ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder

Area of Science:

• Genetics
• Neuroscience
• Mitochondrial Biology

Background:

• Mitochondrial disorders stem from numerous nuclear genes, often presenting complex and unsolved etiologies.
• Investigated an autosomal recessive syndrome characterized by leukodystrophy and neuroregression in six patients from five families.

Purpose of the Study:

• To identify the genetic cause of a novel autosomal recessive leukodystrophy and neuroregression syndrome.

Main Methods:

• Comprehensive examinations including neurological, radiological, genetic, metabolic, and dysmorphological assessments.
• Utilized exome sequencing, autozygosity mapping, Sanger sequencing, microsatellite haplotyping, karyotyping, and whole mitochondrial DNA sequencing.
• Performed various molecular and microscopic analyses on patient tissue samples.

Main Results:

• Identified a homoallelic missense founder mutation in the ISCA2 gene.
• Observed mitochondrial depletion, reduced complex I activity, and decreased expression of ISCA2, ISCA1, and IBA57 in patient fibroblasts.
• MRI revealed consistent white matter abnormalities; skeletal muscle histology showed myofiber size variation and atrophy.

Conclusions:

• ISCA2 deficiency is demonstrated to cause a hereditary mitochondrial neurodegenerative white matter disease presenting in infancy.
• This finding elucidates the genetic basis for a specific type of leukodystrophy.