur cluster assembly 2 (ISCA2)-related multiple mitochondrial dysfunction syndrome 4 (MMDS4) is a fatal autosomal recessive mitochondrial leukoencephalopathy. The disease typically manifests with rapid neurodevelopmental deterioration during the first months of life leading to a vegetative state and early death. MRI demonstrates a demyelinating leukodystrophy. We describe an eleven-year-old boy with a milder phenotype of ISCA2 related disorder manifesting as: normal early development, acute infantile neurologic deterioration leading to stable spastic quadriparesis, optic atrophy and mild cognitive impairment. The first MRI demonstrated a diffuse demyelinating leukodystrophy. A sequential MRI revealed white matter rarefaction with well-delineated cysts. The patient harbors two novel bi-allelic variants (p.Ala2Asp and p.Pro138Arg) in ISCA2 inherited from heterozygous carrier parents. This report expands the clinical spectrum of ISCA2-related disorders to include a milder phenotype with a longer life span and better psychomotor function and cavitating leukodystrophy on MRI. We discuss the possible genetic explanation for the different presentation.
Insights
Iron-sulfur cluster assembly 2 (ISCA2) gene variants cause mitochondrial leukoencephalopathy. A milder phenotype presents with unique MRI findings and a longer lifespan, expanding the known clinical spectrum.
Area of Science:
- Genetics
- Neuroscience
- Mitochondrial Biology
Background:
- Iron-sulfur cluster assembly 2 (ISCA2)-related multiple mitochondrial dysfunction syndrome 4 (MMDS4) is a severe, fatal mitochondrial leukoencephalopathy.
- Typically presents in infancy with rapid neurodevelopmental decline, leading to a vegetative state and early death, characterized by demyelinating leukodystrophy on MRI.
Observation:
- A unique case of an 11-year-old boy with a milder ISCA2-related disorder is presented.
- Manifestations included normal early development followed by acute neurological deterioration, resulting in stable spastic quadriparesis, optic atrophy, and mild cognitive impairment.
- Initial MRI showed diffuse demyelinating leukodystrophy, with subsequent scans revealing white matter rarefaction and cysts.
Findings:
- The patient carries two novel bi-allelic variants in the ISCA2 gene: p.Ala2Asp and p.Pro138Arg.
- These variants were inherited from heterozygous carrier parents.
Implications:
- This case expands the clinical spectrum of ISCA2-related disorders, demonstrating a milder phenotype with prolonged survival and better psychomotor function.
- The findings highlight cavitating leukodystrophy as a potential MRI characteristic in milder forms.
- Further research into genotype-phenotype correlations may explain the diverse clinical presentations of ISCA2-related disorders.
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