ISCA2 plays a role in the biogenesis of Fe–S clusters and a recent report described subjects displaying infantile‐onset leukodystrophy due to bi‐allelic mutation of ISCA2. We present two additional unrelated cases, and provide a more complete clinical description that includes hyperglycinemia, leukodystrophy of the brainstem with longitudinally extensive spinal cord involvement, and mtDNA deficiency. Here, ISCA2 is linked to leukodystrophy.